Category Archives: Stem Cells

Stem cell research has long been seen as a new frontier for disease therapeutics. By coaxing stem cells to form 3D miniature lung structures, University researchers are helping explain why.

In a collaborative study, University researchers devised a system to generate self-organizing human lung organoids, or artificially-grown organisms. These organoids are 3D models that can be used to better understand lung diseases.

Jason Spence, the assistant professor of internal medicine and cell and developmental biology, who was a senior author of the study, said one of the key implications of these lungs is the controlled environment they offer for future research.

These mini lungs will allow us to study diseases in a controlled environment and to develop and test new drugs, he said.

Specifically, Spence said, scientists will be able to take skin samples from patients with a particular form of a lung disease, reprogram the cells into stem cells and then generate lung tissue for further study. He said by analyzing the disease in a controlled environment, researchers can gain insight into the progression of various diseases and then tailor drugs for treatment.

Rackham student Briana Dye was also a lead author of the study. She said the team manipulated numerous signaling pathways involved with cell growth and organ formation to make the miniature lungs.

First, Dye said the scientists used proteins called growth factors to differentiate embryonic stem cells into endoderm, the germ layer that gives rise to the lungs. Different growth factors were then used to cause the endoderm to become lung tissue.

We add specific growth factors, proteins that turn on pathways in the cells, that will then cause them to lift off the monolayer so that we have this 3D spherical tissue, she said.

Previous research has used stem cells in a similar manner to generate brain, intestine, stomach and liver tissue. Dye said one of the advantages of stem cell research is its direct path to studying human tissue.

We have worked with many animal models in the past, Dye said. Animal models present obstacles because they dont exactly behave the way human tissue and cells do. This is why stem cells are so promising.

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Research develops mini-lung structures

Scientists have developed a blood test using human stem cells that predicts whether new drugs will cause severe side effects. The test, which only requires blood from a single donor, could help prevent catastrophic inflammatory reactions known as a cytokine storm in people participating in drug trials.

"As biological therapies become more mainstream, its more likely that drugs being tested on humans for the first time will have unexpected and potentially catastrophic effects," says Professor Jane Mitchell from the National Heart and Lung Institute at Imperial College London, who led the study. "Weve used adult stem cell technology to develop a laboratory test that could prevent another disaster like the TGN1412 trial."

In 2006 six healthy young men were hospitalized with multiple organ failure after experiencing a cytokine storm as a result of taking part in the first tests in humans of the drug TGN1412.

Tests on human cells are essential because biological therapies, or "biologics" (such as the cancer drugs Herceptin and Avastin), use antibodies which are specific to humans. They can cause severe reactions, such as a cytokine storm, that dont occur in animal studies.

Cytokine storm reactions are difficult to predict using tests where just one cell type is used because they require interactions between blood cells and endothelial cells (the cells which form the lining of blood vessels).

However, because endothelial cells are located deep within the body and are difficult to access, they are normally only grown from tissue removed in surgery, during post-mortem, or from umbilical vessels after birth. Current testing is therefore performed on endothelial cells from one donor and white blood cells from a different donor.

This in itself can present issues; when cells from two different donors are used, one may have an immune reaction to the other, meaning the body is already primed for inflammation before the drug is added, potentially leading to false test results.

The Imperial College London team has developed a new method of testing which requires blood from only one donor, making it far more reliable.

By taking stem cells from the blood of a volunteer and using them to grow endothelial cells in a dish, a process which takes seven to 20 days, then adding them to the donor's white blood cells, they have recreated the unique conditions found in the donor's blood vessels. When the researchers added TGN1412 to the test tube, the cells released a cytokine storm, just as would happen inside the body.

The scientists are now developing an off-the-shelf kit to enable drug companies to use the test on a large scale.

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Blood test uses human stem cells to predict severe drug reactions

Nr0b1 is a negative regulator of Zscan4c in mouse embryonic stem cells
Nr0b1 is a negative regulator of Zscan4c in mouse embryonic stem cells. Setsuko Fujii et al (2015), Scientific Reports http://dx.doi.org/10.1038/srep09146 Nuclear receptor subfamily 0, group...

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Nr0b1 is a negative regulator of Zscan4c in mouse embryonic stem cells - Video

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Scientists at the University of Copenhagen have captured thousands of progenitor cells of the pancreas on video as they made decisions to divide and expand the organ or to specialize into the endocrine cells that regulate our blood sugar levels.

The study reveals that stem cells behave as people in a society, making individual choices but with enough interactions to bring them to their end-goal. The results could eventually lead to a better control over the production of insulin-producing endocrine cells for diabetes therapy.

The research is published in the scientific journal PLOS Biology.

Why one cell matters

In a joint collaboration between the University of Copenhagen and University of Cambridge, Professor Anne Grapin- Botton and a team of researchers including Assistant Professor Yung Hae Kim from DanStem Center focused on marking the progenitor cells of the embryonic pancreas, commonly referred to as 'mothers', and their 'daughters' in different fluorescent colours and then captured them on video to analyse how they make decisions.

