Category Archives: Massachusetts Stem Cells

Sheldon Krimsky, a leading scholar of environmental ethics who explored issues at the nexus of science, ethics and biotechnology, and who warned of the perils of private companies underwriting and influencing academic research, died on April 23 in Cambridge, Mass. He was 80.

His family said that he was at a hospital for tests when he died, and that they did not know the cause.

Dr. Krimsky, who taught at Tufts University in Massachusetts for 47 years, warned in a comprehensive way about the increasing conflicts of interest that universities faced as their academic researchers accepted millions of dollars in grants from corporate entities like pharmaceutical and biotechnology companies.

In his book Science in the Private Interest (2003), he argued that the lure of profits was potentially corrupting research and in the process undermining the integrity and independence of universities.

But his wide-ranging public policy work went way beyond flagging the dangers inherent in the commercialization of science. The author, co-author or editor of 17 books and more than 200 journal articles, he delved into numerous scientific fields stem-cell research, genetic modification of food and DNA privacy among them and sought to pinpoint potential problems.

He was the Ralph Nader of bioethics, Jonathan Garlick, a stem-cell researcher at Tufts and a friend of Dr. Krimsky, said in a phone interview, referring to the longtime consumer advocate.

He was saying, if we didnt slow down and pay attention to important check points, once you let the genie out of the bottle there might be irreversible harm that could persist across many generations, Dr. Garlick added. He wanted to protect us from irreversible harm.

In Genetic Justice (2012), Dr. Krimsky wrote that DNA evidence is not always reliable, and that government agencies had created large DNA databases that posed a threat to civil liberties. In The GMO Deception (2014), which he edited with Jeremy Gruber, he criticized the agriculture and food industries for changing the genetic makeup of foods.

His last book, published in 2021, was Understanding DNA Ancestry, in which he explained the complications of ancestry research and said that results from different genetic ancestry testing companies could vary in their conclusions. Most recently, he was starting to explore the emerging subject of stem-cell meat meat made from animal cells that can be grown in a lab.

Mr. Nader, in fact, had a long association with Dr. Krimsky and wrote the introduction to some of his books.

There was really no one like him: rigorous, courageous, and prolific, Mr. Nader said in an email. He tried to convey the importance of democratic processes in open scientific decision making in many areas. He criticized scientific dogmas, saying that science must always leave open options for revision.

Sheldon Krimsky was born on June 26, 1941, in Brooklyn. His father, Alex, was a house painter. His mother, Rose (Skolnick) Krimsky, was a garment worker.

Sheldon, known as Shelly, majored in physics and math at Brooklyn College and graduated in 1963. He earned a Master of Science degree in physics at Purdue University in 1965. At Boston University, he earned a Master of Arts degree in philosophy in 1968 and a doctorate in the philosophy of science in 1970.

He is survived by his wife, Carolyn Boriss-Krimsky, a playwright, artist and author, whom he married in 1970; a daughter, Alyssa Krimsky Clossey; a son, Eliot; three grandchildren; and a brother, Sidney.

Dr. Krimsky began his association with Tufts in what is now called the Department of Urban and Environmental Policy and Planning in 1974 and helped build it up over the decades. He also taught ethics at the Tufts University School of Medicine and was a visiting scholar at Columbia University, Brooklyn College, the New School and New York University.

He began to explore the conflicts of interest in academic research in the late 1970s, when he led a team of students on an investigation into whether the chemical company W.R. Grace had contaminated drinking wells in Acton, Mass.

Dr. Krimsky has said that when the company learned that he would be releasing a negative report the wells were later designated a Superfund site one of its top executives asked the president of Tufts to bury the study and fire him. The president refused. But Dr. Krimsky was disturbed that the company had tried to interfere, and it prompted him to begin studying how corporations, whether or not they had made financial contributions, sought to manipulate science.

He spoke truth to power, Dr. Garlick said. He wanted to give voice to skepticism and give voice to the skeptics.

Dr. Krimsky was a longtime proponent of what he called organized skepticism.

When claims are made, you have to start with skepticism until the evidence is so strong that your skepticism disappears, he told The Boston Globe in 2014. You dont in science start by saying, Yes, I like this hypothesis, and it must be true.

He was a fellow of the American Association for the Advancement of Science and headed its committee on scientific freedom and responsibility from 1988 to 1992. He was also a fellow of the Hastings Center, a bioethics research institute in Garrison, N.Y., and served on the editorial boards of seven scientific journals.

When he wasnt working, he liked to play the guitar and harmonica. He divided his time between Cambridge and New York City.

Shelly never gave up hope of a better world, Julian Agyeman, a professor in Dr. Krimskys department and its interim chairman, was quoted as saying in a Tufts obituary. He was the consummate activist-advocate-scholar.

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Sheldon Krimsky, Who Warned of Profit Motive in Science, Dies at 80 - The New York Times

This love story is straight out of a Nicholas Sparks or John Green tear-jerker.

Alexis Gould Stafford, 21, was undergoing chemotherapy at a childrens hospital when she met her future husband, Ricky Stafford, 23, who was in remission and there for a check-up.

Our story is similar to The Faultin Our Stars,' Alexis told Kennedy News, comparing their courtship to the 2014 movie about a teenage couple who meet and fall in love in a cancer support group. But its not a very happy movie when I think back on my life and on our story its a happy story and thats the difference.

The couple met at Primary Childrens Hospital in Salt Lake City, Utah, in 2016, after Alexis, then 15, heard music blasting from then 17-year-old Rickys room.

I thought it was going to be a little boy but Ricky was tall with dark thick hair he was in remission at the time. He came out and started dancing and introducing himself and we became friends right away, Alexis said.

Alexis had been diagnosed with stage four neuroblastoma cancer of the nerves in September 2015 and spent much of the next 17 months as an in-patient, enduring six rounds of intense chemo, four major surgeries, two stem cell transplants and countless other treatments.

Ricky had been diagnosed with acute lymphoblastic leukemia cancer affecting white blood cells in February 2014 and underwent five months of intense chemo followed by two years of oral chemo.

I was feeling alone because most of the kids at the hospital were young, so to have somebody who was around my age and knew what I was going through just made everything so much easier, Alexis said.

The teens quickly became best friends as they bonded over their illness and being two of the oldest kids in the hospital.

The two continued their friendship as Ricky visited Alexis in the hospital while she underwent treatment over the next year.

As a teenage kid, sometimes you prioritize physical traits but in that situation, Lexi was bald and really small and skinny and didnt have any eyelashes or anything like that. But what drew me to her was just her smile and the spirit that accommodated her she just has a way of making people feel loved without even saying anything, Ricky shared.

I was very aware she was in the middle of something very heavy, having just gone through cancer myself not too long before.

Unfortunately, Rickys health deteriorated and his cancer returned the next year while he was in Boston, Massachusetts, on a mission for the Church of Jesus Christ of Latter-Day Saints in April 2017.

Alexis wanted to support her best friend as he had done for her and began flying to Boston to be with him. Thats when the two realized their true feelings for one another and fell in love.

It made all the difference in the world to have her there through my cancer journey, Ricky said.

Having someone there who you love and loves you is kind of essential when youre going through trials in life. It makes you want to fight harder but it also makes the journey easier because youre not enduring the pain by yourself, youre sharing some of that weight.

Wanting to take advantage of every bit of life they had left, Ricky proposed to Alexis just two months into dating. He popped the question on the anniversary of his leukemia diagnosis, Feb. 24, 2018.

Despite his ongoing battle with cancer, the couple was married on Sept. 15 of that year the anniversary of the day Alexis was diagnosed with cancer at 18 and 19 years old.

I think I was a little bit selfish asking her to marry me at that moment because I had just been diagnosed with cancer again and I didnt have a job or a game plan. But I asked her to marry me because I needed someone who understood what I was going through to be there for me because I was scared, Ricky said of the decision.

A lot of people would run from a situation like that but Lexi didnt run and Im so grateful for that.

Alexis was not expecting the proposal but was happy to accept and begin her life with Ricky. We knew that life isnt always promised and we decided to spend what time we have together, Alexis said.

He surprised me and proposed on the day of the anniversary of when he was diagnosed and then we got married on my diagnosis day we took the hard dates and made them a reason to smile, she added.

The couple began their engagement during Rickys relapse, but he was able to finish his intense chemo treatment just two months before they tied the knot. He continued to take oral steroids for another two years and finally went into remission in January 2020.

But the Staffords struggles werent over yet. Several months after Ricky began remission, Alexis health took another turn for the worse that December. She began to bleed internally while having biopsies done to test for a potential tumor, and by January 2021 she was in hospice.

Fortunately after three months, with the consistent support of her best friend-turned-husband, Alexis beat the odds yet again, recovering enough to be discharged.

Im five years cancer-free now and Ricky is technically in remission but in a couple of years hell be confirmed cancer-free as well, she said.

Now were just focusing on spending whatever time we have together and making the most out of life.

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We met during cancer treatments, fell in love and got married - New York Post

Animals carry "mutational clocks" in their cells that dictate how quickly their DNA picks up mutations. And across species, animals tend to die once they've hit a certain number of mutations, new research finds.

It turns out that, in long-lived mammals like humans, these mutational clocks tick slower than they do in short-lived mammals like mice, meaning humans reach that threshold number of mutations at a later age than mice do. This discovery, the researchers said, could help solve a long-standing mystery in biology.

This mystery, known as Peto's paradox, describes a perplexing phenomenon that has defied explanation since the 1970s. At that time, scientists knew that animal cells accrued mutations in their DNA over time, and that as the number of mutations increased, so too did the risk of those cells turning cancerous. On paper, this suggests that the world's longest-living and largest animals should face the highest risk of cancer, because the chance of picking up cancer-causing mutations increases over time and as the total number of cells in an organism goes up.

But oddly enough, large, long-lived animals develop cancer at similar rates as tiny, short-lived creatures this is Peto's paradox. Now, in a new study, published April 13 in the journal Nature, scientists offer a partial potential solution to this puzzle: They discovered that short- and long-lived mammals both accumulate a similar number of genetic mutations over their lifespans, but the long-lived animals do so at a far slower rate.

"I was really surprised" at the strength of the relationship between lifespan and mutation rate in different species, said Alex Cagan, a staff scientist at the Wellcome Sanger Institute in England and first author of the study. The study results help explain one aspect of Peto's paradox, by showing that having a lengthy lifespan doesn't put animals at higher risk of cancer-causing mutations. However, the authors didn't find a strong link between animals' body masses and their mutational clocks, so their results don't address the question of why big animals don't have high rates of cancer.

Related: Scientists discover 4 distinct patterns of aging

The results do support the theory that animals age, at least in part, due to the build-up of mutations in their cells over time although the study doesn't reveal exactly how the mutations contribute to the aging process, Cagan said.

"Based on our results, yes, you can tell a mammal is close to the end of its species' lifespan when it has [approximately] 3,200 mutations in its colonic epithelial stem cells," which was the specific population of cells that the team analyzed. "But we don't think that it's because at 3,201, the animal will drop dead from mutation overload," Cagan said. Rather, the authors think that the relationship between animals' mutational clocks and aging might be a bit more nuanced.

