transplantation

A new way to make heart stem cells could potentially repair the damage of heart disease

/ Karen Ring / Leave a comment

Today we’re going to talk about heart failure. It’s a sobering topic given that over 20 million people world wide are currently suffering from this disease. Heart failure happens when the body’s heart can no longer pump blood effectively, which can lead to many nasty side effects and inevitably hastens death.

Typical strategies for treating heart failure focus on managing symptoms and delaying disease progression. But for patients, many of whom are elderly, a life of chronic management and frequent hospital stays is daunting. They deserve better.

Here’s where stem cell research could provide new treatments for heart failure. Some stem cells can be coaxed into new heart tissue that could repair damage and restore heart function. While other types of stem cells can release factors that facilitate the development of new blood vessels or that reduce tissue scarring, both of which improve heart function. Some of these treatments are being tested in clinical trials (for instance CIRM is funding a stem cell trial for heart disease sponsored by Capricor Therapeutics), although none have been approved yet.

But there’s good news on this front. Today, the Gladstone Institutes published a study in Cell Stem Cell describing a new method for making transplantable heart stem cells that improved heart function in mice and could potentially treat heart failure in humans.

A new method for making transplantable heart stem cells

The goal of the Gladstone study was to generate a specific type of heart stem cell called a cardiovascular progenitor cell that could survive and develop into the different types of mature heart cells to improve heart function when transplanted into mice.

Using technology previously developed in the lab of Gladstone Professor Sheng Ding, the team used a cocktail of chemicals to turn skin cells into cardiac progenitor cells (CPCs). These cells are like stem cells but specific to the heart and thus can only make heart cells. The CPCs they made had two important qualities: they could be expanded in a culture dish for multiple generations and they could develop into the three main types of adult heart cells (cardiomyocytes, endothelial cells and smooth muscle cells) that are required for heart regeneration.

Scientists made a new type of heart stem cell that can turn into the three main types of adult heart cells. (Image: Yu Zhang)

Gladstone scientists made a new type of heart stem cell that can make the three main types of adult heart cells. (Image: Yu Zhang)

Because of their ability to replicate and to become adult heart cells, they named these cells induced expandable cardiovascular progenitor cells or ieCPCs. They transplanted ieCPCs in mice that had suffered a heart attack and were pleased to see that 90% of engrafted cells (the ones that survived and stuck around) developed into functioning heart cells that worked seamlessly with the existing heart cells to improve the damaged heart’s ability to pump blood. From a single injection of one million ieCPCs, the improvements in heart function lasted for three months.

In a Gladstone News Release, first author on the study, Yu Zhang, explained why ieCPCs are better for transplantation into damaged hearts than adult heart cells like cardiomyocytes or the muscle cells of the heart:

“Scientists have tried for decades to treat heart failure by transplanting adult heart cells, but these cells cannot reproduce themselves, and so they do not survive in the damaged heart. Our generated ieCPCs can prolifically replicate and reliably mature into the three types of cells in the heart, which makes them a very promising potential treatment for heart failure.”

Another benefit to ieCPCs was that they did not generate tumors when transplanted. This can happen with non-heart stem cells or with cells derived from pluripotent stem cells.

What does the future hold for ieCPCs?

A heart attack can kill more than one billion heart cells, and while the heart has some regenerative ability, it cannot replace that many cells on its own. The Gladstone study is exciting because it provides a new population of heart stem cells that can be expanded in a dish to generate a large donor population of stem cells for transplantation.

Senior author Shen Ding spoke to the robustness of their new stem cell technology:

Sheng Ding

Sheng Ding

“Cardiac progenitor cells could be ideal for heart regeneration. They are the closest precursor to functional heart cells, and, in a single step, they can rapidly and efficiently become heart cells, both in a dish and in a live heart. With our new technology, we can quickly create billions of these cells in a dish and then transplant them into damaged hearts to treat heart failure.”

Additionally, their new method opens the doors for generating patient-specific stem cell treatments.

“Because these cells are generated from skin cells, it opens the door for personalized medicine, using a patient’s own cells to treat their disease.”

