Category Archives: Stem Cells

BOSTON A year ago, a man living with HIV walked into the exam room of Maile Young Karris, MD, from the UC San Diego Medical Center. He had seen on the news that there was a cure for HIV, and asked Karris: "How can I get it?"

Karris, who specializes in HIV primary care, explained that although one man then known as the London patient had been off medication for 18 months and remained in remission, that cure, if it were really a cure, was not available to him or, really, to any other patient with HIV.

"I'm often very hopeful. I believe we will get there," she told Medscape Medical News. "We're sort of just one scientific advance away."

But back then, she had to explain that the London patient, like the Berlin patient before him, had to get to the point of almost dying from cancer before the stem cell transplant that changed his immune system was even a possibility, and that both men had undergone a painful and invasive immunologic makeover.

So when it was reported at the virtual Conference on Retroviruses and Opportunistic Infections (CROI) 2020 that the London patient, now identified as Adam Castillejo, is still in remission a year later, even the researcher who performed the transplant was willing to say it's probably a cure.

But that likely won't change the way Karris or other HIV providers care for patients.

When Ravindra Gupta, MD, from University College London, presented the case of the London patient at CROI 2019, he was very careful to say "remission", not "cure".

But when he presented the case at CROI this year, he called it a cure, and he and his colleagues, in their report of the evidence published in the LancetHIV, state that "these findings probably represent the second recorded HIV-1 cure."

In May 2016, Castillejo received a stem cell transplant to treat stage4 Hodgkin's lymphoma, a non-AIDS-defining cancer. That transplant, like the one that Timothy Ray Brown, the so-called Berlin patient, received contained stem cells with two genetic mutations that remove the CCR5 receptor from the surface of the T-cell. Without that receptor, most HIV strains can't invade cells and, therefore, can't proliferate.

When Gupta presented preliminary findings last year, Castillejo had only been off HIV treatment for 18 months and was nearly 2 years out from his transplant. Back then, the team only took blood samples, but they showed that HIV wasn't present.

Then, just last month, samples from Castillejo including blood, plasma, semen, and tissue from his rectum, cecum, sigmoid colon and terminal ileum, and auxiliary lymph nodes were subjected to DNA, RNA, and other testing to see if the virus really was gone.

Although Castillejo's T-cell count is starting to approach where it had been before the transplant, there is no evidence that HIV is replicating in the blood, semen, or tissue samples tested, Gupta reported.

There were remnants of HIV genetic sequences in T-cells and in lymph node samples, though.

"Those can be regarded as so-called fossils," artifacts of past infection, not proof that HIV was still alive in his system, the researchers explain in the published report.

The findings are exciting, said Sharon Lewin, MBBS, PhD, from the Peter Doherty Institute for Infection and Immunity at the University of Melbourne in Australia, who was not involved in the study.

"It makes me think about a new definition of cure," she told Medscape Medical News. It's "the idea that clearing intact virus is what we're doing. And people may well have defective remnants of the virus, but that defective remnant can't replicate."

Of course, this is all still conjecture, she acknowledged. No one knows how long someone has to follow a person like Brown or Castillejo to know for sure that it will never come back. But she seems reassured that Castillejo had made it past the 27-month mark, which is when the viral load of the Mississippi baby rebounded.

When Gupta presented data on the London patient last year, "it was electric," said Rajesh Gandhi, MD, from Massachusetts General Hospital in Boston. "I think most of us remember where we were."

So it's probably not a surprise that people living with HIV were also electrified. It was a topic that popped up in many exam rooms, which some clinicians blamed on newspapers headlines such as "HIV Is Reported Cured in a Second Patient."

And even for patients who weren't asking directly for a stem cell transplant, the question of cure was urgent for many of them.

"I think most of my patients weren't thinking that it is so easy that they want to go through the rigors of chemotherapy," Gandhi told Medscape Medical News. But "people have definitely come in to my clinic asking: 'What type of cure research are you doing?'"

Gandhi said he directs patients back to what does work: a single pill a day to control HIV.

Right now, Gandhi has a patient who has had both cancer and HIV. The cancer is now gone, but the HIV remains. The patient shared his cancer diagnosis with family but still hasn't disclosed his HIV status.

"He could get all the support from his family around cancer, but he never could share his HIV diagnosis," Gandhi said. "I think this is what motivates people to ask about the London patient and the Berlin patient."

People are still afraid of HIV.

Karris has noticed the same thing. Not long ago, a woman came to the clinic and reported that her partner had pulled a knife on her.