To see how quickly mutational clocks tick in different mammals, the team analyzed genetic material from 16 species: humans, black-and-white colobus monkeys, cats, cows, dogs, ferrets, giraffes, harbor porpoises, horses, lions, mice, naked mole-rats, rabbits, rats, ring-tailed lemurs and tigers. Of these species, humans have the longest lifespan at roughly 80 years; mice and rats had the shortest lifespans, between about 3 and 4 years.

From each of these species, the researchers collected DNA from "crypts," which are tiny folds found in the lining of the small intestines and colon. The cells in each crypt all descend from a single stem cell, meaning they're all clones of that stem cell. Past studies suggest that, at least in humans, crypt cells pick up mutations at a constant rate as a person ages.

In total, the researchers analyzed more than 200 crypt tissue samples from the 16 species; each sample contained a few hundred cells, Cagan noted.

"The ability to sequence the genomes of very small cell populations (e.g. those that are found within one crypt) is fairly new, so this study could not have easily been done 20 years ago," said Kamila Naxerova, an assistant professor at Harvard Medical School and a principal investigator at the Massachusetts General Hospital Center for Systems Biology, who was not involved in the study.

Related: Anti-aging vaccine shows promise in mice will it work in humans?

The team determined the total number of DNA mutations present in each sample, and by taking each animal's age into account, they were able to estimate how quickly these mutations cropped up over the organism's lifespan. In some species, including dogs, mice and cats, the team had enough samples to compare the total number of mutations in individuals of different ages for instance, a 1-year-old mouse versus a 2-year-old mouse to double-check the accuracy of their mutation rate estimates.

Through their analysis, the authors discovered that, just like in humans, the crypt cells of other mammals also accrue mutations at a constant rate, year to year. But what was striking was that this mutation rate differed drastically between species. Human crypts accumulated the lowest number of new mutations each year, at only 47, while mouse crypts picked up the most, at a whopping 796 per year.

"This difference is staggering, given the large overall similarities between human and mouse genomes," Naxerov and Alexander Gorelick, a postdoctoral fellow at Harvard Medical School and Massachusetts General Hospital, wrote in an accompanying Nature commentary on the study.

Overall, the mutation rate of each species showed an inverse correlation to its lifespan, meaning that as an animal's lifespan increased the rate of new mutations per year decreased. That ultimately meant that "the total number of mutations at the end of an animal's life was roughly similar across species," Naxerova and Gorelick noted.

The new study doesn't hint at why long-lived animals' mutational clocks tick slower than those of short-lived animals, Cagan said. That said, an earlier study, published in October 2021 in the journal Science Advances, provides one explanation.

In that study, scientists sampled fibroblasts a type of cell found in connective tissue from the lungs of mice, guinea pigs, blind mole-rats, naked mole-rats and humans and then exposed these cells to a mutagen, or a chemical that damages DNA. "Our reasoning was that cells from long-lived species may cope much better with a mutagen than cells from short-lived species," said Jan Vijg, a professor and chair of the Department of Genetics at the Albert Einstein College of Medicine and senior author of the Science Advances report.

And that's just what they found. "Cells from a short-lived mouse quickly accumulated a lot of mutations, while in the very long-lived naked mole-rat or human, the same dose of mutagen did not even induce any mutations," said Vijg, who was not involved in the new Nature study. This suggests that long-lived animals may be better at repairing DNA damage and preventing mutations than short-lived animals, and this may partially explain why they accumulate mutations at a slower rate.

One limitation of both recent studies is that they each included just one cell type intestinal crypt cells or lung fibroblasts, Vijg said. That said, analyses of additional cell types would likely turn up similar results, he said. "I would expect that the findings would generalize to most other somatic cells," meaning cells that aren't eggs or sperm, Naxerova agreed.

Related: Natural rates of aging are fixed, study suggests

Cagan and his team are launching such studies into additional tissue types now. At the same time, they're moving beyond mammals to study a wide range of vertebrates and invertebrates, to see if the same relationship holds across the animal kingdom, he said. For example, the team recently got a hold of tissue samples from a super-rare Greenland shark that washed ashore in the U.K. and may have been about 100 years old at the time of its death, he said. Scientists estimate that this species can live at least up to 272 years, Live Science previously reported.

Within that research, Cagan's team hopes to reveal how the steady accumulation of mutations actually contributes to aging assuming it does at all, Cagan said. On this front, the team has proposed a theory.

They suggest that, as all somatic cells pick up mutations over time, some of those cells will develop mutations in critical genes that would normally regulate the cells' behavior. These corrupted cells become worse at their jobs but are able to multiply more efficiently than their neighbors, the theory suggests. And as these cells take over tissues in the body, this would ultimately cause organ systems to malfunction, leading to disease and death, Cagan said.

So "it's not that every cell stops working because it's accumulated a lot of mutations," he said. Rather, problematic mutations in specific cells cause those cells to go rogue, take over tissues and crowd out all the healthier, better-functioning cells. Therefore, the mutational clock of each species likely sets the pace at which these rogue cells take over, such that "it takes a lifetime before these clonal expansions of poorly functioning cells have disrupted the tissues so much that the animal can no longer function."

Such rogue cells could be described as "selfish," since they spread to the detriment of cells around them, Naxerov and Gorelick wrote in their commentary. There's evidence from animal studies that such selfish cells can emerge in the haematopoietic system the bodily system that makes blood and drive disease by contributing to chronic inflammation, Naxerov told Live Science.

"It could be that selfish clones in other organs contribute to disease and aging as well, but I think this is largely hypothetical for now," she said.

Originally published on Live Science.

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Ticking time bombs of DNA mutation may dictate when animals die - Livescience.com

When it comes to health policy, former Utah Republican Sen. Orrin Hatch, who died Saturday at age 88, leaves a complex legacy of major legislative achievements, changing positions, compromises and fierce opposition. In many ways, though, Hatch's evolution and leadership on health policy during his four decades in the U.S. Senate mirror that of the Republican Party.

When he came to Washington as a neophyte politician after an upset victory in 1976, Hatch was a conservative firebrand, one of the early leaders of the "New Right" bent on dismantling the federal welfare state and banning abortion. A former trial lawyer, the new senator had never before held public office.

But the election of Ronald Reagan in 1980 and the Republican takeover of the Senate that made Hatch chairman of the powerful Labor and Human Resources Committee (now the Health, Education, Labor and Pensions Committee) turned him into something of a pragmatist. That pragmatism, it should be noted, was somewhat forced: Even though Hatch was technically the chair, there were enough moderate Republicans on the panel to give the ranking Democrat, Massachusetts' Edward Kennedy, effective control over what could be passed by the committee.

So Hatch learned to compromise and to legislate. In 1984, he negotiated with liberal Rep. Henry Waxman, D-Calif., what is still referred to as the "Hatch-Waxman Act." It's better known as the law that allowed, for the first time, approval of generic copies of brand-name drugs. Although far from a panacea, it is still the single-biggest advance in the fight to rein in high drug prices.

When the Democrats took back the Senate after the 1986 elections, Kennedy became chairman of the committee and Hatch, the ranking Republican. The two teamed up on a series of landmark legislative achievements, from the Ryan White program on AIDS treatment and the Americans with Disabilities Act to the first major federal child care law. And while Hatch was a strong foe of national health insurance, he and Kennedy ultimately pushed through Congress in 1997 the bill to create the Children's Health Insurance Program, which provides low-cost health insurance for low-income families who don't qualify for Medicaid.

The stridently anti-abortion Hatch was outspoken about his support for federal funding for research on embryonic stem cells derived from aborted fetuses. "I think it's the ultimate pro-life position, because I believe being pro-life is not just caring for the unborn but caring for those who are living," he told NPR in 2007.

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But like much of the Republican Party in Congress, Hatch returned to his conservative roots after the election of President Barack Obama in 2008. A supporter of the so-called individual mandate requiring people to have health insurance when it was the quasi-official GOP position in the early 1990s, Hatch became an outspoken foe. "Congress has never crossed the line between regulating what people choose to do and ordering them to do it," he said in 2010.

After moderate Utah Republican Sen. Robert Bennett was ousted in a primary in 2010 and replaced by conservative favorite Mike Lee, Hatch grew more conservative to win reelection in 2012. His final term in the Senate was marked by efforts to overturn the Affordable Care Act and further restrict abortion access. The devout Mormon, who in his spare time wrote lyrics for best-selling Christian music, even called the ACA "the stupidest, dumb-a** bill that I've ever seen. Now some of you may have loved it; if you do, you are one of the stupidest dumb-a** people I've ever met." He later apologized for the statement.

A former Kennedy aide, Jim Manley, told The Salt Lake Tribune that "no one epitomizes the rightward lurch of the Republican Party more than Sen. Hatch."

In one final twist, however, Hatch pushed as his successor the 2012 GOP presidential nominee, Mitt Romney. In just his first few years, Romney has become one of the most moderate Republicans in the chamber. That may prove to be Orrin Hatch's final legacy.

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. It is an editorially independent operating program of KFF (Kaiser Family Foundation).

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Sen. Orrin Hatch's legacy tracks the GOP's evolution on health - Wisconsin Public Radio

Nat Med. Author manuscript; available in PMC 2015 Mar 13.

Published in final edited form as:

PMCID: PMC4358898

NIHMSID: NIHMS667490

1Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology and Development, Rockefeller University, New York, New York, USA.

1Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology and Development, Rockefeller University, New York, New York, USA.

1Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology and Development, Rockefeller University, New York, New York, USA.

1Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology and Development, Rockefeller University, New York, New York, USA.

2Present address: Department of Stem Cell and Regenerative Biology & Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA.

The skin protects mammals from insults, infection and dehydration and enables thermoregulation and sensory perception. Various skin-resident cells carry out these diverse functions. Constant turnover of cells and healing upon injury necessitate multiple reservoirs of stem cells. Thus, the skin provides a model for studying interactions between stem cells and their microenvironments, or niches. Advances in genetic and imaging tools have brought new findings about the lineage relationships between skin stem cells and their progeny and about the mutual influences between skin stem cells and their niches. Such knowledge may offer novel avenues for therapeutics and regenerative medicine.

Adult stem cells reside in niches that provide spatially distinct microenvironments for stem cell maintenance and function. The conceptual framework for stem cell niches, their compositions and their operating logistics is constantly being updated. Initially, niches were thought to be composed solely of heterologous cell populations that originate from a lineage different from the stem cells they regulate1. Recent studies have added several important modifications: differentiated progeny and stem cells can coexist within a niche, suggesting that niche signals alone are not sufficient to dictate stemness2,3; downstream progeny of stem cells can regulate their stem cell parents and thus become a component of the niche4,5; and communications between stem cells and their niches are reciprocal, as stem cells may also regulate the assembly and maintenance of their niches6.

The skin is a complex organ harboring several distinct populations of stem cells and a rich array of cell types (), making it an ideal model for studying the interplay between stem cells and their niches. The outermost layer is the epidermis, a stratified structure that is maintained by stem cells located at the most basal layer and acts as a protective barrier. Underneath the epidermis is the dermis, enriched for dermal fibroblasts that produce collagens and elastic fibers of extracellular matrix (ECM) and give the skin its elasticity. Below the dermis lies the subcutaneous fat, which acts as protective padding, insulation and an energy reservoir.

