liver

The Most Important Gift of All

/ Kevin McCormack / Leave a comment
Photo courtesy American Hospital Association

There are many players who have a key role in helping make a stem cell therapy work. The scientists who develop the therapy, the medical team who deliver it and funders like CIRM who provide the money to make this all happen. But vital as they are, in some therapies there is another, even more important group; the people who donate life-saving organs and tissues for transplant and research.

Organ and tissue donation saves lives, increases knowledge of diseases, and allow for the development of novel medications to treat them. When individuals or their families authorize donation for transplant or medical research, they allow their loved ones to build a long-lasting legacy of hope that could not be accomplished in any other way.

Four of CIRM’s clinical trials involve organ donations – three kidney transplant programs (you can read about those here, here and here) and one targeting type 1 diabetes.

Dr. Nikole Neidlinger, the Chief Medical Officer with Donor Network West – the federally designated organ and tissue recovery organization for Northern California and Nevada – says it is important to recognize the critical contribution made in a time of grief and crisis by the families of deceased donors. 

“For many families who donate, a loved one has died, and they are in shock. Even so, they are willing to say yes to giving others a second chance at life and to help others to advance science. Without them, none of this would be possible. It’s the ultimate act of generosity and compassion.”

The latest CIRM-funded clinical trial involving donated tissue is with Dr. Peter Stock and his team at UCSF. They are working on a treatment for type 1 diabetes (T1D), where the body’s immune system destroys its own pancreatic beta cells. These cells are necessary to produce insulin, which regulates blood sugar levels in the body.

In the past people have tried transplanting beta cells, from donated pancreatic islets, into patients with type 1 diabetes to try and reverse the course of the disease. However, this requires islets from multiple donors and the shortage of organ and tissue donors makes this difficult to do.

Dr. Stock’s clinical trial at UCSF aims to address these limitations.  He is going to transplant both pancreatic islets and parathyroid glands, from the same donor, into T1 patients. It’s hoped this combination approach will increase beta cell survival, potentially boosting long-term insulin production and removing the need for multiple donors.  And because the transplant is placed in the patient’s forearm, it makes it easier to monitor the effectiveness and accessibility of the islet transplants. Of equal importance, the development of this site will facilitate the transplantation of stem cell derived beta cells, which are very close to clinical application.

“As a transplant surgeon, it is an absolute privilege to be able to witness the life-saving organ transplants made possible by the selfless generosity of the donor families. It is hard to imagine how families have the will to think about helping others at a time of their greatest grief. It is this willingness to help others that restores my faith in humanity”

Donor Network West plays a vital role in this process. In 2018 alone, the organization recovered 702 donor samples for research. Thanks to the generosity of the donors/donor families, the donor network has been able to provide parathyroid and pancreas tissue essential to make this clinical trial a success”

“One organ donor can save the lives of up to eight people and a tissue donor can heal more than 75 others,” says Dr. Neidlinger. “For families, the knowledge that they are transforming someone’s life, and possibly preventing another family from experiencing this same loss, can serve as a silver lining during their time of sorrow. .”

Organs that can be donated

Kidney (x2), Heart, Lungs (x2), Liver, Pancreas, Intestine

Tissue that can be donated

Corneas, Heart valves, Skin, Bone, Tendons, Cartilage, Veins

Currently, there are over 113,000 people in the U.S. waiting for an organ transplant, of which 84 % are in need of kidneys.  Sadly, 22 people die every day waiting for an organ transplant that does not come in time. The prospect of an effective treatment for type 1 diabetes means hope for thousands of people living with the chronic condition.

Salk scientists discover new findings related to the age of organs

/ Yimy Villa / 1 Comment
Dr. Rafael Arrojo e Drigo (left) and Dr. Martin Hetzer (right) at the Salk Institute in San Diego

It has been a long held belief in the scientific community that nerve cells, or possibly the heart, are the oldest cells in the body. This is due to the fact that the brain and heart are the first organs that begin to develop in the womb. Nerve cells have an average lifespan of approximately 80 years without the need of generating new cells. It has been difficult to determine the approximate age of other organs such as the liver and pancreas in the body until now.

Dr. Rafael Arrojo e Drigo and Dr. Martin Hetzer, scientists at the Salk Institute, have discovered a population of cells that reside in the mouse brain, liver, and pancreas that have extremely long lifespans. In some cases, some of these cells were the same age as the animal they were found in. The scientists used a complex labeling and imaging procedure to determine cell age in a mouse model.

Furthermore, the scientists also found that the brain, liver, and pancreas in the mice contain a mixture of “old” and “young” cells, like a mosaic painting composed of small, different colored pieces. They called this phenomenon age mosaicism, referring to the population of identical cells that could only be distinguished by lifespan.

Their method could be applied to other types of tissue in the body, which could provide valuable information, such as the lifelong function of non-dividing cells and how cells lose control over the quality and integrity of important cell structures during aging. The answers to these questions play a key role in understanding ways to prevent the age-related degeneration of organs, such as the brain in Alzheimer’s Disease or the pancreas in Type II Diabetes.

In a press release, Dr. Hetzer is quoted as saying that,

“Determining the age of cells and subcellular structures in adult organisms will provide new insights into cell maintenance and repair mechanisms and the impact of cumulative changes during adulthood on health and development of disease. The ultimate goal is to utilize these mechanisms to prevent or delay age-related decline of organs with limited cell renewal such as the brain, pancreas and heart.”

The full results of the study were published in Cell Metabolism.