Sheng Ding’s lab is one to watch if you follow research in stem cell biology and regenerative medicine. We recently blogged about a different but equally important study from his lab where he made functional pancreatic beta cells from skin as a potential cell therapy for diabetes. I hope that his team will ultimately be able to translate their current research in both diabetes and heart disease towards clinical applications in humans.

From Science Fiction to Science Fact: Gene Editing May Make Personalized Therapies for Blindness

/ Karen Ring / Leave a comment

Have you seen the movie Elysium? It’s a 2013 futuristic science fiction film starring one of my favorite actors Matt Damon. The plot centers on the economic, social and political disparities between two very different worlds: one, an overpopulated earth where people are poor, starving, and have little access to technology or medical care, the other, a terraformed paradise in earth’s orbit that harbors the rich, the beautiful, and advanced technologies.

Med-Bays.

Med-Bays.

The movie is entertaining (I give it 4 stars, Rotten Tomatoes says 67%), but as a scientist, one of the details that stuck out most was the Med-Bays. They’re magical, medical machines that can diagnose and cure any disease, regrow body parts, and even make people young again.

Wouldn’t it be wonderful if Med-Bays actually existed? Unfortunately, we currently lack the capabilities to bring this technology out of the realm of science fiction. However, recent efforts in the areas of personalized stem cell therapies and precision medicine are putting paths for creating potential cures for a wide range of diseases on the map.

One such study, published in Scientific Reports, is using precision medicine to help cure patients with a rare eye disease. Scientists from the University of Iowa and Columbia University Medical Center used CRISPR gene editing technology to fix induced pluripotent stem cells (iPS cells) derived from patients with an inherited form of blindness called X-linked retinitis pigmentosa (XLRP). The disease is caused by a single genetic mutation in the RPGR gene, which causes the retina of the eye to break down, leaving the patient blind or with very little vision. (For more on RP and other diseases of blindness, check out our Stem Cells in your Face video.)

CRISPR is a hot new tool that allows scientists to target and change specific sequences of DNA in the genome with higher accuracy and efficiency than other gene editing tools. In this study, researchers were concerned that it would be hard for CRISPR to correct the RPGR gene mutation because it’s located in a repetitive section of DNA that can be hard to accurately edit. After treating patient stem cells with the CRISPR modifying cocktail, the scientists found that the RPGR mutation had a 13% correction rate, which is comparable to other iPS cell based CRISPR editing studies.

Skin cells from a patient with X-linked Retinitis Pigmentosa were transformed into induced pluripotent stem cells and the blindness-causing point mutation in the RPGR gene was corrected using CRISPR/Cas9. Image by Vinit Mahajan.

Stem cells derived from a patient with X-linked Retinitis Pigmentosa. (Image by Vinit Mahajan)

The authors claim that this is the first study to successfully correct a genetic mutation in human stem cells derived from patients with degenerative retinal disease. The study is important because it indicates that XLRP patients can benefit from personalized stem cell therapy where scientists make individual patient iPS cell lines, use precision medicine to genetically correct the RPGR mutation, and then transplant healthy retinal cells derived from the corrected stem cells back into the same patients to hopefully give them back their sight.

Senior author on the study, Vinit Mahajan explained in a University of Iowa news release:

Vinit Mahajan

Vinit Mahajan

“With CRISPR gene editing of human stem cells, we can theoretically transplant healthy new cells that come from the patient after having fixed their specific gene mutation. And retinal diseases are a perfect model for stem cell therapy, because we have the advanced surgical techniques to implant cells exactly where they are needed.”

It’s important to note that this study is still in its early stages. Stephen Tsang, a co-author on the study, commented:

“There is still work to do. Before we go into patients, we want to make sure we are only changing that particular, single mutation and we are not making other alterations to the genome.”

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Protective cell therapy could mean insulin independence for diabetic patients

/ Karen Ring / Leave a comment

This has already been a productive year for diabetes research. Earlier this month, scientists from UCSF and the Gladstone Institutes successfully made functional human pancreatic beta cells from skin, providing a new and robust method for generating large quantities of cells to replace those lost in patients suffering from type 1 diabetes.