"He'd found her HIV meds in her purse and looked it up," Karris explained. "He took a knife to her because she didn't disclose. He said he was going to cut off her fingertips."

The woman has a suppressed viral load, meaning she can't transmit the virus to her partner. California changed its criminal code in 2017 to make HIV nondisclosure a misdemeanor instead of a felony.

"People are still afraid of HIV," Karris said. "Some people hate the idea that they have HIV. This is one reason people stop taking medicine. They tell me: 'I hate coming here. I don't feel sick. And when I come to the clinic, I'm reminded I'm sick. When I take my meds, I'm reminded I'm sick'."

For patients who feel that way, she has three things to offer. One is the concept of undetectable equals untransmittable, meaning that they aren't putting the people they care about in the position to acquire HIV. That's been transformational for many patients, she said.

The second is that new HIV medications are coming soon that will be taken every month or every other month. "That seems helpful for them," she said. "They like the idea of coming in once a month. Then they don't have to think about it every day."

And finally, she said, she's excited to share a new tidbit, also presented at this year's CROI, that people who have CD4 a T-cell count of at least 500cells/mm3 when they start taking medication now have an average lifespan just 3 years less than those in the general public.

"The gap is closing between people living with HIV and those without," she said. "I try to communicate that. It can be mind-blowing for them, to see that they could live as long as anyone else."

Conference on Retroviruses and Opportunistic Infections (CROI) 2020: Abstract346. Presented March10, 2020.

Follow Medscape on Facebook, Twitter, Instagram, and YouTube

Read more:
Rethinking the Definition of Cure as Patients With HIV Wait - Medscape

OTTAWA, March 13, 2020 (GLOBE NEWSWIRE) -- Effective immediately, Canadian Blood Services is suspending all buccal swabbing events across the country and encouraging the public to register online to get their swab kit delivered in the mail.

This suspension aligns with guidance from the Public Health Agency of Canada to minimize the amount of time individuals spend in large crowds or in crowded spaces in order to reduce the transmission of COVID-19. It also is consistent with the public health measures being implemented by many of the provinces

The safety of registrants and their families is of utmost importance to us. We will be re-assessing this decision in 30 days.

For patients and families who might be concerned, bothCanadian Blood Services Stem Cell Registryand Canadian Blood Services Cord Blood Bankaremembersof the World Marrow Donor Association (WMDA) an international network of registries and cord blood banks that share a global database where all potential donors and cord blood units are listed. As cases of COVID-19 continue to emerge across the world, WMDA has launched a specialCOVID-19 webpagethat is publicly available and updated regularly when new information is shared by member organizations, professional societies and courier companies.

Canadian Blood Services will continue to monitor the COVID-19 situation and provide updates as they are received.Our stem cell registry will continue to coordinate searches in Canada, as well as other international registries to help patients get the stem cells they need. Any critical information is being communicated to the corresponding transplant centre and/or registry toensure thatlife-saving products are safely transported to patients in need.Our donors will continue to be screened for active infections and travel history.

In addition to the cancellation of the swabbing events, Canadian Blood Services is also suspending our popular Whats Your Type events across the country. These are events that are frequently held in public spaces like shopping malls inviting people to find out their blood types. We will revisit this cancellation as well in the coming weeks.

If you requireassistance regarding activations currently in progress for any of the international registries in countries where COVID-19 cases have been recorded, please reach out to the transplant services coordinator team atcbs.onematch@blood.ca

For the latest information, visit our COVID-19 update.

Visit link:
Suspension of group swabbing events in response to COVID-19 pandemic - GlobeNewswire

NEW YORK, March 10, 2020 (GLOBE NEWSWIRE) -- Mesoblast Limited(Nasdaq: MESO; ASX:MSB) today announced that it plans to evaluate its allogeneic mesenchymal stem cell (MSC) product candidate remestemcel-L in patients with acute respiratory distress syndrome (ARDS) caused by coronavirus (COVID-19) in the United States, Australia, China and Europe. The Company is in active discussions with various government and regulatory authorities, medical institutions and pharmaceutical companies to implement these activities.