The skin: an organ with a diverse array of cell types. The hair follicle is a complex appendage of the epidermis. It is composed of an infundibulum that opens to the skin surface, sebaceous glands, and the junctional zone between the glands and the bulge. Hair follicle and melanocyte stem cells reside in the bulge and the hair germ. In full anagen, hair follicle stem cells regenerate the lower two-thirds of the follicle, including the matrix, which produces the hair and its channel. Melanocyte stem cells generate mature melanocytes, which transfer their pigment to differentiating hair cells. The hair follicle also serves as a hub attracting peripheral nerves, blood vessels and arrector pili muscles. The dermis is populated with dermal fibroblasts and various immune cells such as mast cells, dendritic cells and T cells. Deeper in the dermis is a layer of subcutaneous adipocytes.

Hair follicles are notable appendages of the epidermis. In addition to generating hairs that facilitate thermal regulation, hair follicles also serve as anchors for sensory neurons, arrector pili muscles (APMs) and blood vessels. Hair follicles undergo cycles of regeneration and rest driven by stem cells located in a region known as the bulge, and in a cluster of cells below the bulge known as the hair germ. Melanocyte stem cells (MSCs) are intermingled with hair follicle stem cells (HFSCs) in the bulge and the hair germ. The MSCs generate mature melanocytes that produce melanin, which absorbs ultraviolet (UV) light to prevent DNA damage and gives skin and hairs their distinctive colors.

In this Review, we focus on various stem cell populations in the skin, summarizing and comparing recent advances in research on skin stem cell niches that have contributed to the emergence of new concepts. We summarize the niche components and signals that regulate the behavior of epidermal stem cells, HFSCs and MSCs. In addition, we discuss how the dynamics of stem cellniche interactions change during aging, wounding, skin cancer initiation and malignant progression. Lastly, we discuss the clinical implications of recent findings and how studying the stem cell niche might shape the future of regenerative medicine.

In mammals, the skins protective barrier is composed of a stratified epidermis (). The interfollicular epidermis (IFE) between hair follicles is exposed to many external insults, such as UV light, chemicals, allergens and traumatic injuries. To withstand these physical stresses, the epidermal cells, called keratinocytes, form a dense cytoskeletal infrastructure of 10-nm intermediate filaments composed of the keratin subfamily of proteins. Keratin filaments are highly enriched in the vertebrate epidermis and its appendages, but not in the surface epithelium of organisms such as insects, which instead secrete a protective outer shell.

Interfollicular epidermis: architecture, signaling and lineages. The epidermis is a stratified structure. Self-renewing stem cells reside within the basal layer, which adheres through 31 and 64 integrins to an underlying basement membrane of laminin-5rich extracellular matrix that separates the epidermis from the underlying dermis. Secreted factors such as FGF-7, FGF-10, IGF, EGF ligands and TGF- from dermal fibroblasts promote the proliferation of basal epidermal cells. Proliferative basal progenitors generate columnar units of Notch-activated terminally differentiating cells that go through three stages: spinous layers, granular layers and finally dead stratum corneum layers that eventually are shed from the skin surface. Each cell type expresses a different gamut of keratin (K) proteins.

The innermost (basal) epidermal layer consists of undifferentiated proliferative progenitors that express keratins K5 and K14. These progenitors not only replenish the basal layer, but also give rise to nonproliferative, transcriptionally active spinous and granular layers expressing K1, K10 and involucrin, and finally the outer layers of terminally differentiated, dead stratum corneum cells7 (). As demonstrated by retrovirus- and mutation-based lineage tracing data812, these columnar tissue units are in constant flux, as outer layer cells are continually shed and replaced by differentiating cells from inner layers.

Two distinct models have been proposed to explain the behavior of stem cells within the basal layer of the IFE (). The hierarchical model suggests that the IFE is composed of discrete epidermal proliferative units consisting of a slow-cycling stem cell that gives rise to short-lived transit-amplifying cells (TACs), which then depart the basal layer after several divisions to generate upward columnar units of differentiating cells. The stochastic model suggests that basal epidermis is composed of a single type of proliferative progenitor whose daughter cells choose randomly to differentiate or remain as progenitors.

Hierarchical versus stochastic models of epidermal differentiation. In a hierarchical model, rare divisions by stem cells generate rapidly dividing transit amplifying cells, which then give rise to differentiated cells. During lineage tracing, only clones marking the stem cells are long lived, and thus clone sizes become invariant after a period of time. By contrast, in a stochastic model, all basal cells are the same and each division can yield three different outcomes: (i) one differentiated daughter that withdraws from cell cycle and departs from the basal layer, and one progenitor that remains in the basal layer and continues to divide; (ii) two basal progenitors; and (iii) two differentiated daughters. Although the fate choices are random, the probabilities of different outcomes are similar, so that the generation of differentiated cells and the maintenance of committed progenitor pools are balanced at the population level and long-term homeostasis is ensured. In this model, each individual clone will vary in size. Predictions of lineage-tracing results from each model are shown at the top of the diagram; cells outlined in red are the ones retaining lineage-traced marks.

When individually labeled basal cells in tail, ear or hindpaw epidermis were marked by lineage tracing and their progeny were then monitored over the long term, the clonal fate data were compatible with the stochastic model1315. However, in these various labeling strategies, a crucial issue left unresolved was whether basal cells were marked randomly or selectively. By contrast, a recent study on tail skin employed two inducible Cre-lineage tracers in which Cre recombinases are fused with mutated estrogen receptors (ERs), rendering their inducibilty by tamoxifen. One Cre driver was driven by the K14 promoter, active in all basal cells, and the other by the involucrin promoter, active only in a discrete subset of K14+ basal cells that precociously express this typically differentiation-specific gene. In this study, purportedly slow-cycling basal cells marked by K14-CreER but not involucrin-CreER behaved like long-lived stem cells and gave rise to the subset marked by involucrin-CreER, which displays features of more committed basal progenitors16. These findings support the hierarchical model, yet show that progenitors within the basal layer exist and can behave in a stochastic manner. Although it is tempting to speculate that the differences among studies arise from the tools used to mark the basal cells, it is still possible that variation in the epidermis at different body sites accounts for the differences.

Epidermal keratinocytes proliferate before moving upward and differentiating. Dermal fibroblasts facilitate colony formation of human and mouse keratinocytes in vitro and are a rich source for mitogens such as insulin-like growth factors (IGFs), fibroblast growth factor-7 (FGF-7), FGF-10 and epidermal growth factor receptor (EGFR) ligands1719 (). The physiological importance of these factors in regulating epidermal proliferation has been verified in mouse models: epidermis lacking insulin-like growth factor receptor (IGFR) is impaired in basal epidermal proliferation20. Ectopic expression of mesenchymal factor FGF-7 in epidermal cells causes epidermal hyperproliferation21. EGF signaling, as its name suggests, is a particularly potent pathway for epidermal growth22. In mice, activation of transforming growth factor- (TGF-), a positive autocrine regulator of EGFR signaling in the epidermis, or deletion of Mig6, a negative regulator of EGFR signaling in the epidermis, leads to epidermal hyperproliferation23,24. In humans, reduction of expression of the EGFR antagonist, LRIG1, promotes human keratinocyte proliferation in culture.

ECM proteins deposited by basal epidermal keratinocytes and by underlying dermal fibroblasts form a sheath of basement membrane separating epidermis from dermis. Basal epidermal cells adhere to the basement membrane through receptors known as integrins. 31 and 64 are the major epidermal integrins that bind the ligand laminin-5, the major ECM component of the basement membrane (). In human basal epidermis, greater expression of 1 integrin marks a relatively slow-cycling population in vivo that has a higher colony-forming efficiency when plated in culture, suggesting that this population has greater stem cell potential2628.

The functions of integrins have also been explored in animal models. Ablation of 1 integrin in mice compromises basement membrane assembly and impairs proliferation29. Deletion of 6 or 4 integrin, or their ECM ligand laminin-5, leads to epidermolysis bullosa, a skin condition that results in severe blistering of the skin3033. 64 integrin signals through RAC1, a small GTPase in basal cells, to mediate their adhesion to the basement membrane; depletion of Rac1 results in epidermal hyperproliferation34. Although the precise mechanisms mediating these phenotypic changes may be complex, these studies demonstrate that ECM is a critical niche component for the stem cells within the basal layer.

Genetic studies in mice suggest that epigenetic factors are also regulators for epidermal proliferation and differentiation3540. Among these, the histone H3 Lys27 (H3K27) methyltransferases EZH1 and EZH2 are essential for epidermal homeostasis and wound repair38,39, whereas the histone H3K27 demethylase JMJD3 promotes differentiation41. Intriguingly, several epigenetic factors including EZH2 have been implicated in regulating the transcription of genes encoding 6 and 1 integrins in cultured human keratinocytes42, raising the possibility that some epigenetic modifiers might balance epidermal proliferation and differentiation in part by altering the attachment of basal cells to their basement membrane. Most, if not all, adult stem cells rely upon integrins and the ECM for adhesion to their niche, and understanding the interactions between skin stem cells and ECMs will provide a paradigm for understanding similar processes in other adult stem cells.

In addition to spatial cues from their niches, epidermal stem cell behavior may also be modulated by temporal cues such as circadian rhythms. In mice, proliferation of basal epidermal cells peaks at night, when the accumulation of reactive oxygen species is the lowest. Keratinocyte-specific deletion of Arntl (Bmal1), which encodes a transcription factor in the core clock machinery, abrogates this temporal difference by increasing epidermal proliferation during daytime43. Expression of core clock genes also oscillates in cultured human keratinocytes, and perturbation of this oscillation reduces colony-forming efficiency and promotes differentiation44. Although it remains unclear how these successive peaks of expression are established and how circadian rhythms regulate epidermal stem cells, it is tempting to speculate that temporal regulation has evolved to suppress proliferation during daytime, when there are higher risks of DNA damage owing to UV radiation and elevated concentrations of reactive oxygen species.

Epidermal stratification is governed by two mechanisms: delamination, in which basal cells lose their attachment to the basement membrane and move upwards45, and asymmetrical cell division, in which the plane of division is perpendicular to the basement membrane, generating a committed suprabasal daughter and a proliferative basal cell46. Transition from the basal to the spinous layer requires Notch signaling, a highly conserved pathway involved in a wide variety of developmental processes. In mouse epidermis, Notch1, Notch2 and Notch3 receptors and one of their ligands, Jagged1, are expressed suprabasally, whereas Jagged2 is expressed basally47,48 (). Upon ligand-receptor interaction, Notch proteins are cleaved by -secretase, releasing their intracellular domains (NICD1, NICD2 and NICD3), which bind to the transcriptional repressor RBP-J, enabling them to activate the Hes/Hey family of transcription factors and other target genes.

The presence of nuclear NICD and the transcription factor Hes1, as well as the expression of a Notch reporter gene regulated by RBP-J and NICD, have all been used as indicators that Notch signaling is active in spinous cells49. Indeed, constitutive activation of Notch signaling in the basal epidermis results in massive expansion of spinous layers, reduced integrin expression and detachment of epidermis from underlying dermis. Conversely, deletion of Rbpj in embryonic epidermis suppresses formation of spinous layers and reduces basal cell proliferation49. Postnatal loss of Notch signaling paradoxically results in epidermal hyperproliferation, but this turns out to be an indirect consequence of the impaired skin barrier and ensuing inflammation49,50. Notch signaling also acts genetically downstream of the asymmetric cell division machinery that basal progenitors use to generate spinous cells51. When the core components in asymmetric division are compromised, basal cells fail to activate Notch signaling and spinous cell numbers decline51. In humans, the Notch ligand DELTA1 is expressed by basal cells, and DELTA-NOTCH interactions in cultured human keratinocytes promote differentiation52. Together, these data suggest that Notch activation determines spinous cell fate and promotes delamination, and asymmetric cell division balances epidermal proliferation and differentiation through Notch signaling.