Today marks another breakthrough in the development of stem cell therapies for diabetes. Scientists from MIT and the Harvard Stem Cell Institute published a new method in Nature Medicine that encapsulates and protects stem cell-derived pancreatic beta cells in a way that prevents them from being attacked by the immune system after transplantation.

Protecting transplanted cells from the immune system

Stem cell therapy holds promise for diabetes for a number of reasons. First, scientists now have the ability to generate large numbers of insulin producing pancreatic beta cells from human skin and stem cells. This obviates the need for donor beta cells, which are always in short supply and high demand. Second, there’s the issue of the immune system. Transplanting beta cells from a donor into a patient will trigger an immunological reaction, which can only be abated by a lifetime regimen of immunosuppressive drugs.

One way that scientists have addressed the issue of immune rejection is to transplant stem cell-derived beta cells in a protected capsule. A CIRM-funded company called ViaCyte has developed a medical device that acts like a replacement pancreas but is surgically implanted under the skin. It contains human beta cells derived from embryonic stem cells and has a membrane barrier that allows only certain molecules to pass in and out of the device. This way, the foreign pancreatic cells are shielded from the immune system, but they can still respond to changing blood sugar levels in the patient by secreting insulin into the blood stream.

Another way that scientists trick the immune system in diabetes patients uses a similar strategy but instead of a medical device that protects a large population of cells, they encapsulate individual islets (clusters of beta cells) using biomaterials.

However, previous attempts using a biomaterial called alginate to encapsulate islets caused an immune response in the form of fibrosis, or scar tissue, and cell death. Additionally, transplanted alginate microspheres were only able to achieve glycemic control, or control of blood sugar levels, temporarily in animal models.

In the Nature Medicine study, the scientists developed a new method for beta cell encapsulation where they used a chemically modified version of the alginate microspheres – triazole-thiomorpholine dioxide (TMTD) – that didn’t cause an immune reaction and was able to maintain glycemic control in mice that had diabetes.

New protective method makes diabetic mice insulin independent

The scientists tested the conventional alginate microspheres and the modified TMTD-alginate microspheres containing embryonic stem cell-derived human beta islets in diabetic mice.

Encapsulated beta islets were transplanted into diabetic mice. (Nature Medicine)

Encapsulated beta islets were transplanted into diabetic mice. (Nature Medicine)

They found that the conventional smaller alginate microspheres caused fibrosis while larger TMTD-alginate microspheres did not. They observed that the modified TMTD-alginate microspheres were able to achieve glycemic control for over 70 days after transplantation while conventional microspheres didn’t perform as well.

The scientists also looked at the immune response to both types of alginate spheres. They saw lower numbers of immune cells and less fibrosis surrounding the transplanted TMTD microspheres compared to the conventional microspheres.

The final studies were the icing on the cake. The asked whether the modified TMTD microspheres were able to maintain long-term glycemic control or insulin independence, which would mean sustaining blood glucose levels in diabetic mice for over 100 days. They studied diabetic mice that received TMTD microspheres for 174 days. At 150 days, they performed a glucose test and saw that the diabetic mice were just as good at regulating glucose levels as normal mice. Furthermore, after 6 months, these mice showed no build up of fibrotic tissue, indicating that the modified microspheres weren’t causing an immune response and these mice didn’t need immunosuppressive drugs.

What the experts had to say…

This study was picked up by STATnews, which also mentioned another related study published in Nature Biotechnology that tested various alginate derivatives in rodent and monkey models of diabetes.

Julia Greenstein, vice president of discovery research at JDRF, discussed the implications of both studies with STATnews:

“This is really the first demonstration of the ability of these novel materials in combination with a stem-cell derived beta cell to reverse diabetes in an animal model. Our goal is to bring that kind of biological cure across the spectrum of type 1 diabetes.”

First author on both studies, Arturo Vegas, also gave his thoughts and discussed future applications:

Arturo Vegas

Arturo Vegas

“From very early on, we were getting great success. Everything kind of fell into place. You saw less foreign body response. The human beta cells survived exquisitely well. I think we’ve advanced the ball pretty far, almost as far you could get in an academic environment. The talk is shifting toward doing something clinically.”