Mortality in COVID-19 infected patients with the inflammatory lung condition acute respiratory distress syndrome (ARDS) is reported to approach 50%, and is associated with older age, co-morbidities such as diabetes, higher disease severity, and elevated markers of inflammation.1 Current therapeutic interventions do not appear to be improving in-hospital survival.1

Remestemcel-L has potential for use in the treatment of ARDS, which is the principal cause of death in COVID-19 infection.1 This is supported by recently published results from an investigator-initiated clinical study conducted in China which reported that allogeneic MSCs cured or significantly improved functional outcomes in all seven treated patients with severe COVID-19 pneumonia.2

Additionally, in post-hoc analyses of a 60-patient randomized controlled study in chronic obstructive pulmonary disease (COPD), remestemcel-L infusions were well tolerated, significantly reduced inflammatory biomarkers, and significantly improved pulmonary function in those patients with elevated inflammatory biomarkers. Since the same inflammatory biomarkers are also elevated in COVID-19, these data suggest that remestemcel-L could be useful in the treatment of patients with ARDS due to COVID-19.The COPD study results have been submitted for presentation at an international conference, with full results to be submitted for publication shortly.

Remestemcel-L is being studied in numerous clinical trials across several inflammatory conditions, including in elderly patients with lung disease and adults and children with steroid-refractory acute graft versus host disease (aGVHD).3-5 This product candidate is currently being reviewed by the United States Food and Drug Administration (FDA) for potential approval in the treatment of children with steroid-refractory aGVHD.

Remestemcel-L Remestemcel-L is being developed for rare pediatric and adult inflammatory conditions. It is an investigational therapy comprising culture-expanded MSCs derived from the bone marrow of an unrelated donor and is administered in a series of intravenous infusions. Remestemcel-L is believed to have immunomodulatory properties to counteract the inflammatory processes that are implicated in several diseases by down-regulating the production of pro-inflammatory cytokines, increasing production of anti-inflammatory cytokines, and enabling recruitment of naturally occurring anti-inflammatory cells to involved tissues.

Intellectual PropertyMesoblasts intellectual property (IP) portfolio encompasses over 1,000 patents or patent applications in all major markets and includes the use of MSCs obtained from any source for patients with acute respiratory distress syndrome (ARDS),and for inflammatory lung disease due to coronavirus (COVID-19), influenza and other viruses. Additionally, these patents cover Mesoblasts manufacturing processes that yield industrial-scale cellular medicines.This IP position is expected to provide Mesoblast with substantial commercial advantages as it develops its product candidates for these conditions.

References1. Liu Y et al. Clinical features and progression of acute respiratory distress syndrome in coronavirus disease 2019. Medrxiv 2020; https://doi.org/10.1101/2020.02.17.200241662. Leng Z, et al. Transplantation of ACE2- Mesenchymal Stem Cells Improves the Outcome of Patients with COVID-19 Pneumonia[J]. Aging and Disease, 10.14336/AD.2020.02283. Kurtzberg J et al. Annual Meeting of the American Society for Transplantation Cell Therapy, 2020.4. Chaudhury S et al. A Phase 3 Single-Arm, Prospective Study of Remestemcel-L, Ex-Vivo Cultured Adult Human Mesenchymal Stromal Cells, for the Treatment of Steroid Refractory Acute GVHD in Pediatric Patients. Biol Blood Marrow Transplant 2018; 24:S119S290.5. Kurtzberg J et al. Allogeneic human mesenchymal stem cell therapy (remestemcel-L, Prochymal) as a rescue agent for severe refractory acute graft-versus-host disease in pediatric patients. Biol Blood Marrow Transplant. 2014 Feb;20(2):229-35.

About MesoblastMesoblast Limited (Nasdaq: MESO; ASX: MSB) is a world leader in developing allogeneic (off-the-shelf) cellular medicines. The Company has leveraged its proprietary mesenchymal lineage cell therapy technology platform to establish a broad portfolio of commercial products and late-stage product candidates. Mesoblasts proprietary manufacturing processes yield industrial-scale, cryopreserved, off-the-shelf, cellular medicines. These cell therapies, with defined pharmaceutical release criteria, are planned to be readily available to patients worldwide.

Mesoblast has filed a Biologics License Application to the United States Food and Drug Administration (FDA) to seek approval of its product candidate RYONCIL (remestemcel-L) for steroid-refractory acute graft versus host disease (acute GvHD). Remestemcel-L is also being developed for other rare diseases. Mesoblast is completing Phase 3 trials for its product candidates for advanced heart failure and chronic low back pain. If approved, RYONCIL is expected to be launched in the United States in 2020 for pediatric steroid-refractory acute GVHD. Two products have been commercialized in Japan and Europe by Mesoblasts licensees, and the Company has established commercial partnerships in Europe and China for certain Phase 3 assets.