The exact ligand that activates Notch in the mouse epidermis, and the cellular source of that ligand, remains unclear, although evidence thus far implicates cross-talk between stem cells (basal) and their differentiated progeny (suprabasal cells). One possible cell mediator is the primary cilium, a microtubule-based sensory organelle that typically functions in hedgehog signaling but also enhances Notch signaling53. Failure in ciliogenesis leads to compromised Notch signaling and defective epidermal differentiation53.

Unlike the epidermis, which regenerates continually, hair follicles undergo cycles of growth (anagen), degeneration (catagen) and rest (telogen) (). In mice, the first two cycles are synchronized, making hair follicles an ideal system for understanding how stem cells interact with progeny and heterologous cell types in the niche to transition between quiescence and regeneration.

Hair follicle lineage and niche signals regulate hair follicle stem cells. (a) HFSCs can exist in two states. Quiescent bulge stem cells (Bu-SCs) are located in the outer layer of this niche and contribute to the generation of the outer root sheath. Primed stem cells reside in the hair germ, sandwiched between the bulge and a specialized dermal cluster known as the dermal papilla. They are responsible for generating the transit amplifying cell (TAC) matrix, which then gives rise to the hair shaft and its inner root sheath (IRS) channel. Although matrix and IRS are destroyed during catagen, many of the outer root sheath (ORS) cells are spared and generate a new bulge right next to the original one at the end of catagen. The upper ORS contributes to the outer layer of the new bulge, and the middle ORS contributes to the hair germ. Some of the lower ORS cells become the differentiated inner keratin 6+ (K6+) bulge cells, which provide inhibitory signals to Bu-SCs, raising their activation threshold for the next hair cycle. (b) During telogen, K6+ bulge cells produce BMP6 and FGF-18, dermal fibroblasts (DFs) produce BMP4 and subcutaneous adipocytes express BMP2. Together, these factors maintain Bu-SCs and hair germ in quiescence. At the transition to anagen, BMP2 and BMP4 are downregulated, whereas the expression of activation factors including noggin (NOG), FGF-7, FGF-10 and TGF-2 from dermal papillae and PDGF- from adipocyte precursor cells (APCs) is elevated. This, in turn, stimulates hair germ proliferation, and a new hair cycle is launched. Bu-SCs maintain their quiescent state until TAC matrix is generated and starts producing SHH.

HFSCs can be subdivided into two populations that share similar molecular signatures: a quiescent one located in the bulge (Bu-SCs) and a primed population within the hair germ just below the bulge, which is more prone to proliferation54 (). Previous lineage-tracing studies have demonstrated that these two populations are responsible for initiating hair growth2,55,56, and recently live imaging has provided a more precise means of delineating their relative contributions to these early steps57.

Neither Bu-SCs nor hair germ give rise to differentiated cells directly. At anagen onset, the hair germ is always the first to proliferate54,58. Hair germ develops into matrix, a pool of TACs that proliferate rapidly before terminally differentiating to form the hair shaft and its surrounding channel, the inner root sheath (IRS). By contrast, Bu-SCs primarily give rise to the outer root sheath (ORS), a population of cells that retains many stem cell characteristics and envelops the differentiating core of each hair follicle as well as the bulb of matrix TACs at the base of the mature follicle2,57 ().

During catagen, matrix and most lower ORS cells apoptose, middle ORS cells form a new hair germ and upper ORS cells form a new bulge adjacent to the original one2. The newly formed bulge and hair germ house the HFSCs for the next hair cycle. By contrast, the previous bulge becomes an HFSC reservoir for injury repair. Interestingly, some lower ORS cells escape apoptosis, follow a short-circuited differentiation program and become the inner layer of the new bulge. Marked by K6, these inner bulge cells anchor the hair shaft but have lost stemness, despite returning to the bulge2 ().

HFSCs are maintained in a quiescent state during most of the hair cycle and only proliferate early in anagen. Several secreted factors from stem cell progeny and dermal cells are important in regulating the proliferative status of Bu-SCs and hair germs. HFSC quiescence is largely maintained by bone morphogenetic proteins (BMPs). Originally named for their functions in bone and cartilage formation, BMPs have now been implicated in many developmental processes and stem cell systems. During telogen, dermal fibroblasts express BMP4, whereas subcutaneous fat expresses BMP2 (ref. 59). The K6+ inner bulge layer secretes high levels of BMP6 and another quiescence factor, FGF-18 (ref. 2; ). Together, these factors maintain quiescence of both Bu-SCs and hair germ.

The dermal papilla located beneath the hair germ is an essential niche component that initiates hair regeneration. Upon dermal papilla ablation, telogen-phase hair follicles never reenter the hair cycle60,61. Several dermal papillaspecific factors have been implicated in hair follicle activation. During progression from early to late telogen, levels of hair germactivating factors, including FGF-7, FGF-10, TGF-2 and the BMP inhibitor noggin, become elevated in dermal papillae54,62, whereas levels of BMP4 in dermal fibroblasts and BMP2 in mature adipocytes are downregulated, lowering the overall threshold for HFSC activation59. In addition, adipocyte precursor cells secrete platelet-derived growth factor- (PDGF-) to activate PDGF signaling in dermal papillae, which then relays a yet-to-be-identified signal to activate hair germ63.

WNT signaling, a prominent pathway in development and cancer, is also critical for hair germ activation: the downstream WNT effector, nuclear -catenin, accumulates in the activated hair germ and leads to target gene activation54. Without -catenin, hair follicles arrest in telogen58,64. WNT signaling is also required in dermal papillae, as hair follicles regenerate more slowly when -catenin is conditionally targeted there65. Although the exact WNT ligand(s) and source(s) mediating these effects remain to be identified, potential sources include the hair germ itself54 and dermal fibroblasts59,66. Together, these activation cues overpower the inhibitory signals and launch regeneration ().

Several lines of evidence suggest that Bu-SC activation may rely upon signals distinct from those used in hair germ activation. In contrast to the hair germ, which proliferates to form the matrix TACs upon anagen initiation, Bu-SCs remain quiescent until TACs emerge, a time when dermal papillaactivating cues are further distanced from the bulge. A recent study shows that Bu-SC activation depends on sonic hedgehog (SHH), a potent mitogen secreted by the newly formed TAC matrix. Moreover, by mid-anagen, as hair follicles grow downward and matrix-derived SHH moves away from the bulge, Bu-SCs resume quiescence. Matrix-derived SHH also signals dermal papillae to intensify expression of noggin and FGF-7, which, together with SHH, maintain the matrix and lower ORS in a highly proliferative state throughout anagen5. Thus, although cross-talk between the dermal papilla and the hair germ initiates anagen, Bu-SCs depend upon signals from the emerging TAC pool for their activation ().

Circadian rhythms also seem to have an impact on hair follicles, as they do on the epidermis. Expression of core circadian clock genes oscillates throughout the day in Bu-SCs, matrix and dermal papillae6769. Furthermore, during the resting phase, the Bu-SC population displays an intriguing heterogeneity in core clock gene expression67, and depletion of circadian clock proteins in mice delays anagen entry68. That said, epithelial lineagespecific knockouts of these genes have only mild effects on hair cycle progression43,67,69, suggesting that circadian rhythms may not act on HFSCs directly to control their activities. Future studies should help to delineate the actions of the circadian clock on specific niche components and reveal how these mechanisms might regulate hair cycles.

In mice, HFSCs and MSCs are intermingled in the bulge and hair germ70, providing a unique opportunity to explore how two different types of stem cells coordinate their actions within a shared niche (). As a new hair cycle initiates, MSCs become activated to generate proliferative committed progenitor melanocytes. In mature hair follicles, these melanocytes reside within the inner core of the matrix, where they produce and transfer melanin pigment to differentiating hair cells. As catagen ensues, melanocytes degenerate along with the rest of the matrix.

Signals from both HFSCs and dermal papillae are essential to synchronize MSC activation and differentiation with those of HFSCs7174. In the hair bulb during anagen, KIT ligand (secreted by the dermal papilla) and endothelins (secreted by the matrix) work in concert to prompt melanocyte differentiation. Interestingly, when telogen-phase HFSCs are conditionally targeted for loss of transcription factor NFIB, they aberrantly upregulate endothelin-2 (Edn2), which promotes precocious differentiation of MSCs near the KIT ligandexpressing dermal papilla. Adjacent hair germ cells take up melanin, prompting their apoptosis. Once the hair cycle is launched, these defects are resolved as the dermal papilla moves away from the bulge, thereby sparing the remaining HFSCs and MSCs74. Notably, Edn2 expression in mouse skin can be induced upon UV irradiation75, suggesting that the synchrony between HFSCs and MSCs might also be uncoupled in stress conditions.

Endothelin-1 is naturally induced by WNT signaling in early-anagen hair follicles72. Injection of endothelin receptor B antagonists can rescue the melanocyte expansion that results from either HFSC-specific Nfib deletion or elevated WNT signaling72,74. HFSCs might also produce WNTs and TGF-s, offering other potential routes for coordinating MSC and HFSC behaviors71,72,74. Whether MSCs release instructive signals to HFSCs is an intriguing question that awaits future studies.

As our bodys first line of defense, the skin is equipped with an impressive arsenal of immune cells. Immune cells and epithelial cells can influence each others functionality and behavior. Mouse epidermis is populated with dendritic epidermal T cells (DETCs) and Langerhans cells76,77, whereas dermis is enriched for dendritic cells, mast cells, macrophages, T cells and T cells77 ().

During injuries, compromising the epidermal barrier triggers inflammatory responses, which cause hyperproliferation of epidermal cells. In mice, DETCs in wounded skin produce FGF-7, FGF-10 and IGF-1, which are important for survival, proliferation and migration of epidermal cells78,79. Recently, FGF-9 secreted from dermal T cells has been reported to promote dermal WNT activation and induce hair follicle neogenesis in wounded epidermis80.

Interestingly, there are some similarities and differences between the injury-induced immune responses in mice and humans. Human epidermal resident T cells also upregulate IGF-1 upon wounding81. Nevertheless, a robust population of dermal T cells is lacking in humans, which might account for poor hair follicle neogenesis in humans following injury80. Notably, when p120-catenin, a component of adherens junctions, is conditionally ablated in the epidermis, barrier functions remain seemingly intact. However, nuclear factor-B signaling is induced, triggering inflammation and epidermal hyperplasia82. These findings suggest that pathogen-independent, intrinsic mechanisms coexist with pathogen-dependent ones to balance immune responses in skin.

The distribution and function of immune cells change during hair morphogenesis and cycling77, suggesting that hair follicles might also influence the immune cell composition in skin. Indeed, hair follicles can act as entry points for immune cells to move into the epidermis: upon temporary ablation of epidermal Langerhans cells and inflammation, the junctional zone and infundibulum of hair follicles produce chemokines CCL2 and CCL20, respectively, to recruit new Langerhans cell precursors to the epidermis, whereas bulge cells express high levels of CCL8 that repel them83.