According to STATnews, Vegas and his team are working on tests now in monkey models. “Vegas said that if the primate studies are successful, the next step will be developing a therapy to be used in people.”

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The Ogawa-Yamanaka Prize Crowns Its First Stem Cell Champion

/ Karen Ring / Leave a comment

A world of dark

Imagine if you woke up one day and couldn’t see. Your life would change drastically, and you would have to painfully relearn how to function in a world that heavily relies on sight.

A retina of a patient with macular degeneration. (Photo credit: Paul Parker/SPL)

A retina of a patient with macular degeneration. (Photo credit: Paul Parker/SPL)

While most people don’t lose their sight overnight, many suffer from visual impairments that slowly happen over time. Glaucoma, cataracts, and macular degeneration are examples of debilitating eye diseases that eventually lead to blindness.

With almost 300 million people world wide with some form of visual impairment, there’s urgency in the scientific community to develop safe therapies for clinical applications. One of the most promising strategies is using human induced pluripotent stem (iPS) cells derived from patients to generate cell types suitable for transplantation into the human eye.

However, this task is more easily said than done. Safety, regulatory, and economical concerns make the process of translating iPS cell therapies from the bench into the clinic an enormous challenge worthy only of a true scientific champion.

A world of light

Dr. Masayo Takahashi

Dr. Masayo Takahashi

Meet Dr. Masayo Takahashi. She is a faculty member at the RIKEN Centre for Developmental Biology, a prominent female scientist in Japan, and a bona fide stem cell champion. Her mission is to cure diseases of blindness using iPS cell technology.

Since the Nobel Prize-winning discovery of iPS cells by Dr. Shinya Yamanaka eight years ago, Dr. Takahashi has made fast work using this technology to generate specific cells from human iPS cells that can be transplanted into patients to treat an eye disease called macular degeneration. This disease results in the degeneration of the retina, an area in the back of the eye that receives light and translates the information to your brain to produce sight.

Dr. Takahashi generates cells called retinal pigment epithelial (RPE) cells from human iPS cells that can replace lost or dying retinal cells when transplanted into patients with macular degeneration. What makes this therapy so exciting is that Dr. Takahashi’s iPS-derived RPE cells appear to be relatively safe and don’t cause an immune system reaction or cause tumors when transplanted into humans.

Because of the safety of her technology, and the unfulfilled needs of millions of patients with eye diseases, Dr. Takahashi made it her goal to take iPS cells into humans within five years of Dr. Yamanaka’s discovery.

Ogawa-Yamanaka Stem Cell Prize

It’s no surprise that Dr. Takahashi succeeded in her ambitious goal. Her cutting edge work has led to the first clinical trial using iPS cells in humans, specifically treating patients with macular degeneration. In September 2014, the first patient, a 70-year-old Japanese woman, received a transplant of her own iPS-derived RPE cells and no complications were reported.

Currently, the trial is on hold “as part of a safety validation step and in consideration of anticipated regulatory changes to iPS cell research in Japan” according to a Gladstone Institute news release. Nevertheless, this first iPS cell trial in humans has overcome significant regulatory hurdles, has set an important precedent for establishing the safety of stem cell therapies, and has given scientists hope that iPS cell therapies can become a reality.

Dr. Deepak Srivastava presents Dr. Takahashi with the Ogawa-Yamanaka Prize.

Dr. Deepak Srivastava presents Dr. Takahashi with the Ogawa-Yamanaka Prize.

For her accomplishments, Dr. Takahashi was recently awarded the first ever Ogawa-Yamanaka Stem Cell Prize and honored at a special event held at the Gladstone Institutes in San Francisco yesterday. This prize was established by a generous gift from Mr. Hiro Ogawa in collaboration with Dr. Shinya Yamanaka and Dr. Deepak Srivastava at the Gladstone Institutes. The award recognizes scientists who conduct translational iPS cell research that will eventually be applied to patients in the clinic.