Mesoblast has locations in Australia, the United States and Singapore and is listed on the Australian Securities Exchange (MSB) and on the Nasdaq (MESO). For more information, please see http://www.mesoblast.com, LinkedIn: Mesoblast Limited and Twitter: @Mesoblast

Forward-Looking StatementsThis announcement includes forward-looking statements that relate to future events or our future financial performance and involve known and unknown risks, uncertainties and other factors that may cause our actual results, levels of activity, performance or achievements to differ materially from any future results, levels of activity, performance or achievements expressed or implied by these forward-looking statements. We make such forward-looking statements pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995 and other federal securities laws. Forward-looking statements should not be read as a guarantee of future performance or results, and actual results may differ from the results anticipated in these forward-looking statements, and the differences may be material and adverse. Forward- looking statements include, but are not limited to, statements about: the initiation, timing, progress and results of Mesoblasts preclinical and clinical studies, and Mesoblasts research and development programs; Mesoblasts ability to advance product candidates into, enroll and successfully complete, clinical studies, including multi-national clinical trials; Mesoblasts ability to advance its manufacturing capabilities; the timing or likelihood of regulatory filings and approvals, manufacturing activities and product marketing activities, if any; the commercialization of Mesoblasts product candidates, if approved; regulatory or public perceptions and market acceptance surrounding the use of stem-cell based therapies; the potential for Mesoblasts product candidates, if any are approved, to be withdrawn from the market due to patient adverse events or deaths; the potential benefits of strategic collaboration agreements and Mesoblasts ability to enter into and maintain established strategic collaborations; Mesoblasts ability to establish and maintain intellectual property on its product candidates and Mesoblasts ability to successfully defend these in cases of alleged infringement; the scope of protection Mesoblast is able to establish and maintain for intellectual property rights covering its product candidates and technology; estimates of Mesoblasts expenses, future revenues, capital requirements and its needs for additional financing; Mesoblasts financial performance; developments relating to Mesoblasts competitors and industry; and the pricing and reimbursement of Mesoblasts product candidates, if approved. You should read this press release together with our risk factors, in our most recently filed reports with the SEC or on our website. Uncertainties and risks that may cause Mesoblasts actual results, performance or achievements to be materially different from those which may be expressed or implied by such statements, and accordingly, you should not place undue reliance on these forward-looking statements. We do not undertake any obligations to publicly update or revise any forward-looking statements, whether as a result of new information, future developments or otherwise.

Release authorized by the Chief Executive.

For further information, please contact:

Original post:
Mesoblast To Evaluate Anti-Inflammatory Cell Therapy Remestemcel-L For Treatment Of COVID-19 Lung Disease - BioSpace

Although most of the news from the world of health and medicine has been quite bleak lately, there are still major strides being made in the sector in an effort to combat the worst illnesses that plague humankind. One such stride was just announced, and its certainly worth celebrating: A second person has been cured of HIV.

In a study published in the medical journal, The Lancet, which comes via Medical News Daily, researchers in London say theyve been able to cure a patient of HIV; meaning the patient tested negative for HIV for an extended period of time (30 months as of March, 2020) despite the lack of antiretroviral therapy.

The person whos been cured, Adam Castillejo, was formerly known only as the London patient in order to protect his identity. But Castillejo, who lives in London, came forward recently, and said that he aims to be an ambassador of hope.

The first person to be cured of HIV, Timothy Ray Brown, an American known originally as the Berlin patient, revealed his identity in 2010, saying that I wanted to do what I could to make [a cure] possible. My first step was releasing my name and image to the public. Brown lived and was treated in Berlin. Incidentally, he is technically the second Berlin patient because the results from treatment of the first one are debatable.

AIDS Policy Project with Timothy Ray Brown (third from left with sunglasses). Griffin Boyce.

Castillejo, as well as Brown, were cured of HIV not by antiretroviral medications, which are often able to drastically mitigate the effects, and transmission rate of, HIV, but rather by stem cell transplants from donor bone marrow. Both Castillejo and Brown hadand may still have, that is unclearcancer along with HIV, and were treated with the stem cell transplants primarily to tackle the former disease. (It seems in Castillejos case doctors and researchers were hoping to cure both simultaneously.)

Both Brown and Castillejo underwent a procedure known as a Hematopoietic stem cell transplantation (or HSCT), which involves injecting bone marrow stem cells from a donor, whos often times a parent or sibling, into the recipients bloodstream. Castillejos HSCT treatment was different from Browns, as well as many others, because it was performed with cells that expressed the CCR5 gene.

A video from the MD Anderson Cancer Center that gives a brief outline of how bone marrow stem cell transplants work.