Intriguingly, both bulge and matrix appear to express immunosuppressants, leading to reduced signaling to immune cells; this has prompted the hypothesis that these sites may be immune privileged84,85. If so, such immune privilege must have limits, as both hair follicles and epidermis are targeted by immune cells upon allotransplantation. Moreover, in autoimmune disorders such as alopecia areata, immune cells target the hair bulb and the matrix, sparing only Bu-SCs, which leads to reversible hair loss86. In contrast, Bu-SCs are destroyed in discoid lupus erythematosus and lichen planopilaris, resulting in irreversible hair loss87,88. As the molecules mediating cross-talk between epithelial stem cells and immune cells continue to be discovered, more specific and effective therapies should emerge to maintain the skins ability to defeat harmful stimuli caused by injuries and infections, but eliminate excess responses during inflammation and autoimmune responses.

The skin is the largest sensory organ, innervated by numerous fibers of primary sensory neurons whose cell bodies are located in trigeminal and dorsal root ganglia. These neurons are a heterogeneous population, including nociceptors, mechanoreceptors and proprioceptors ().

Anatomically, sensory nerves are in close contact with cells in the epidermis and hair follicles. Free nerve endings terminate at different layers of the epidermis89. Mechanoreceptive nerve endings encase a region of the hair follicle immediately above the bulge90,91. In neonatal animals, the temporal sequence of innervation correlates with hair follicle morphogenesis, suggesting that the two processes are interdependent92. Skin-derived cues have been shown to have an impact on sensory innervation and dendritic arborization93,94. Conversely, signals from peripheral nerves may influence hair follicles. For example, premature hair follicle regression is elicited by the neuropeptides substance P and CGRP, which trigger neurogenic inflammation95. In addition, peripheral nerves that innervate the cells above the bulge secrete SHH and may govern the behavior of these cells in wounding90. As the complex communication circuits between skin and peripheral nerves become better understood at the molecular level, novel strategies may emerge to restore proper wiring and sensory functions after injuries such as severe burns.

The skin vasculature supplies the skin with nutrients, hormones and immune cells and plays a role in thermal control. Although arteries and veins are located in the lower (reticular) dermis, arborizing capillary networks can be found in the region above the bulge96 (). These capillary networks might influence hair cycling: when angiogenesis is inhibited, anagen induction is delayed, indicating that angiocrine factors may regulate HFSC activity97. Intriguingly, the cells above the bulge express angiogenic factor EGFL6, an ECM protein96. Whether EGFL6 recruits blood vessels to the hair follicle remains to be explored. Intriguingly, minoxidil, an active ingredient used to treat androgenic alopecia (male-pattern baldness), is a vasodilator that has been proposed to work by increasing blood flow to the skin and thus potentially stimulating hair follicle growth. Future studies should help to reveal molecular cross-talk between skin vasculature and HFSCs.

HFSCs also control the formation and attachment of the arrector pili muscle (APM) responsible for piloerection (goosebumps6; ). Bu-SCs express nephronectin, an ECM protein in the same family as EGFL6. Both nephronectin and EGFL6 are ligands for 81 integrin. Nephronectin is enriched in the bulge basement membrane, where it recruits 81+ dermal cells. In turn, nephronectin-integrin activation in these dermal cells induces the expression of smooth muscle actin, an APM marker. In mice lacking nephronectin, fewer APMs are formed and their anchorage is shifted to the EGFL6-expressing cells above the bulge, suggesting that EGFL6 may compensate for nephronectin6. Taken together, these studies suggest that different hair follicle compartments recruit and assemble different hair follicleassociated structures, including peripheral nerves, blood vessels and APMs, in part through expression of different ECM proteins.

The skin shows profound structural and functional changes with age, including dermal and epidermal thinning, reduction in epidermal proliferation and injury repair, loss of dermal elasticity and wrinkling, and graying, thinning and loss of hair. Aged HFSCs maintain their numbers and gene signatures. However, telogen lengthens with age, suggesting that quiescent HFSCs become increasingly resistant to activation98,99.

In culture, HFSCs from aged mice proliferate more slowly and generate fewer large colonies than their younger counterparts, indicating that intrinsic changes with age affect HFSC proliferation. In vivo, prolonged telogen in aged mice might be due to more BMP inhibitory cues and/or fewer WNT-activating signals, the balance of which determines HFSC activity. Indeed, elevated Bmp2, Bmp4 and Bmp6 expression and protein secretion from aged adipose tissue, and to a lesser extent aged dermal fibroblasts, may further raise the threshold for activating aged HFSCs. Correspondingly, aged HFSCs display upregulation of BMP targets Nfatc1 and Id2, reinforcing HFSC quiescence98. The composition of immune cells in skin also changes with age100, and age-related increases in proinflammatory cytokine signaling have been described101. Because immune-related changes are heavily influenced by pathogen exposure and skin barrier integrity, they add a variable component to the age-related decline in HFSC activity.

Lastly, although age-related systemic changes affect various organs, including those of the nervous system, muscle and heart102104, only modest increases in HFSC proliferation result from joining the circulatory systems of older and younger mice (parabiosis)98. Therefore, much of the age-related decline in HFSC function appears to arise from more local signals or the HFSCs themselves98. Moreover, these findings suggest that even though some common mechanisms of the aging process are shared, each stem cell niche and the macroenvironment surrounding it have unique regulators, complicating the search for a fountain of youth.

When skin is wounded, its stem cells must respond rapidly to restore the compromised barrier and repair tissue damage. Wound healing involves three overlapping phases: inflammation, tissue formation and tissue remodeling105. Inflammation occurs immediately after injury. Following platelet aggregation, various leukocyte lineages, including neutrophils, macrophages, mast cells and T cells, are recruited to the wound site. In addition to clearing dead cells and fighting against infections, these leukocytes secrete cytokines and growth factors such as TGF-s, IGFs and FGFs that promote angiogenesis, migration and proliferation of keratinocytes and dermal fibroblasts, synthesis of ECMs and sometimes generation of new hair follicles in the process of epidermal regeneration7880. During tissue formation, granulation tissue, consisting of newly formed blood vessels, macrophages and fibroblasts, begins to cover the wound. Epidermal cells then migrate over the granulation tissue to reepithelialize the wound. Adipocyte precursor cells are also activated at this stage to generate mature adipocytes important for fibroblast recruitment106. During tissue remodeling, the epidermis and dermal fibroblasts deposit new ECM proteins to strengthen the repaired tissue105.

Following full-thickness wounds, cells from both the hair follicles and the IFE migrate into the site of damage16,56,90,107109. Mice lacking either hair follicles or HFSCs show delayed wound healing110. That said, very few HFSC-derived cells persist within the reepithelialized epidermis of a full-thickness wound. Lineage tracing of Gli1+ cells above the bulge and Lrig1+ cells in the junctional zone show that their progeny can persist longer90,109, but even these hair follicle progeny are largely replaced by epidermal progeny following repair16. Overall, the data on full-thickness wounds have led to the now widely held view that input from hair follicles plays relatively minor roles, whereas IFE plays a major role in wound reepithelialization.

In humans, exposure to UV damage from the sun increases the risk of oncogenic transformation of long-lived skin stem cells. Basal cell carcinoma (BCC), the most common cancer worldwide, is rooted in deregulated, sustained SHH signaling111. By contrast, squamous cell carcinoma (SCC), an aggressive skin cancer with significant risk of metastasis, can arise from oncogenic RAS transformation and accompanying loss of tumor suppressors such as p53, BRCA1 or TGF- receptors, and/or their downstream effectors112. The roots of both BCCs and SCCs have been traced to multiple stem cell populations in the hair follicles and epidermis, whereas matrix seems to lack tumor-initiating capacity113116. In mice, cutaneous injuries have been reported to exacerbate BCC malignant progression117,118, a finding consistent with the higher risk of cancer in patients with chronic wounds.

Tumor-initiating cells, frequently referred to as cancer stem cells (CSCs), are also influenced by their niches, which are greatly altered by infiltration of blood vessels and immune cells as well as perturbations in the cross-talk of niches with their malignant stem cell residents (). CSCs have been purified and characterized from mouse skin papillomas and SCCs119121. At a near single-cell level, SCC-CSCs can induce the formation of a new SCC when transplanted into a host recipient mouse120. Additionally, the expansion of CSCs and their SCC progeny has been monitored by in vivo lineage tracing122. CSCs exist at the tumor-stroma interface and express high levels of integrins120,121. CSC cycling activities are influenced by cues from their niche, where signals from TGF- and signals from integrin and focal adhesion kinase counteract each other to inhibit or promote CSC proliferation, respectively120. SCC-CSCs express vascular endothelial growth factor (VEGF), which stimulates elaborate tumor vascularization. Interestingly, VEGF may also act on CSCs in an autocrine fashion to increase their proliferation and thereby sustain tumor growth123 (). Therefore, CSCs are analogous to their normal counterparts in that they rely upon autocrine and paracrine niche signals for their self-renewal and differentiation.

Signaling pathways in skin cancers. (a) The squamous cell carcinomacancer stem cell niche. CSCs are often found at the tumor-stroma interface, together with an elaborate vasculature, immune cells and aberrant fibroblasts. (b) Upon activation of 1 integrins by extracellular matrix ligands such as fibronectin (FN), focal adhesion kinase (FAK) and its associate tyrosine kinase Src become hyperactivated and promote proliferation of CSCs. By contrast, TGF- signaling counteracts integrin activity and enhances CSC quiescence. In addition, CSCs secrete VEGF, which acts in an autocrine fashion to enhance CSC proliferation and in a paracrine fashion to promote formation of new blood vessels.

With the identification of CSCs in situ, it is now possible to tackle the question of intrinsic versus extrinsic regulation of CSCs during tumor progression. Gene expression signatures have been reported for purified SCC-CSCs120. Large-scale screens, either genome-wide or with preselected gene sets, have allowed researchers to identify which of the myriad changes in gene expression are causative for SCCs124,125. In the future, it will be interesting to discover whether altering some of these drivers in CSCs also affects CSC niches, as seen, for instance, with VEGF123.

The use of cultured human keratinocytes to treat burn patients has been a success in regenerative medicine17,126,127. However, although these autologous grafts fulfill the need for epidermal barrier protection, they lack hair follicles, sweat glands and peripheral nerves. In addition, although the dermis underneath the engrafted epidermis recovers eventually, the entire process takes months, and the dermis is never restored fully.

The considerable progress in understanding stem cellniche interactions in hair follicles and sweat glands opens new avenues for therapeutic advances, offering possible improvements for skin grafting and alopecia treatments. During embryonic development, WNT signaling within the epidermis and BMP inhibition in underlying mesenchyme triggers hair follicle formation128,129. Analogously, similar cross-talk between adult hair germs and dermal papillae stimulates each new round of hair cycling54. Intriguingly, fibroblasts from the upper dermis of neonatal skin also possess robust capacity for hair induction, whereas those from the lower dermis are not effective130. Collectively, these studies suggest that proper niche cell types, signaling and spatial organization are all important considerations for regenerating hair follicles.

In their native niche, adult HFSCs become active only upon hair cycle initiation, when they function in making new hair follicles. When transplanted onto immunocompromised mice, however, mixtures of dissociated HFSCs and mesenchymal cells regenerate not only hair follicles but also sebaceous glands and epidermis131. A three-dimensional culture method has recently been developed that involves seeding a mixture of dissociated hair follicle cells and dermal cells from adult mice or humans in collagen gels. Upon transplantation some of these mini-organoids can grow into functional hair follicles that receive nerve innervation, form APMs and undergo hair cycles and piloerection132.