In an interview with CIRM, Dr. Deepak Srivastava, the Director of the Gladstone Institute of Cardiovascular Disease and the Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, described the prestigious prize and the ceremony held at the Gladstone to honor Dr. Takahashi:

Dr. Deepak Srivastava

The Ogawa-Yamanaka prize prize is meant to incentivize and honor those whose work is advancing the translational use of stem cells for regenerative medicine. Dr. Masayo Takahashi is a pioneer in pushing the technology of iPS cell-derived cell types and actually introducing them into people. She’s the very first person in the world to successfully overcome all the regulatory barriers and the scientific barriers to introduce this new type of stem cell into a patient. And she’s done so for a condition of blindness called macular degeneration, which affects millions of people world wide, and for which there are very few treatments currently. We are honoring her with this prize for her pioneering efforts at making this technology one that can be applied to patients.

The new world that iPS cells will bring

As part of the ceremony, Dr. Takahashi gave a scientific talk on the new world that iPS cells will bring for patients with diseases that lack cures, including those with visual impairments. The Stem Cellar team was lucky enough to interview Dr. Takahashi as well as attend her lecture during the Gladstone ceremony. We will cover both her talk and her interview with CIRM in an upcoming blog.

The Stem Cellar team at CIRM was excited to attend this momentous occasion, and to know that CIRM-funding has supported many researchers in the field of iPS cell therapy and regenerative medicine. We would like to congratulate Dr. Takahashi on her impressive and impactful accomplishments in this area and look forward to seeing progress in iPS cell trial for macular degeneration.

 

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CIRM-funded clinical trial for spinal cord injury reports promising results

/ Karen Ring / 3 Comments

Today, the Menlo Park-based biotech company Asterias Biotherapeutics reported positive results from the first three patients treated in its Phase 1/2a clinical study using stem cell therapy to treat patients with spinal cord injury. This trial is funded by a CIRM Strategic Partnerships Award grant of $14.3 million.

asteriasAsterias has developed a stem cell therapy called AST-OPC1 that uses oligodendrocyte progenitor cells (OPCs), a kind of cell found in the nervous system, to treat patients that have suffered from different types of spinal cord injury. Damage to the spinal cord causes a range of paralysis based on where it occurs. People with spinal cord trauma to the mid-back often retain the use of their hands and arms but can no longer walk and may lose bladder function. Patients with spinal cord injuries in their neck  can be paralyzed completely from their neck down.

astopc1OPCs are precursors to an important cell type in the central nervous system called the oligodendrocyte. These cells are responsible for forming a conductive sheet around nerve cells that allows nerves to send electrical signals and messages safely from one nerve to another. Both OPCs and oligodendrocytes provide support and protection to nerves in the spinal cord and brain, and they can also facilitate repair of damaged nerves by secreting survival and growth factors as well as promoting the formation of new blood vessels.

In this first part of the Phase 1/2a clinical trial three patients with complete cervical (neck) spinal cord injuries were given a “low dose” of two million AST-OPC1 cells to test the safety and feasibility of their stem cell treatment. The first patient was treated at the Shepard Center in Atlanta,  and at the two month post-injection assessment, the patient experienced no side effects and an improvement from a complete to an incomplete injury on the ASIA impairment injury scale. The other two patients received injections at the Rush University Medical Center in Chicago. Both procedures were reported to have gone smoothly, and the patients are still being monitored.

Asterias plans to treat a second group of patients with higher doses of AST-OPC1 cells (10-20 millions cells). Chief Medical Officer Dr. Edward Wirth explained their strategy:

 The safety data in the first cohort now paves the way for testing the higher doses of AST-OPC1 (10-20 million cells) that we believe correspond most closely to the doses that showed the greatest efficacy in animal studies.

If both the low dose and high dose groups report no serious side effects, Asterias will turn to the Food and Drug Administration (FDA) for approval to expand the patient population of this clinical trial phase from 13 patients up to 40. Asterias hopes that adding more patients “will increase the statistical confidence of the safety and efficacy readouts, reduce the risks of the AST-OPC1 program and position the product for potential accelerated regulatory approvals.”

Spinal cord injury affects more than 12,000 people every year. It remains a major unmet medical need without any FDA-approved therapies or medical devices that improve or restore patient spinal cord function. CIRM is hopeful that Asterias will continue to see positive results with the SCiStar trial and will be able to progress its AST-OPC1 program into late-stage clinical trials and eventually into an FDA-approved stem cell therapy for spinal cord injury.