In Castillejos case, stem cells with genomes that express the CCR5 gene were selected because of the fact that it allows for the production of the CCR5 protein: a protein that makes people far more resistant to HIV-1, which accounts for the vast majority of global HIV infections.

While Castillejo received stem cells that did express the CCR5 gene, Brown did notat least according to the study in The Lancet. In fact, according to a 2017 article in New Scientist (which says that Brown received cells with a mutated CCR5 gene, rather than an unexpressed CCR5 gene), some experts believe the curing of Browns HIV was actually due to a potential side effect of his procedure, known as graft-versus-host disease. According to New Scientist, these experts believe that the donor cells attacked Browns native, HIV-infected immune cells, subsequently killing off the virus.

In Castillejos case, on the other hand, it seems there was no graft-versus-host issue that could account for his diminishment of HIV infection levels beyond whats expected to be detectable. Instead, the authors of the study say that one of the implications here is that the Long-term remission of HIV-1 can be achieved utilizing these kinds of cells. The authors also say this method does not require total body irradiation, which would usually be required in cases like these to weaken a recipients immune system in order to allow them to accept donor cells.

An HIV-infected T cell. NIAID

Unfortunately, it seems the treatment that cured Castillejo of HIV is a nonstarter when it comes to mass deployment. There are fatal side effects associated with HSCT, with host-versus-graft chief among them, and doctors say that it should only be performed when there are no other options left.

Prof. Ravindra Kumar Gupta from the University of Cambridge in the U.K., the lead author of the study, told Medical News Daily that [Its] important to note that this curative treatment is high risk and only used as a last resort for patients with HIV who also have life threatening hematological [blood] malignancies.

But Gupta and the other authors of the study still appear to be optimistic that this stands as a proof-of-concept for the idea of using CCR5 gene editing to cure HIV on a larger scale. They warn in their study, however, that several barriers, including the need for increased gene editing efficiency and a lack of robust safety data, still stand in the way of something that could be used as a scalable strategy for tackling HIV.

What do you think about this method of treating HIV? Do you think gene editing will play a big role in curing HIV, or do you think there are other, more promising treatments worth pursuing instead? Let us know your thoughts in the comments.

Feature image: C. Goldsmith / Eliot Lash

Read the rest here:
A Second Person Has Been Cured of HIV - Nerdist

Life is rife with patterns. Its common for living things to create a repeating series of similar features as they grow: think of feathers that vary slightly in length on a birds wing or shorter and longer petals on a rose.

Stanford researchers used advanced microscopy and mathematical modeling to discover a pattern that governs the growth of neurons in the flatworm brain, shown here. Using this technique, they hope to find patterns that guide the growth of cells in other parts of the body in order to pave the way to bioengineer artificial tissues and organs. (Image credit: Courtesy of Wang Lab)

It turns out the brain is no different. By employing advanced microscopy and mathematical modeling, Stanford researchers have discovered a pattern that governs the growth of brain cells or neurons. Similar rules could guide the development of other cells within the body, and understanding them could be important for successfully bioengineering artificial tissues and organs.

Their study, published in Nature Physics, builds on the fact that the brain contains many different types of neurons and that it takes several types working in concert to perform any tasks. The researchers wanted to uncover the invisible growth patterns that enable the right kinds of neurons to arrange themselves into the right positions to build a brain.

How do cells with complementary functions arrange themselves to construct a functioning tissue? said study co-author Bo Wang, an assistant professor of Bioengineering. We chose to answer that question by studying a brain because it had been commonly assumed that the brain was too complex to have a simple patterning rule. We surprised ourselves when we discovered there was, in fact, such a rule.

The brain they chose to examine belonged to a planarian, a millimeter-long flatworm that can regrow a new head every time after amputation. First, Wang and Margarita Khariton, a graduate student in his lab, used fluorescent stains to mark different types of neurons in the flatworm. They then used high-resolution microscopes to capture images of the whole brain glowing neurons and all and analyzed the patterns to see if they could extract from them the mathematical rules guiding their construction.

What they found was that each neuron is surrounded by roughly a dozen neighbors similar to itself, but that interspersed among them are other kinds of neurons. This unique arrangement means that no single neuron sits flush against its twin, while still allowing different types of complementary neurons to be close enough to work together to complete tasks.

The researchers found that this pattern repeats over and over across the entire flatworm brain to form a continuous neural network. Study co-authors Jian Qin, an assistant professor of chemical engineering, and postdoctoral scholar Xian Kong developed a computational model to show that this complex network of functional neighborhoods stems from the tendency of neurons to pack together as closely as possible without being too close to other neurons of the same type.