Another major advance is the identification of progenitors that give rise to sweat glands in mice. In homeostasis and mild injury, most adult sweat gland progenitors behave unipotently, only giving rise to myoepithelial or luminal epithelial cells. However, upon engraftment, purified myoepithelial stem cells can generate an entire gland, containing both myoepithelial and luminal epithelial layers; this is reminiscent of their multipotent behavior during development133. Together, these studies further reinforce the idea that stem cell potential and behavior are not fixed, and can be altered upon exposure to different environments. With ever-increasing knowledge of stem cell populations, regulatory signals within the niche, and the ecosystem of the skin, the ability to regenerate a fully functional skin for tissue replacement in regenerative medicine should continue to improve.

Recent findings have brought forth the complexity of cellular and molecular regulators within the skin stem cell niche during development, homeostasis, injury, aging and cancer. Several open questions remain. First, although many putative niche factors have been identified, their functional importance can be firmly established only by knocking out specific factors spatially and temporally from specific niche components that express them. To date, this has rarely been achieved for any given mammalian stem cell system. Second, although several cell types, including blood vessels and sensory neurons, make stereotypic and spatially distinct contacts with epithelial cells, specific signals governing these connections remain to be identified. Third, given the heterogeneity and complexity of tumor development, our understanding of the cancer stem cell niche is still in its infancy. Fourth, biological processes such as pregnancy, lactation, hypoxia and circadian rhythms can also impact skin stem cells44,67,134136. Whether these influences are mediated through effects on any niche components remains to be explored.

These hurdles will probably be overcome with continued development of stem cellspecific genetic tools, identification of new markers to characterize specific stem cell populations more precisely, and improvements in imaging strategies. With its rich cellular composition, the skin will continue to serve as an important paradigm in the quest to understand stem cell niches. In the era of tissue engineeringdriven by the hope that in the future we will be able to manipulate stem cell behavior in situ, suppress tumor formation and progression and grow functional tissues for regenerative medicineit is even more important and timely to tackle the complexity of niche components within the skin.

We are grateful to members of E.F.s lab, in particular S. Naik, for comments on the manuscript. Y.-C.H. was a New York Stem Cell Foundation Druckenmiller Postdoctoral Fellow and is now supported by US National Institutes of Health Pathway to Independence Award (K99-R00). L.L. is a Helen Hay Whitney Postdoctoral Fellow. E.F. is an Investigator of the Howard Hughes Medical Institute. This work was supported by grants from the US National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01-AR031737 to E.F., R01-AR050452 to E.F. and K99-AR063127 to Y.-C.H.), and by a grant from the Ellison Foundation (E.F.).

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1.5 million loan will further support clinical manufacture of mocravimod for the adjunctive treatment of Acute Myeloid Leukemia (AML)

DUBLIN and SAINT-LOUIS, France, April 4, 2022 /PRNewswire/ --Priothera, a late-clinical stage biotechnology company pioneering the development of its S1P receptor modulator drug, mocravimod, today announces that it has entered a 1.5 million Loan Agreement with the regional Bpifrance in Strasbourg (Grand Est Bpifrance), via Priothera SAS, its French affiliate.

This R&D innovation loan will be used to further support the clinical manufacture of mocravimod for a European, US and Asian registration-enabling clinical trial with mocravimod in Acute Myeloid Leukemia (AML) patients undergoing allogeneic hematopoietic stem cell transplant (HSCT).

Brice Suire, Co-Founder and Chief Financial Officer of Priothera, said: "This non-dilutive financing, alongside the funding from the European Investment Bank that we announced recently, will play an important role in financing the development of mocravimod. It will allow us to strengthen our local French team and accelerate delivery of the clinical supply of mocravimod needed for our upcoming registration-enabling global clinical trial. We are very pleased with the confidence shown by Grand Est Bpifrance in supporting the Company in its development program."

Alban Stamm, Innovation Manager at BpifranceAlsace commented: "We believe that Priothera, with its drug candidate mocravimod, has the potential to enable a major breakthrough in preventing transplant rejection which would provide a tremendous benefit to AML patients undergoing a stem cell transplant. The Bpifrance loan will support Priothera's key objective of establishing human proof of concept and generating registrational data, allowing the company to create significant socio-economic value in France and beyond that for patients globally."

Mocravimod, a sphingosine 1 phosphate (S1P) receptor modulator which has been previously tested in multiple autoimmune indications, is being developed to enhance the curative potential of HSCT in patients with AML. Moreover, it has shown clinically relevant benefits in an early clinical study in patients with hematologic malignancies undergoing HSCT.

About Priothera

Priothera is leading the way in developing orally applied sphingosine 1 phosphate (S1P) receptor modulators for the treatment of hematological malignancies. S1P receptor modulators are known to largely reduce egress of T cells from lymphatic tissues and not being immunosuppressants, thereby allowing for inhibition of graft-versus-host-disease (GvHD) while maintaining graft-versus-leukemia benefits in patients receiving HSCT.

Priothera which was founded in 2020 by an experienced team of drug development experts is headquartered in Dublin, Ireland. The Company is backed by international founding investors Fountain Healthcare Partners (Dublin, Ireland), funds managed by Tekla Capital Management, LLC (Boston, Massachusetts), HealthCap (Stockholm, Sweden) and EarlyBird Venture Capital (Berlin, Germany).

For more information please visit: http://www.priothera.com

About Bpifrance

Bpifrance is the one stop shop for entrepreneurs with a vastly comprehensive toolbox offered in the field to customers through 50 local branches. Our mission is simple: we believe in serving the future, by being entrepreneur-centric and heavily decentralized.

http://www.bpifrance.fr

Contacts

PriotheraFlorent Gros, CEOE : [emailprotected]

MEDiSTRAVA ConsultingSylvie Berrebi, David Dible, Sandi Greenwood, Frazer HallE: [emailprotected]T: +44 (0)203 928 6900

SOURCE Priothera

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Priothera Receives R&D Innovation Loan from Bpifrance - PR Newswire

From hydras to humans, this short book by two marine biologists explores the peculiar process of regeneration, showing that it is a far bigger subject than it might at first seem

By Simon Ings

Is the regeneration of a forest after fire fundamentally the same as an animal regrowing a body part?

KarenHBlack/Getty Images

What Is Regeneration?

Jane Maienschein and Kate MacCord

University of Chicago Press (out 6 April)

SOME animals are able to grow an entire new body from tiny parts. Crabs and lobsters can regenerate lost tentacles and claws. Hydras and some worms can regrow their heads. We humans can replace our skin, hair, fingernails and even our liver.

Regeneration is such a peculiar ability that, even in science, it is surprisingly under-researched. As a result, there is much we still dont know. What Is Regeneration? is a collaborative effort between Jane Maienschein and Kate MacCord, both at the Marine Biological Laboratory in Woods Hole, Massachusetts, to fill some of the gaps. Together, they explore why regeneration occurs when it does, why it doesnt always happen and what the process can tell us about the grander mysteries of birth, death and development.

It turns out to be a seemingly simple phenomena that, on closer inspection, becomes far more complicated. For instance, are we thinking only about regeneration of structure, about regeneration of function or both? Is the regeneration of the gut flora in your intestines after a course of antibiotics or the regeneration of woodland after a forest fire at all similar to regrowing a body part?

To try to pin it down, the authors begin with a history of the study of the subject, starting with Aristotle and ending with Magdalena Zernicka-Goetzs ongoing research on cellular signalling. Their account pivots on the work of Thomas Hunt Morgan (better known as a pioneer of chromosomal genetics) and, in particular, his 1901 book Regeneration. Morgan, more than anyone before or since, attempted to establish clear boundaries around the phenomenon, and the terminology he came up with remains useful.

He identified three kinds of regeneration. The first two are restorative regeneration, which occurs in response to injury, and physiological regeneration, which describes replacement, as when an elk moults its antlers and new ones grow in their place. The third, morphallaxis, refers to more extreme cases, such as when a hydra, cut into pieces, reorganises itself into a new hydra without going through the normal processes of cell division.

The key to this categorisation is that the mechanisms of regeneration arent, as the authors put it, a special response to changing environmental conditions but, rather, an internal normal process of growth and development.

So here is the problem: if the mechanisms of regeneration cant be distinguished from those of growth and development, what is to stop everything ceaselessly regenerating? What dictates the process of regrowth and why does it happen only in some tissues, in some species and only some of the time?

Maienschein and MacCord argue that, to fully understand this, we need to see regeneration as a window into the world of biology in general, and the complex feedback loops that decide what grows, divides and dies, where and when.

Far from being an interesting curio, then, studying regeneration can tell us much about life in general, from a cellular level right up to the level of ecosystems, and inform everything from regenerative therapies using stem cells to ecosystem protection and recovery.

Seen through this lens, regeneration is a far bigger subject than it might at first seem, and Maienschein and MacCord take fewer than 200 pages to anatomise the complexities and ambiguities that their simple question throws up. It is to their credit that they mostly focus on the big picture and dont make the biology any more complex than it needs to be.

More on these topics:

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What is Regeneration? review: A dive into the science of regrowth - New Scientist

The first quarter of 2022 was one to forget for the biotech industry.

A public market downturn that began last year accelerated, sending the stock values of many biotech companies spiraling lower. The pace of drugmaker initial public offerings, which set a record in 2021, slowed to a trickle, making the path to Wall Street harder for emerging startups. Biotechs tightened their purse strings, leading to a string of restructurings.

Still, there were a few bright spots.The Food and Drug Administration approved a first-of-its-kind cancer immunotherapy, while a pioneering gene editing treatment continued to show promise and a major acquisition closed, calming concerns of greater regulatory scrutiny on buyout deals.

Several key FDA decisions lie ahead in the second quarter and each, if positive, may help the sector regain its momentum. Here are five to watch:

FDA advisory committee meetings are important moments for drugmakers as their outcomes can have a significant impact on a prospective medicine's approval chances. A two-day gathering in June is even more important for Bluebird, which could run out of money if the FDA doesn't approve two gene therapies a group of experts are set to review.

The gene therapies, known as beti-cel and eli-cel, would be just the third and fourth gene therapies for inherited diseases to reach market in the U.S. They would represent significant medical advances for patients with the blood disease beta thalassemia and the childhood brain disorder cerebral adrenoleukodystrophy.

Approvals also would lead the FDA to award the company with two priority review vouchers that can speed up drug reviews and be sold to other companies.

Bluebird has said those vouchers are critical to its financial future. In March, the company's top financial executive resigned amid a cash crunch that could leave the company insolvent within a year. Selling the vouchers could extend its runway and give Bluebird the chance to rebound.

However, Bluebird needs the blessing of the FDA and its advisers first, neither of which are a given. Both programs have been slowed in the past due to safety concernsand testing of eli-cel is on hold after a clinical trial participant developed a type of bone marrow cancer. The FDA extended its review of both drugs earlier this year.

The two-day advisory panel will take place on June 9 and June 10. The FDA will decide whether to approve beti-cel by Aug. 19 and eli-cel by Sept. 16.