Prior to this work, there were methods to predict how specific types of pancreas cells would evolve as the embryo develops. However, by looking at individual cells, the scientists found that even within one group of cells presumed to be of the same type, some will divide many times to make the organ bigger while others will become specialized and will stop dividing.

The scientists witnessed interesting occurrences where the 'mother' of two 'daughters' made a decision and passed it on to the two 'daughters' who then acquired their specialization in synchrony. By observing enough cells, they were able to extract logic rules of decision-making, and with the help of Pau Ru, a mathematician from the University of Cambridge, they developed a mathematical model to make long-term predictions over multiple generations of cells.

Stem cell movies

'It is the first time we have made movies of a quality that is high enough to follow thousands of individual cells in this organ, for periods of time that are long enough for us to follow the slow decision process. The task seemed daunting and technically challenging, but fascinating", says Professor Grapin-Botton.

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Stem cells make similar decisions to humans

An injection of a patient's bone marrow stem cells during rotator cuff surgery significantly improved healing and tendon durability, according to a study presented today at the 2015 Annual Meeting of the American Academy of Orthopaedic Surgeons (AAOS).

Each year in the U.S., more than 2 million people have rotator cuff surgery to re-attach their shoulder tendon to the head of the humerus (upper arm bone). Rotator cuff tears can occur during a fall or when lifting an extremely heavy object; however, most tears are the result of aging and overuse.

The French study, of which a portion appeared in the September 2014 issue of International Orthopaedics, included 90 patients who underwent rotator cuff surgery. Researchers tried to make the two groups as equivalent as possible based on rotator cuff tear size, tendon rupture location, dominate shoulder, gender and age. Forty-five of the patients received injections of bone marrow concentrate (BMC) mesenchymal stem cells (MSCs) at the surgical site, and 45 had their rotator cuff repaired or reattached without MSCs.

Patient ultrasound images were obtained each month following surgery for 24 months. In addition, MRI images were obtained of patient shoulders at three and six months following surgery, and at one year, two years, and 10 years following surgery.

At six months, all 45 of the patients who received MSCs had healed rotator cuff tendons, compared to 30 (67 percent) of the patients who did not receive MSCs. The use of bone marrow concentrate also prevented further ruptures or retears. At 10 years after surgery, intact rotator cuffs were found in 39 (87 percent) of the MSC patients, but just 20 (44 percent) of the non-MSC patients.

In addition, "some retears or new tears occurred after one year," said Philippe Hernigou, MD, an orthopaedic surgeon at the University of Paris and lead study author. "These retears were more frequently associated with the control group patients who were not treated with MSCs.

"While the risk of a retear after arthroscopic repair of the rotator cuff has been well documented, publications with long-term follow-up (more than three years) are relatively limited," said Dr. Hernigou. "Many patients undergoing rotator cuff repair surgery show advanced degeneration of the tendons, which are thinner and atrophic (more likely to degenerate), probably explaining why negative results are so often reported in the literature, with frequent post-operative complications, especially retear. Observations in the MSC treatment group support the potential that MSC treatment has both a short-term and long-term benefit in reducing the rate of tendon retear."

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Stem cells may improve tendon healing, reduce retear risk in rotator cuff surgery

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Researchers from the University of Michigan have cooked-up the perfect recipe for growing miniature, three-dimensional human lungs from stem cells, but you wont find this recipe in a cookbook it appears in the latest edition of the journal eLife.

Lead author Dr. Jason Spence, a professor at the UM Medical School in Ann Arbor, and colleagues from the Cincinnati Childrens Hospital Medical Center, the University of California, San Francisco (UCSF), Seattle Childrens Hospital and the University of Washington reported in their paper how they converted human pluripotent stem cells (hPSCs) into mini lungs.

Their work compliments with other recent research in the field (including building lung tissue from the scaffold of donated organs), the publishers of eLife said, and their method produces an organ that is more similar to the human lung than previous efforts because it can grow structures that closely resemble both the large proximal airways and the small distal airways.

The process

They took hPSCs (both embryonic and induced) and added a protein known as ActivinA, which is involved in lung development. They left the stem cells for four days, and during this period, a type of tissue known as endoderm formed. Found in early embryos, forms several internal organ types, including the lung and the liver.

[STORY: Testing astronauts' lungs in the ISS airlock]

Next, they added a second protein a growth factor called Noggin and again left the growing tissues for four days. The endoderm was then induced to form 3D spherical structures known as the foregut spheroids. At this point, the scientists worked to make these structures expand and form into lung tissue by exposing the cells to proteins involved in lung development.

Once the spheroids were transferred into the protein mixture, they were allowed to incubate at room temperature for 10 minutes until the mixture solidified. They were treated with additional proteins every four days and transferred into a new protein mixture every 10 to 15 days.

The process is used to create lung organoids that should survive in culture for over 100 days and develop into well-organized structures containing cell types found in the lung, the study authors explained. The mini-lungs are essentially self-organizing, and once they are formed, they require no additional manipulation to generate three-dimensional tissues, they added.

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Growing 3D miniature lungs from stem cells

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Newswise ANN ARBOR, Mich. Scientists have coaxed stem cells to grow the first three-dimensional mini lungs.