While neuroscientists might someday adapt this methodology to study neuronal patterning in the human brain, the Stanford researchers believe the technique could be more usefully applied to the emerging field of tissue engineering.

The basic idea is simple: tissue engineers hope to induce stem cells, the powerful, general-purpose cells from which all cell types derive, to grow into the various specialized cells that form a liver, kidney or heart. But scientists will need to arrange those diverse cells into the right patterns if they want the heart to beat.

The question of how organisms grow into forms that carry out useful functions has fascinated scientists for centuries, Wang said. In our technological era, we are not limited to understanding these growth patterns at the cellular level but can also find ways to implement these rules for bioengineering applications.

This work was supported by the Burroughs Wellcome Fund.

See the article here:
The hidden pattern that drives brain growth | Stanford News - Stanford University News

Transfusion of red blood cells (RBCs) is a life-saving treatment for numerous conditions such as severe anaemia, injury-related trauma, supportive care in cardiovascular surgery, transplant surgery, pregnancy-related complications, solid malignancies and blood-related cancers.

However, blood banks particularly in developing countries often face a severe shortage of whole blood as well as components of blood like red blood cells.

Researchers across the world are exploring possibilities to generate RBCs outside the body (in vitro) from haematopoietic stem cells (HSCs). These HSCs have the capability to give rise to the different types of cells found in the blood. Various groups have been able to produce RBCs in the laboratory from HSCs.

However, the process takes a long time - around twenty-one days. The resources required to grow cells in the laboratory over such a long duration can be very expensive for generation of RBCs on a large scale for clinical purposes.

A team of researchers led by Dr. L. S. Limaye, ex-scientist at the Department of Biotechnologys National Centre for Cell Science (NCCS) at Pune have found a way to tackle the issue.

They have found that the process can be speeded up by adding a very low concentration of a small protein molecule called `transforming growth factor 1 (TGF-1), along with a hormone called `erythropoietin (EPO), to the growth medium. They could cut down the process time by three days.

Dr. Limaye noted that several tests to assess the quality of the cells formed, and examination of many of their characteristics, including physical appearance, revealed that the RBCs formed using this procedure were normal.

The findings are worthy of further exploration. Additional investigations based on the insights gained from these studies could help assess the relevance of using this approach for blood transfusions in the future. The researchers have published a report on their work in the journal, `Stem Cell Research and Therapy.

(India Science Wire)

Go here to read the rest:
New approach to speed up red blood cells generation in the lab - BusinessLine

Shinya Yamanaka's 2006 discovery of induced pluripotent stem cells (iPSCs) ignited a revolution in the field of stem cell biology (1). For the first time, nearly all human somatic tissues could be produced from iPSCs reprogrammed from blood or skin cells, in a process that took only weeks. This advance was particularly crucial for obtaining surrogate tissues from cell types that are otherwise difficult to procure and do not readily expand in vitro, such as cardiac or neural cells. Additionally, many ethical concerns are avoided, because this technology uses a patient's own genetic material to create iPSCs rather than relying on embryonic stem cells. In the aftermath of Yamanaka's discovery, entire biomedical industries have developed around the promise of using human iPSCs (hiPSCs) and their derivatives for in vitro disease modeling, drug screening, and cell therapy (2).

The hiPSC technology has had a particularly notable impact in cardiac regenerative medicine, a field where scientists and clinicians have been working to devise new methods to better understand how cardiovascular disease manifests and how to restore cardiovascular function after disease strikes (3). The heart is limited in its ability to regenerate lost cardiomyocytes (beating heart muscle cells), following an adverse event such as a heart attack (4). Cardiomyocytes derived from hiPSCs (hiPSC-CMs) may represent a potential replacement option for dead cells in such a scenario. However, certain issues remain to be addressed, such as whether hiPSC-CMs can integrate with host myocardial tissue in the long term (5).

While using hiPSC-CMs for in vivo cell therapy may become practical in the future, employing hiPSC-CMs for high-throughput drug discovery and screening is becoming a reality in the present (6). Cardiovascular diseases can be recapitulated in a dish with patient-specific hiPSC-CMs. For example, if a patient exhibits a cardiac arrhythmia caused by a genetic abnormality in a sarcomeric protein or ion channel, that same rhythm problem can be recapitulated in vitro (7). Thanks to advances in hiPSC differentiation protocols, hiPSC-CMs can now be mass-produced to study cardiovascular disease mechanisms in vitro (8).