Bristol Myers Squibb has been largely absent from major dealmaking since absorbing Celgene in a merger three years ago. However,the one time the pharma company did spring for a deal was in October 2020, when it paid $13 billion to buy MyoKardia and a heart drug known as mavacamten.

Bristol Myers was willing to pay that high price on optimism that mavacamten could become a top seller. On a conference call in February, CEO Giovanni Caforio pointed to the drug, which treats a typically inherited heart condition known as hypertrophic cardiomyopathy, as one of three emerging treatments in its pipeline with "at least $4 billion in revenue potential." Hitting those numbers will be key for Bristol Myers, as some of its most lucrative products will lose patent protection later this decade.

Still, commercial success is no guarantee. Many patients with hypertrophic cardiomyopathy don't have symptoms, and other medications and surgical options are available. Competition could be looming in the form of a similar drug from Cytokinetics that's in late-stage testing. On the February call, some analysts also questioned Bristol Myers' projections, which rely heavily on a sharp increase in diagnosis rates.

The FDA in November extended its review of mavacamten to evaluate a proposed post-approval patient monitoring plan, the details of which Bristol Myers hasn't shared. Its decision deadline is April 28.

The FDA is set to issue a verdict by June 29 on what could become the first new ALS drug to reach the U.S. market in five years.

ALS, better known to some as amyotrophic lateral sclerosis or Lou Gehrig's disease, is a progressive and fatal disorder hallmarked by the breakdown of nerve cells and the deterioration of essential functions like walking, eating and breathing. Patients with the disease typically live just two to five years after being diagnosed.To date, the FDA has cleared only two treatments specifically for ALS, each with limited effects on function and survival.

Amylyx Pharmaceuticals, a small drug company based in Cambridge, Massachusetts, believes it has another option in a pairing of chemicals named AMX0035. In a study of about 140 patients, Amylyx said those who received its medicine declined significantly slower compared to those on a placebo, as measured by a rating scale used to evaluate day-to-day functions in ALS patients. Amylyx also said that further analyses from an extension phase of the study found a benefit on survival.

The company, patient advocates and some doctors believe these outcomes offer enough evidence to approve AMX0035. The FDA has shown interest in the drug as well, allowing Amylyx to submit it while running another, larger study to confirm the results seen so far. However, the agency also has reservations about the way Amylyx designed its key study and the ways in which data were analyzed. Such concerns were on display during a meeting this week, in which neuroscience and drug development experts advised the FDA against approving AMX0035 in a narrow vote.

That vote puts the agency in a difficult position. ALS patients and advocacy groups have campaigned for the approval of more treatments, including Amylyx's, noting the limited options currently available as well as the devastating and fatal nature of their disease. The FDA has met with advocates and said it's listening to them, but with the crux of Amylyx's approval application in doubt, regulators could hold off green-lighting the company's drug until that larger study produces full results in 2024.

By late June, the FDA will decide whether to approve Bristol Myers' CAR-T cell therapy Breyanzi for earlier treatment of a common form of lymphoma.

To date, the complex cancer treatments have only been cleared for use after patients have run out of other options, limiting their reach and commercial potential. However, last year Bristol Myers and Gilead presented clinical trial data showing their respective CAR-T therapies Breyanzi and Yescarta outperformed standard "second-line" treatment, a combination of chemotherapy and stem cell transplant.

The results were a major proof point for CAR-T, which had reached market in the U.S. based on smaller studies without control arms. They were also validation for Bristol Myers and Gilead, both of which spent billions of dollars to acquire the products.

Gilead is likely to beat Bristol Myers to an approval, with an FDA decision expected imminently for Yescarta in second-line treatment. Yescarta has also been approved for longer, with an additional clearance for another lymphoma type.

However, approvals in second-line lymphoma could also draw renewed attention to the cost and manufacturing issues of CAR-T treatment. Bristol Myers priced Breyanzi at $410,000, while Yescarta has a list price of $373,000. Both companies require several weeks to produce the personalized treatments, a challenge that may grow more difficult if a broader group of patients are eligible.

Over the past year, the FDA office in charge of reviewing new cancer medicines has revisited its approach to accelerated approvals, most notably convening a meeting of outside experts last spring to review six previously granted OKs.

Agency officials have penned opinion pieces signaling tougher standards. FDA pressure has also led a number of companies to withdraw accelerated approval applications. Some companies have even pulled previously cleared drug indications after they were unable to confirm benefits observed in earlier testing.

The FDA's scrutiny appears to be turning next to a class of cancer medicines known as PI3K inhibitors, several of which are already on the market. In late April, the agency will again gather its panel of advisers to review whether randomized trial data is needed to appropriately support their use.

The group will also discuss an application by TG Therapeutics for accelerated approval of a combination drug regimen containing its marketed PI3K blocker Ukoniq. Previously, the FDA had announced an investigation into a possible increased risk of death with the medicine.

The agency has set a target decision date of June 25 for TG's treatment combination.

Already, the FDA's focus on PI3K inhibitors appears to have had an effect. In January, Gilead said it would withdraw two indications for its drug Zydelig after having difficulty enrolling patients in confirmatory studies. In addition,the agency told MEI Pharma and partner Kyowa Kirin this month that they would need to gather more data for their experimental PI3K inhibitor before seeking approval.

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5 FDA decisions to watch in the second quarter - BioPharma Dive

OSAKA, Japan, and CAMBRIDGE, Massachusetts, April 5, 2022 Takeda (TSE:4502/NYSE:TAK) and the New York Academy of Sciences today announced the winners of the fourth Innovators in Science Award for their excellence in, and commitment to, innovative science that has significantly advanced the field of research in gastroenterology. Each winner receives an unrestricted prize of $200,000 USD.

The 2022 Senior Scientist Award winner is Jeffrey Gordon, M.D., Director of the Edison Family Center for Genome Sciences and Systems Biology and Dr. Robert J. Glaser Distinguished University Professor at Washington University School of Medicine in St. Louis. Dr. Gordon is widely recognized as the Father of Microbiome Science and has served as the research mentor for more than 140 doctoral students and post-doctoral fellows who have become the next generation of leaders in the field. His pioneering interdisciplinary research has revealed the profound effects of the human gut microbial community on physiology and metabolism. Dr. Gordons preclinical studies have yielded fundamental insights about the mechanisms that underlie the formation and functioning of the human gut microbiome, as well as its causal links to disease states, including malnutrition. Dr. Gordons group has developed microbiome-targeted therapeutic foods for the precision repair of the gut microbiomes of malnourished children and restoration of their growth.

This award is a wonderful recognition of the excitement and promise that the field of microbiome research offers, and of the collective efforts of the inspiring group of talented students, staff, and collaborators who I've been privileged to work with as we strive to better understand how the gut impacts our health, said Dr. Gordon.

The 2022 Early-Career Scientist Award winner is Elaine Y. Hsiao, Ph.D., De Logi Associate Professor of Biological Sciences at UCLA. Dr. Hsiao has made groundbreaking discoveries into how the gut microbiome influences the brain and behavior. Her research has upended conventional thinking about the cause and treatment of neurological diseases such as autism and epilepsy. Some of Dr. Hsiaos most impactful work investigating the influence of the maternal microbiome on fetal brain development has laid the foundation for hypotheses of microbial contributions to risk for neurodevelopmental disease. Dr. Hsiao has also advanced the understanding of how microbiota influence serotonin-producing endocrine cells in the gut research that has the potential to affect the understanding of intestinal and neurological diseases.

Winning the Innovators in Science Award is a great privilege for me as an early-career scientist, said Dr. Hsiao. Not only does it signal a welcome to new researchers to help advance the field, it also recognizes the discoveries made possible by my talented and inspiring colleagues in the lab who share my dedication to uncovering interactions between the gut, its native microbes, and the brain. This award will continue to motivate me to go where science leads, and toward better understanding how life works in ways that I hope will one day benefit people.

The work of Dr. Gordon and Dr. Hsiao to uncover more about the role of our gut microbiome in disease pathology and apply that understanding to create meaningful interventions for patients suffering from gastrointestinal, neurological diseases, and beyond is truly inspiring, said Andrew Plump, M.D., Ph.D., president, Research & Development at Takeda. We proudly support the Innovators in Science Award because at Takeda we deeply value the pursuit of science and those who push the boundaries of what is possible to dramatically improve peoples lives.

We are pleased to join Takeda in championing the tireless work of researchers around the world, said Nicholas Dirks, Ph.D., president and CEO of the New York Academy of Sciences. The 2022 Innovators in Science Award winners are pursuing groundbreaking medical research that reveals the workings of the gut microbiome to potentially bring innovations to patients everywhere who are affected by gastrointestinal disease and more.

The 2022 winners will be honored at the Innovators in Science Award ceremony and symposium October 13-14, 2022, in Boston. For more information and to register for the 2022 Innovators in Science Award virtual symposium, please visit: https://www.nyas.org/awards/innovators-in-science-award/

About the Innovators in Science Award

The Innovators in Science Award grants two unrestricted prizes of US $200,000 each year: one to an early-career scientist and the other to a well-established senior scientist who have distinguished themselves for the creative thinking and impact of their research. The Innovators in Science Award is a limited submission competition in which research universities, academic institutions, government, or non-profit institutions, or equivalent from around the globe with a well-established record of scientific excellence are invited to nominate their most promising early-career scientists and their most outstanding senior scientists. The therapeutic focus rotates each year through one of five fields neuroscience, gastroenterology, rare diseases, oncology, and regenerative medicine. The 2022 focus was gastroenterology, next year the focus will be on oncology. Prize winners are determined by a panel of judges, independently selected by the New York Academy of Sciences, with expertise in these disciplines. The New York Academy of Sciences administers the Award in partnership with Takeda.

About Takeda

Takeda is a global, values-based, R&D-driven biopharmaceutical leader headquartered in Japan, committed to discover and deliver life-transforming treatments, guided by our commitment to patients, our people and the planet. Takeda focuses its R&D efforts on four therapeutic areas: Oncology, Rare Genetics and Hematology, Neuroscience, and Gastroenterology (GI). We also make targeted R&D investments in Plasma-Derived Therapies and Vaccines. We are focusing on developing highly innovative medicines that contribute to making a difference in peoples lives by advancing the frontier of new treatment options and leveraging our enhanced collaborative R&D engine and capabilities to create a robust, modality-diverse pipeline. Our employees are committed to improving quality of life for patients and to working with our partners in health care in approximately 80 countries and regions. For more information, visithttps://www.takeda.com.

About the New York Academy of Sciences

The New York of Academy of Sciences is an independent, not-for-profit organization that since 1817 has been committed to advancing science for the benefit of society. With more than 20,000 Members in 100 countries, the Academy advances scientific and technical knowledge, addresses global challenges with science-based solutions, and sponsors a wide variety of educational initiatives at all levels for STEM and STEM related fields. The Academy hosts programs and publishes content in the life and physical sciences, the social sciences, nutrition, artificial intelligence, computer science, and sustainability. The Academy also provides professional and educational resources for researchers across all phases of their careers. Please visit us online atwww.nyas.org.