Previous research has focused on deriving lung tissue from flat cell systems or growing cells onto scaffolds made from donated organs. In a study published in the online journal eLife the multi-institution team defined the system for generating the self-organizing human lung organoids, 3D structures that mimic the structure and complexity of human lungs.

These mini lungs can mimic the responses of real tissues and will be a good model to study how organs form, change with disease, and how they might respond to new drugs, says senior study author Jason R. Spence, Ph.D., assistant professor of internal medicine and cell and developmental biology at the University of Michigan Medical School.

The scientists succeeded in growing structures resembling both the large airways known as bronchi and small lung sacs called alveoli.

Since the mini lung structures were developed in a dish, they lack several components of the human lung, including blood vessels, which are a critical component of gas exchange during breathing.

Still, the organoids may serve as a discovery tool for researchers as they churn basic science ideas into clinical innovations. A practical solution lies in using the 3-D structures as a next step from, or complement to, animal research.

Cell behavior has traditionally been studied in the lab in 2-D situations where cells are grown in thin layers on cell-culture dishes. But most cells in the body exist in a three-dimensional environment as part of complex tissues and organs.

Researchers have been attempting to re-create these environments in the lab, successfully generating organoids that serve as models of the stomach, brain, liver and human intestine.

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Scientists Coax Stem Cells to Form 3D Mini Lungs

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IMAGE:Karsten Sauer, Ph.D., is an associate professor at The Scripps Research Institute. view more

Credit: Photo courtesy of The Scripps Research Institute.

LA JOLLA, CA - March 23, 2015 - Stem cells can generate any type of cell in the body, but they are inactive most of the time--and for good reason. When stem cells become too active and divide too often, they risk acquiring cell damage and mutations. In the case of blood stem cells (also called hematopoietic stem cells or HSCs), this can lead to blood cancers, a loss of blood cells and an impaired ability to fight disease.

Now scientists at The Scripps Research Institute (TSRI) have found that a particular enzyme in HSCs is key to maintaining healthy periods of inactivity. Their findings, published recently in the journal Blood, show that animal models without this enzyme experience dangerous HSC activation and ultimately succumb to lethal anemia.

"These HSCs remain active too long and then disappear," said TSRI Associate Professor Karsten Sauer, senior author of the new study. "As a consequence, the mice lose their red blood cells and die."

With this new understanding of the enzyme, called Inositol trisphosphate 3-kinase B (ItpkB), scientists are closer to improving therapies for diseases such as bone marrow failure syndrome, anemia, leukemia, lymphoma and immunodeficiencies.

Stem Cells Need Rest

HSCs are a type of adult stem cell that lives in little niches in the bone marrow. They are normally inactive, or "quiescent," and only divide to self-renew about every two months.

However, when mature blood cells are lost, for example through severe bleeding or during infections, HSCs become activated to generate new "progenitor" cells--the cells that replenish the blood supply and produce immune cells to fight disease. Once the blood cells have been replenished, the HSC become quiescent again.

The balance between inactivity and activity is important because HSC activation generates side products that harm HSC. In addition, every division introduces a risk of mutation, sometimes leading to cancer. "It's like a car wearing down its own engine while it is doing its work," said Sauer. "Like people, HSCs need long periods of rest to remain healthy and work well."

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TSRI team discovers enzyme that keeps blood stem cells functional to prevent anemia

In a first of its kind effort, students of a city-based college have donated their stem cells and created a registry. Nearly 1,000 students of Meenakshi College for Women in Kodambakkam have registered as potential stem cell donors with Datri Blood Stem Cell Donors Registry. Another 500 students are expected to register on March 30.

The unique initiative was the brainchild of college principal K.S. Lakshmi. It all began after a casual visit to the Cancer Institute, Adyar. I had undergone two surgeries for a tumour in the throat which turned out to be benign.

During one of my visits to the hospital I noticed the hopelessness of the cancer patients. I wanted to donate only money but I was told that more than money the hospital wanted donations for a registry of stem cells, she said.

She took it up with the students in her college during the prayer assembly sessions. The students were encouraged to discuss the issue and soon through the colleges various student clubs it gathered momentum.

Only students above 18 years are allowed to donate. The student-donors had to get a consent letter from their parents. Encouragingly, only one parent refused to allow his daughter to participate, the principal said.

Datri provided a donation kit to each donor and also explained what the students had to do. The students were registered by providing their names with the college ID. They may change their mind at a later date but their donations could be used for research purposes at least, Ms. Lakshmi said.

To safeguard the interest of the donors the college took an undertaking from Datri that the donor stem cells would not be misused.

Datris co-founder Raghu Rajagopal said it was phenomenal that so many women had registered as potential donors. The donation drives help as the probability of finding a match (of stem cells) in ones own family is less than 25 per cent. I may get 15 requests for stem cells today but only one might be the right match, he says.

Of the 80,000 donors registered with Datri more than 11,000 are based in Tamil Nadu. So far the organisation has facilitated 92 transplants, six of them for patients living abroad.

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