My graduate thesis in the laboratories of Joseph Wu and Sean Wu at Stanford University focused on in vitro applications of hiPSC-CMs for cardiovascular disease modeling and for high-throughput screening of chemotherapeutic compounds to predict cardiotoxicity. I initially embarked on a project using hiPSC-CMs to model viral myocarditis, a viral infection of the heart, caused by the B3 strain of coxsackievirus (9). I began by demonstrating that hiPSC-CMs express the receptors necessary for viral internalization and subsequently found that hiPSC-CMs were highly susceptible to coxsackievirus infection, exhibiting viral cytopathic effect within hours of infection. I also identified compounds that could alleviate coxsackievirus infection on hiPSC-CMs, a translationally relevant finding, as there remains a shortage of treatments for viral myocarditis.

Using a genetically modified variant of coxsackievirus B3 expressing luciferase, I developed a screening platform for assessing the efficacy of antiviral compounds. Pretreatment with interferon-, ribavirin, or pyrrolidine dithiocarbamate markedly suppressed viral replication on hiPSC-CMs by activating intracellular antiviral response and viral protein clearance pathways. These compounds alleviated viral replication in a dose-dependent fashion at low concentrations without causing cellular toxicity.

I next sought to use hiPSC-CMs to screen anticancer chemotherapeutic compounds for their off-target cardiovascular toxicities (10). Cardiotoxicity represents a major cause of drug withdrawal from the pharmaceutical market, and several chemotherapeutic agents can cause unintended cardiovascular damage (11). Using cultured hiPSC-CMs, I evaluated 21 U.S. Food and Drug Administrationapproved tyrosine kinase inhibitors (TKIs), commonly prescribed anticancer compounds, for their cardiotoxic potential. HiPSC-CMs express the major tyrosine kinase receptor proteins such as the insulin, insulin-like growth factor (IGF), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF) receptors, lending validity to this cellular model.

Initially, human induced pluripotent stem cells (hiPSCs) can be produced by reprogramming skin or blood cells by nonviral or viral reprogramming methods. Cardiac differentiation protocols allow for the creation of cardiomyocytes derived from hiPSCs (hiPSC-CMs) for downstream applications, including in vitro disease modeling, drug screening, and regenerative cell therapy.

With data from a battery of cellular apoptosis, contractility, electrophysiology, and signaling assays, I generated a cardiac safety index to help align in vitro toxicity data to clinical drug safety guidelines (12). From the safety index, I determined that a subclass of VEGF receptor 2/PDGF receptorinhibiting tyrosine kinase inhibitors, some of which exhibit toxicity clinically, also elicited cardiotoxicities in hiPSC-CMs. These manifested as substantial alterations in cellular electrophysiology, contractility, and viability when administered at clinically relevant concentrations. I also discovered that cotreatment with either IGF or insulin partially rescued TKI-induced toxicity by up-regulating antiapoptotic signaling pathways. This work could prove useful for groups aiming to develop effective screening platforms to assess new chemotherapeutic compounds for cardiotoxic side effects.

I also collaborated with the Center for the Advancement of Science in Space (CASIS) to send a sample of hiPSC-CMs to the International Space Station. As humankind ventures beyond our home planet, it is imperative that we better understand how the heart functions for long periods of time in microgravity. Analysis of these hiPSC-CMs revealed microgravity-induced alterations in metabolic gene expression and calcium handling (13).

In recent years, the stem cell field has experienced an explosion of studies using hiPSC-CMs as a model cellular system to study cardiovascular biology. As improvements in hiPSC-CM mass production continue, we will see a rise in studies using these cells for disease modeling and drug screening. Thus, although hiPSC-CM technology is in its infancy, it holds great potential to improve cardiovascular health.

PHOTO: COURTESY OF A. SHARMA

FINALIST

Arun Sharma

Arun Sharma received his undergraduate degree from Duke University and a Ph.D. from Stanford University. Having completed a postdoctoral fellowship at the Harvard Medical School, Sharma is now a senior research fellow jointly appointed at the Smidt Heart Institute and Board of Governors Regenerative Medicine Institute at the Cedars-Sinai Medical Center in Los Angeles. His research seeks to develop in vitro platforms for cardiovascular disease modeling and drug cardiotoxicity assessment. http://www.sciencemag.org/content/367/6483/1206.1

The rest is here:
Stem cells to help the heart - Science Magazine

A 40-year-old HIV patient has been declared cured after a promising treatment has left him with no active virus. The man, Adam Castillejo, was the subject of extensive research in early 2019 after doctors failed to find HIV in his body over an 18-month period after previously being diagnosed in 2003.