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Study Identifies Safer Stem Cell Therapies

/ Karen Ring / Leave a comment

To reject or not reject, that is the question facing the human immune system when new tissue or cells are transplanted into the body.

Stem cell-therapy promises hope for many debilitating diseases that currently have no cures. However, the issue of immune rejection has prompted scientists to carefully consider how to develop safe stem cell therapies that will be tolerated by the human immune system.

Before the dawn of induced pluripotent stem cells (iPSCs), embryonic stem cells (ESCs) were suggested as a potential source for transplantable cells and tissue. However, ESCs run into a couple of issues, including their origin, and the fact that ESC-derived cells likely would be rejected when transplanted into most areas of a human due to differences in genetic backgrounds.

The discovery of iPSCs in the early 2000’s gave new hope to the field of stem cell therapy. By generating donor cells and tissue from a patient’s own iPSCs, transplanting those cells/tissue back into the same individual shouldn’t – at least theoretically – cause an immune reaction. This type of transplantation is called “autologous” meaning that the stem cell-derived cells have the same genetic background as the person.

Unfortunately, scientists have run up against a roadblock in iPSC-derived stem cell therapy. They discovered that even cells derived from a patient’s own iPSCs can cause an immune reaction when transplanted into that patient. The answers as to why this occurs remained largely unanswered until recently.

In a paper published last week in Cell Stem Cell, scientists from the University of California, San Diego (UCSD) reported that different mature cell types derived from human iPSCs have varying immunogenic effects (the ability to cause an immune reaction) when transplanted into “humanized” mice that have a human immune system. This study along with the research conducted to generate the humanized mice was funded by CIRM grants (here, here).

In this study, retinal pigment epithelial cells (RPE) and skeletal muscle cells (SMC) derived from human iPSCs were transplanted into humanized mice. RPEs were tolerated by the immune system while SMCs were rejected. (Adapted from Zhao et al. 2015)

Scientists took normal mice and replaced their immune system with a human one. They then took human iPSCs generated from the same human tissue used to generate the humanized mice and transplanted different cell types derived from the iPSCs cells into these mice.

Because they were introducing cells derived from the same source of human tissue that the mouse’s immune system was derived from, in theory, the mice should not reject the transplant. However, they found that many of the transplants did indeed cause an immune reaction.

Interestingly, they found that certain mature cell types derived from human iPSCs created a substantial immune reaction while other cell types did not. The authors focused on two specific cell types, smooth muscle cells (SMC) and retinal pigment epithelial cells (RPE), to get a closer look at what was going on.

iPSC-derived smooth muscle cells created a large immune response when transplanted into humanized mice. However, when they transplanted iPSC-derived retinal epithelial cells (found in the retina of the eye), they didn’t see the same immune reaction. As a control, they transplanted RPE cells made from human ESCs, and as expected, they saw an immune response to the foreign ESC-derived RPE cells.

RPE_1

iPSC derived RPE cells (green) do not cause an immune reaction (red) after transplantation into humanized mice while H9 embryonic stem cell derived RPE cells do. (Zhao et al. 2015)

When they looked further to determine why the humanized mice rejected the muscle cells but accepted the retinal cells, they found that SMCs had a different gene expression profile and higher expression of immunogenic molecules. The iPSC-derived RPE cells had low expression of these same immunogenic molecules, which is why they were well tolerated in the humanized mice.

Results from this study suggest that some cell types generated from human iPSCs are safer for transplantation than others, an issue which can be addressed by improving the differentiation techniques used to produce mature cells from iPSCs. This study also suggests that iPSC-derived RPE cells could be a safe and promising stem cell therapy for the treatment of eye disorders such as age-related macular degeneration (AMD). AMD is a degenerative eye disease that can cause vision impairment or blindness and usually affects older people over the age of 50. Currently there is no treatment for AMD, a disease that affects approximately 50 million people around the world. (However there is a human iPSC clinical trial for AMD out of the RIKEN Center for Developmental Biology in Japan that has treated one patient but is currently on hold due to safety issues.)