The New York Academy of SciencesRoger Tordartorda@nyas.org

TakedaJapanese MediaRyoko Matsumotoryoko.matsumoto@takeda.com+81 (0) 3-3278-3414

U.S. and International MediaKerry Bryantkerry.bryant@takeda.com

Excerpt from:
Takeda and the New York Academy of Sciences Announce 2022 Innovators in Science Award Winners - The New York Academy of Sciences

MorphoSys and Incyte Announce Swissmedic Temporary Approval of Minjuvi(R) (tafasitamab) in Combination with Lenalidomide for the Treatment of Adults with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

PLANEGG and MUNICH, GERMANY and MORGES, SWITZERLAND / ACCESSWIRE / March 22, 2022 / MorphoSys AG (FSE:MOR) (NASDAQ:MOR) and Incyte (INCY) today announced that the Swiss agency for therapeutic products (Swissmedic), has granted temporary approval for Minjuvi(R) (tafasitamab) in combination with lenalidomide, followed by Minjuvi monotherapy, for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), after at least one prior line of systemic therapy including an anti-CD20 antibody, who are not eligible for autologous stem cell transplant (ASCT). Incyte holds exclusive commercialization rights for Minjuvi in Switzerland.

The approval of Minjuvi by Swissmedic is excellent news, said Jonathan Dickinson, Executive Vice President and General Manager, Incyte Europe. There are a substantial number of people living with relapsed or refractory DLBCL in Switzerland and were pleased to be able to offer them a new treatment option.

DLBCL is a fast-growing cancer and can be very hard to treat. Up to 40% of DLBCL patients either relapse after they have been treated or dont respond to initial treatment at all, said Mike Akimov, M.D., Ph.D., Head of Global Drug Development, MorphoSys. Minjuvi addresses this unmet need and its approval in Switzerland is a crucial milestone for these patients.

The approval is based on the results from the L-MIND study evaluating the safety and efficacy of tafasitamab in combination with lenalidomide as a treatment for patients with relapsed or refractory DLBCL who are not eligible for autologous stem cell transplant (ASCT). The results showed a best objective response rate (ORR) of 56.8% (primary endpoint), including a complete response (CR) rate of 39.5% and a partial response rate (PR) of 17.3%, as assessed by an independent review committee. The median duration of response (mDOR) was 43.9 months after a minimum follow up of 35 months (secondary endpoint). Tafasitamab together with lenalidomide was shown to provide a clinically meaningful response and the side effects were manageable.[2]

Incyte and MorphoSys share global development rights to tafasitamab; Incyte has exclusive commercialization rights to tafasitamab outside the U.S. Tafasitamab is co-marketed by Incyte and MorphoSys under the brand name Monjuvi(R) (tafasitamab-cxix) in the U.S., and is marketed by Incyte under the brand name Minjuvi in Europe, the UK and Canada.

About Diffuse Large B-Cell LymphomaDLBCL is the most common type of non-Hodgkin lymphoma in adults worldwide, comprising 40% of all cases[3]. Each year around 16,000 patients in Europe are diagnosed with relapsed or refractory DLBCL[4],[5],[6]. The condition is characterized by rapidly growing masses of malignant B-cells in the lymph nodes, spleen, liver, bone marrow or other organs[7]. It is an aggressive disease with about one in three patients not responding to initial therapy or relapsing thereafter[8],[9],[10],[11].

About L-MINDThe L-MIND trial is a single arm, open-label Phase 2 study (NCT02399085) investigating the combination of tafasitamab and lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have had at least one, but no more than three prior lines of therapy, including an anti-CD20 targeting therapy (e.g., rituximab), who are not eligible for high-dose chemotherapy (HDC) or autologous stem cell transplant (ASCT). The studys primary endpoint is overall response rate (ORR). Secondary outcome measures include duration of response (DoR), progression-free survival (PFS) and overall survival (OS). The study reached its primary completion in May 2019.

For more information about L-MIND, visit https://clinicaltrials.gov/ct2/show/NCT02399085.

About Minjuvi(R) (tafasitamab)Tafasitamab is a humanized Fc-modified CD19 targeting monoclonal antibody. In 2010, MorphoSys licensed exclusive worldwide rights to develop and commercialize tafasitamab from Xencor, Inc. Tafasitamab incorporates an XmAb(R) engineered Fc domain, which mediates B-cell lysis through apoptosis and immune effector mechanism including Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) and Antibody-Dependent Cellular Phagocytosis (ADCP).

In the U.S., Monjuvi(R)(tafasitamab-cxix) is approved by the U.S. Food and Drug Administration in combination with lenalidomide for the treatment of adult patients with relapsed or refractory DLBCL not otherwise specified, including DLBCL arising from low grade lymphoma, and who are not eligible for autologous stem cell transplant (ASCT). This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

In Europe, Minjuvi(R) (tafasitamab) received conditional approval, in combination with lenalidomide, followed by Minjuvi monotherapy, for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who are not eligible for autologous stem cell transplant (ASCT).

Tafasitamab is being clinically investigated as a therapeutic option in B-cell malignancies in several ongoing combination trials.

Minjuvi(R) and Monjuvi(R) are registered trademarks of MorphoSys AG. Tafasitamab is co-marketed by Incyte and MorphoSys under the brand name Monjuvi(R) in the U.S., and marketed by Incyte under the brand name Minjuvi(R) in Europe, the UK and Canada.

XmAb(R) is a registered trademark of Xencor, Inc.

About MorphoSysAt MorphoSys, we are driven by our mission to give more life for people with cancer. As a global commercial-stage biopharmaceutical company, we use groundbreaking science and technologies to discover, develop, and deliver innovative cancer medicines to patients. MorphoSys is headquartered in Planegg, Germany, and has its U.S. operations anchored in Boston, Massachusetts. To learn more, visit us at http://www.morphosys.com and follow us on Twitter and LinkedIn.

About Incyte Incyte is a Wilmington, Delaware-based, global biopharmaceutical company focused on finding solutions for serious unmet medical needs through the discovery, development and commercialization of proprietary therapeutics. For additional information on Incyte, please visit Incyte.com and follow @Incyte.

MorphoSys Forward-Looking StatementsThis communication contains certain forward-looking statements concerning the MorphoSys group of companies. The forward-looking statements contained herein represent the judgment of MorphoSys as of the date of this release and involve known and unknown risks and uncertainties, which might cause the actual results, financial condition and liquidity, performance or achievements of MorphoSys, or industry results, to be materially different from any historic or future results, financial conditions and liquidity, performance or achievements expressed or implied by such forward-looking statements. In addition, even if MorphoSys results, performance, financial condition and liquidity, and the development of the industry in which it operates are consistent with such forward-looking statements, they may not be predictive of results or developments in future periods. Among the factors that may result in differences are that MorphoSys expectations may be incorrect, the inherent uncertainties associated with competitive developments, clinical trial and product development activities and regulatory approval requirements, MorphoSys reliance on collaborations with third parties, estimating the commercial potential of its development programs and other risks indicated in the risk factors included in MorphoSys Annual Report on Form 20-F and other filings with the U.S. Securities and Exchange Commission. Given these uncertainties, the reader is advised not to place any undue reliance on such forward-looking statements. These forward-looking statements speak only as of the date of publication of this document. MorphoSys expressly disclaims any obligation to update any such forward-looking statements in this document to reflect any change in its expectations with regard thereto or any change in events, conditions or circumstances on which any such statement is based or that may affect the likelihood that actual results will differ from those set forth in the forward-looking statements, unless specifically required by law or regulation.

Incyte Forward-looking Statements Except for the historical information set forth herein, the matters set forth in this press release, including statements regarding whether and when Minjuvi might provide a successful treatment option for adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), the Companys ongoing clinical development program for tafasitamab, and its DLBCL program generally, contain predictions, estimates, and other forward-looking statements.These forward-looking statements are based on the Companys current expectations and subject to risks and uncertainties that may cause actual results to differ materially, including unanticipated developments in and risks related to: unanticipated delays; further research and development and the results of clinical trials possibly being unsuccessful or insufficient to meet applicable regulatory standards or warrant continued development; the ability to enroll sufficient numbers of subjects in clinical trials and the ability to enroll subjects in accordance with planned schedules; the effects of the COVID-19 pandemic and measures to address the pandemic on the Companys clinical trials, supply chain, and other third-party providers and development and discovery operations; determinations made by Swissmedic and other regulatory authorities; the Companys dependence on its relationships with its collaboration partners; the efficacy or safety of the Companys products and the products of the Companys collaboration partners; the acceptance of the Companys products and the products of the Companys collaboration partners in the marketplace; market competition; sales, marketing, manufacturing, and distribution requirements; and other risks detailed from time to time in the Companys reports filed with the Securities and Exchange Commission, including its annual report for the year ending December 31, 2021. The Company disclaims any intent or obligation to update these forward-looking statements.

# # #

For more information, please contact:

MorphoSys

Media contactsThomas BiegiVice PresidentTel.: +49 (0)89 / 89927 26079[emailprotected]

Investor contactsDr. Julia NeugebauerSenior DirectorTel: +49 (0)89 / 899 27 179[emailprotected]

Jeanette BressiDirector, U.S. CommunicationsTel: +1 617-404-7816[emailprotected]

Myles CloustonSenior DirectorTel: +1-857-772-0240[emailprotected]

Incyte

Media contactsEla ZawislakTel: + 41 21 581 5200[emailprotected]

Investor contactChristine ChiouSenior Director, Investor RelationsTel: +1 302 274 4773[emailprotected]

Catalina Loveman Executive Director, Public AffairsTel: +1 302 498 6171[emailprotected]

[1] Nationaler Krebsbericht; published 14th October 2021; https://www.bfs.admin.ch/bfs/de/home/aktuell/neueveroeffentlichungen.assetdetail.19305696.html;Accessed: March 2022[2] Duell et al. Long-term outcomes from the phase II L-MIND study of tafasitamab (MOR208) plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma. Haematologica. 2021. 106(9): 2417-2426. Doi: 10.3324/haematol.2020.275958[3] Cancer Research UK. Diffuse large B cell lymphoma. Available at https://www.cancerresearchuk.org/about-cancer/non-hodgkin-lymphoma/types/diffuse-large-B-cell-lymphoma. Accessed: October 2021.[4] DRG Epidemiology data.[5] Kantar Market Research (TPP testing 2018).[6] Friedberg, Jonathan W. Relapsed/Refractory Diffuse Large B-Cell Lymphoma. Hematology Am Soc Hematol Educ Program 2011; 2011:498-505. doi: 10.1182/asheducation-2011.1.498[7] Sarkozy C, et al. Management of relapsed/refractory DLBCL. Best Practice Research & Clinical Haematology. 2018 31:209-16. doi.org/10.1016/j.beha.2018.07.014.[8] Skrabek P, et al. Emerging therapies for the treatment of relapsed or refractory diffuse large B cell lymphoma. Current Oncology. 2019 26(4): 253-265. doi.org/10.3747/co.26.5421.[9] DRG Epidemiology data[10] Kantar Market Research (TPP testing 2018).[11] Friedberg, Jonathan W. Relapsed/Refractory Diffuse Large B-Cell Lymphoma. Hematology Am Soc Hematol Educ Program 2011; 2011:498-505. doi: 10.1182/asheducation-2011.1.498.

The DGAP Distribution Services include Regulatory Announcements, Financial/Corporate News and Press Releases.Archive at http://www.dgap.de

SOURCE: MorphoSys AG

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MorphoSys and Incyte Announce Swissmedic Temporary Approval of Minjuvi(R) (tafasitamab) in Combination with Lenalidomide for the Treatment of Adults...