Castillejo, known by the nickname London Patient lived with the disease for many years, taking medicine to manage it since 2012. That same year he was diagnosed with Hodgkins Lymphoma and later endured a bone marrow transplant. That operation may have ultimately cured him of HIV and appears to have made him only the second person to ever be cured of the disease that causes AIDS.

As ScienceAlert reports, the bone marrow transplant that doctors performed on Castillejo used cells from a donor with a very special genetic quirk. The cells are thought to work against HIV in the body, but there was no guarantee that the transplant would provide any concrete benefits beyond treating the cancer.

However, it appears as though the decision to treat Castillejo with the unique stem cells worked in more ways than one and last year doctors announced they couldnt find the virus in his body after 18 months. At the time, they were hesitant to declare the London Patient cured, but after a new round of testing returned the same results, they are more confident that the active form of the virus has indeed been defeated.

This is a unique position to be in, a unique and very humbling position, Castillejo told the New York Times. I want to be an ambassador of hope.

While this sounds like incredible news and for Castillejo, it certainly is the treatment is not an option for everyone. With cancer limiting their options, doctors used the stem cell transplant as a last resort to keep him alive. Its a serious operation and one that was only performed because Castillejos condition was so dire.

Castillejo and the other HIV patient who had similar results, known as the Berlin Patient, may be uniquely fortunate. The doctors note that there are others who have had the same transplant performed but did not improve as rapidly as the others. There are obviously many factors at work here and as exciting as it is to see a second person cured of this terrible disease, theres a lot more work to be done before we can say HIV has been truly beaten.

Read more here:
HIV patient appears to be cured after stem cell treatment - New York Post

Bone remodeling and regeneration are dependent on resident stem/progenitor cells with the capability to replenish mature osteoblasts and repair the skeleton.

Until now, it has been thought that stem cells for bone lie within the bone marrow and the outer surface of the bone. Many studies have described the existence of a network of vascular channels that helped distribute blood cells out of the bone marrow. However, none of the studies had proved the existence of cells within these channels.

A new study by the scientists from the UConn School of Dental Medicine has discovered the population of stem cells that reside along the vascular channels within the cortical bone and have the ability to generate new bone. These stem cells stretch across the bone and connect the inner and outer parts of the bone.

Lead investigator Dr. Ivo Kalajzic, professor of reconstructive sciences, said, This is a discovery of perivascular cells residing within the bone itself that can generate new bone-forming cells. These cells likely regulate bone formation or participate in bone mass maintenance and repair.

This is the first study that reports the existence of these progenitor cells within the cortical bone that can generate new bone-forming cellsosteoblaststhat can be used to help remodel a bone.

To reach this conclusion, the scientists observed the stem cells within an ex vivo bone transplantation model. These cells migrated out of the transplant and started to reconstruct the bone marrow cavity and form new bone.

However, further study is required to determine the cells potential to regulate bone formation and resorption.

The study is presented in the journal Stem Cells.

Read this article:
These new stem cells have the ability to generate new bone - Tech Explorist

By Stephanie Chow | March 12, 2020

Three Faculty of Medicine researchers Drs. Zachary Laksman, Bruce Verchere and Tim Kieffer have collectively received more than $1.6M from the Stem Cell Network (SCN) to advance their work in stem cell and regenerative medicine research.

The SCN investment, which will advance research collaborations across the country, aims to translate stem cell-based therapies from bench to bedside for the benefit of all Canadians.

Dr. Zachary Laksman, Department of Medicine, Division of Cardiology

UBC Collaborators: Dr. Glen Tibbits, Dr. Liam Brunham, Dr. Francis Lynn, Dr. Shubhayan Sanatani

Project: Pipeline Towards Stem Cell Driven Personalized Medicine for Atrial Fibrillation

Dr. Bruce Verchere, Department of Pathology & Laboratory Medicine

UBC Collaborators: Dr. Francis Lynn, Dr. Megan Levings, Tim Kieffer, Dr. Dina Panagiotopoulos, Dr. Brad Hoffman

Project: Genetic Manipulation of hES-derived Insulin-producing Cells to Improve Graft Outcomes

Dr. Tim Kieffer, Department of Cellular & Physiological Sciences

UBC Collaborators: Dr. James Piret, Dr. Megan Levings

Project: A Bioprinted Insulin-Producing Device for Diabetes

Read this article:
Faculty members receive funding to advance stem cell research - UBC Faculty - UBC Faculty of Medicine