The senior author on this study, Dr. Yang Xu, commented on the importance of this study in relation to AMD in a UCSD press release:

Dr. Yang Xu

Dr. Yang Xu

Immune rejection is a major challenge for stem cell therapy. Our finding of the lack of immune rejection of human iPSC-derived retinal pigment epithelium cells supports the feasibility of using these cells for treating macular degeneration. However, the inflammatory environment associated with macular degeneration could be an additional hurdle to be overcome for the stem cell therapy to be successful.

Xu makes an important point by acknowledging that iPSC-derived RPE cells aren’t a sure bet for curing AMD just yet. More research needs to be done to address other issues that occur during AMD in order for this type of stem cell therapy to be successful.

 

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New Regenerative Liver Cells Identified

/ Karen Ring / Leave a comment

It’s common knowledge that your liver is a champion when it comes to regeneration. It’s actually one of the few internal organs in the human body that can robustly regenerate itself after injury. Other organs such as the heart and lungs do not have the same regenerative response and instead generate scar tissue to protect the injured area. Liver regeneration is very important to human health as the liver conducts many fundamental processes such as making proteins, breaking down toxic substances, and making new chemicals required to digest your food.

The human liver.

The human liver

Over the years, scientists have suggested multiple theories for why the liver has this amazing regenerative capacity. What’s known for sure is that mature hepatocytes (the main cell type in the liver) will respond to injury by dividing and proliferating to make more hepatocytes. In this way, the liver can regrow up to 70% of itself within a matter of a few weeks. Pretty amazing right?

So what is the source of these regenerative hepatocytes? It was originally thought that adult liver stem cells (called oval cells) were the source, but this theory has been disproved in the past few years. The answer to this million-dollar question, however, likely comes from a study published last week in the journal Cell.

Hybrid hepatocytes (shown in green) divide and regenerate the liver in response to injury. (Image source: Font-Burgada et al., 2015)

Hybrid hepatocytes (green) divide and regenerate the liver in response to injury. (Image source: Font-Burgada et al., 2015)

A group at UCSD led by Dr. Michael Karin reported a new population of liver cells called “hybrid hepatocytes”. These cells were discovered in an area of the healthy liver called the portal triad. Using mouse models, the CIRM-funded group found that hybrid hepatocytes respond to chemical-induced injury by massively dividing to replace damaged or lost liver tissue. When they took a closer look at these newly-identified cells, they found that hybrid hepatocytes were very similar to normal hepatocytes but differed slightly with respect to the types of liver genes that they expressed.

A common concern associated with regenerative tissue and cells is the development of cancer. Actively dividing cells in the liver can acquire genetic mutations that can cause hepatocellular carcinoma, a common form of liver cancer.

What makes this group’s discovery so exciting is that they found evidence that hybrid hepatocytes do not cause cancer in mice. They showed this by transplanting a population of hybrid hepatocytes into multiple mouse models of liver cancer. When they dissected the liver tumors from these mice, none of the transplanted hybrid cells were present. They concluded that hybrid hepatocytes are robust and efficient at regenerating the liver in response to injury, and that they are a safe and non-cancer causing source of regenerating liver cells.

Currently, liver transplantation is the only therapy for end-stage liver diseases (often caused by cirrhosis or hepatitis) and aggressive forms of liver cancer. Patients receiving liver transplants from donors have a good chance of survival, however donated livers are in short supply, and patients who actually get liver transplants have to take immunosuppressant drugs for the rest of their lives. Stem cell-derived liver tissue, either from embryonic or induced pluripotent stem cells (iPSC), has been proposed as an alternative source of transplantable liver tissue. However, safety of iPSC-derived tissue for clinical applications is still being addressed due to the potential risk of tumor formation caused by iPSCs that haven’t fully matured.

This study gives hope to the future of cell-based therapies for liver disease and avoids the current hurdles associated with iPSC-based therapy. In a press release from UCSD, Dr. Karin succinctly summarized the implications of their findings.

“Hybrid hepatocytes represent not only the most effective way to repair a diseased liver, but also the safest way to prevent fatal liver failure by cell transplantation.”

This exciting and potentially game-changing research was supported by CIRM funding. The first author, Dr. Joan Font-Burgada, was a CIRM postdoctoral scholar from 2012-2014. He reached out to CIRM regarding his publication and provided the following feedback:

CIRM Postdoctoral Fellow Jean Font-Burgada

CIRM postdoctoral scholar Joan Font-Burgada

“I’m excited to let you know that work CIRM funded through the training program will be published in Cell. I would like to express my most sincere gratitude for the opportunity I was given. I am convinced that without CIRM support, I could not have finished my project. Not only the training was excellent but the resources I was offered allowed me to work with enough independence to explore new avenues in my project that finally ended up in this publication.”

 

We at CIRM are always thrilled and proud to hear about these success stories. More importantly, we value feedback from our grantees on how our funding and training has supported their science and helped them achieve their goals. Our mission is to develop stem cell therapies for patients with unmet medical needs, and studies such as this one are an encouraging sign that we are making progress towards to achieving this goal.

Related links:

UCSD Press Release

CIRM Spotlight on Liver Disease Research

CIRM Spotlight on Living with Liver Disease

What a Difference Differentiation can Make: a Little Change can Reduce the Risk of Rejection

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No one likes to be rejected. It hurts. But while rejection is something most of us experience at least a couple of times in our life, researchers at Stanford have found a way to reduce the risk of rejection, at least when it comes to one form of stem cells. Reporting in the latest issue of Nature Communications they have found that turning iPS or induced pluripotent stem cells into other, more specialized kinds of cells, can reduce the risk the immune system will attack them.

Our immune systems are things of beauty. They hunt out invaders like viruses and when they spot something that shouldn’t be there, they attack it. It’s a critical part of our body’s way of fighting off disease and staying healthy.

However, the immune system is not perfect. Researchers have known for some time that when you take skin from an individual and turn it into an iPS cell – one that is capable of turning into any other cell in the body – and then transplant that cell back into the same individual their immune system often attacks it. So far, the only individuals this has been done with are mice, but we assume the same would happen in people.

So Joseph Wu and his CIRM-funded Stanford team decided to see what would happen if they took those same iPS cells and, before transplanting them back into the individual they came from, turned them into a more specialized form of cell. The results were encouraging: the immune system didn’t wage an attack.

Dr. Joseph Wu, Stanford University School of Medicine

Dr. Joseph Wu, Stanford University School of Medicine



Researchers were not sure why the body would attack something that was created from its own tissue, but speculated that turning ordinary skin cells into iPS cells created a kind of cell that the immune system hadn’t seen before, or at least hadn’t seen since it since it was an embryo.

In the Stanford news release, Wu said this finding could be really important in helping avoid rejection in organ or other tissue transplants:

“Induced pluripotent stem cells have tremendous potential as a source for personalized cellular therapeutics for organ repair. This study shows that undifferentiated iPS cells are rejected by the immune system upon transplantation in the same recipient, but that fully differentiating these cells allows for acceptance and tolerance by the immune system without the need for immunosuppression.” 

The team first transplanted some iPS cells into genetically identical recipient mice. The transplants were rejected and within 42 days there were no signs that any cells had survived.

Then they took the same kind of iPS cell and differentiated, or ‘re-programmed,’ them so that they turned into endothelial cells, the kind found in the inner lining of blood vessels. Then they transplanted those cells into the mice. At the same time they took some of the mice’s own endothelial cells out, and transplanted them back into genetically identical mice to see how they would compare. Both sets of cells, the iPS-turned-into endothelial and the endothelial cells, survived for at least 63 days after transplantation.

When the researchers repeated the experiment and examined the areas where the cells had been transplanted, they found much greater signs of immune system activity in the mice that were given iPS cells compared to the mice who got iPS cells that had been turned into endothelial cells, and the mice that just got endothelial cells.

For Wu, the bottom line was simple:

“This study certainly makes us optimistic that differentiation — into any nonpluripotent cell type — will render iPS cells less recognizable to the immune system. We have more confidence that we can move toward clinical use of these cells in humans with less concern than we’ve previously had.” 

 We work closely with Joseph Wu and his team on a number of other different projects, most focusing on heart disease.

kevin mccormack