You can also see a youtube video below of Dr. Rafael Arrojo e Drigo and Dr. Martin Hetzer discussing their findings.

Stem cell stories that caught our eye: functioning liver tissue, making new bone, stem cells and mental health

/ Karen Ring / Leave a comment

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Functioning liver tissue. Scientists are looking to stem cells as a potential alternative treatment to liver transplantation for patients with end-stage liver disease. Efforts are still in their early stages but a study published this week in Stem Cells Translational Medicine, shows how a CIRM-funded team at the Children’s Hospital Los Angeles (CHLA) successfully generated partially functional liver tissue from mouse and human stem cells.

Biodegradable scaffold (left) and human tissue-engineered liver (right) (Photo courtesy of The Saban Research Institute at Children’s Hospital Los Angeles)

Biodegradable scaffold (left) and human tissue-engineered liver (right) (Photo courtesy of The Saban Research Institute at Children’s Hospital Los Angeles)

The lab had previously developed a protocol to make intestinal organoids from mouse and human stem cells. They were able to tweak the protocol to generate what they called liver organoid units and transplanted the tissue-engineered livers into mice. The transplants developed cells and structures found in normal healthy livers, but their organization was different – something that the authors said they would address in future experiments.

Impressively, when the tissue-engineered liver was transplanted into mice with liver failure, the transplants had some liver function and the liver cells in these transplants were able to grow and regenerate like in normal livers.

In a USC press release, Dr. Kasper Wang from CHLA and the Keck school of medicine at USC commented:

“A cellular therapy for liver disease would be a game-changer for many patients, particularly children with metabolic disorders. By demonstrating the ability to generate hepatocytes comparable to those in native liver, and to show that these cells are functional and proliferative, we’ve moved one step closer to that goal.”

 

Making new bone. Next up is a story about making new bone from stem cells. A group at UC San Diego published a study this week in the journal Science Advances detailing a new way to make bone forming cells called osteoblasts from human pluripotent stem cells.

Stem cell-derived osteoblasts (bone cells). Image credit Varghese lab/UCSD.

Stem cell-derived osteoblasts (bone cells). Image credit Varghese lab/UCSD.

One way that scientists can turn pluripotent stem cells into mature cells like bone is to culture the stem cells in a growth medium supplemented with small molecules that can influence the fate of the stem cells. The group discovered that by adding a single molecule called adenosine to the growth medium, the stem cells turned into osteoblasts that developed vascularized bone tissue.

When they transplanted the stem cell-derived osteoblasts into mice with bone defects, the transplanted cells developed new bone tissue and importantly didn’t develop tumors.

 In a UC newsroom release, senior author on the study and UC San Diego Bioengineering Professor Shyni Varghese concluded:

“It’s amazing that a single molecule can direct stem cell fate. We don’t need to use a cocktail of small molecules, growth factors or other supplements to create a population of bone cells from human pluripotent stem cells like induced pluripotent stem cells.”

 

Stem cells and mental health. Brad Fikes from the San Diego Union Tribune wrote a great article on a new academic-industry partnership whose goal is to use human stem cells to find new drugs for mental disorders. The project is funded by a $15.4 million grant from the National Institute of Mental Health.

Academic scientists, including Rusty Gage from the Salk Institute and Hongjun Song from Johns Hopkins University, are collaborating with pharmaceutical company Janssen and Cellular Dynamics International to develop induced pluripotent stem cells (iPSCs) from patients with mental disorders like bipolar disorder and schizophrenia. The scientists will generate brain cells from the iPSCs and then work with the companies to test for potential drugs that could be used to treat these disorders.

In the article, Fred Gage explained that the goal of this project will be used to help patients rather than generate data points:

Rusty Gage, Salk Institute.

Rusty Gage, Salk Institute.

“Gage said the stem cell project is focused on getting results that make a difference to patients, not simply piling up research information. Being able to replicate results is critical; Gage said. Recent studies have found that many research findings of potential therapies don’t hold up in clinical testing. This is not only frustrating to patients, but failed clinical trials are expensive, and must be paid for with successful drugs.”

“The future of this will require more patients, replication between labs, and standardization of the procedures used.”

Good from bad: UCSF scientists turn scar-forming cells into healthy liver cells

/ Karen Ring / Leave a comment

Most people know that a healthy liver is key for survival. Unfortunately, maintaining a healthy liver isn’t always easy. There are more than 100 different types of liver disease caused by various factors like viral infection, obesity, and genetics. If left untreated, they can progress to end-stage liver disease, also known as cirrhosis, which effects more than 600,000 Americans and has a high mortality rate. While there is a cure in the form of liver transplantation, there aren’t enough healthy donors available to help out the number of patients who desperately need new livers.

Cirrhosis occurs when liver damage accumulates over time causing the development of scar tissue that eventually replaces healthy liver tissue and impairs liver function. The liver is an amazing organ and can function even with the build-up of scar tissue as long as at least 20% of its composition is healthy cells. This impressive nature is actually a problem because most patients with liver disease aren’t aware of their condition until its progressed past the point of no return.

What’s a damaged liver to do?

So what do patients with end-stage liver disease do if they can’t get a liver transplant? One answer comes in the form of regenerative medicine. Scientists can generate new healthy liver cells in a dish from stem cells derived from the skin cells of patients and could eventually transplant these cells into the damaged liver. However, a major roadblock that prevents this type of cell transplantation therapy from helping patients with liver disease is the built-up scar tissue that prevents the integration of these healthy cells into the damaged liver.

Scientists from UC San Francisco (UCSF) have come up with a new solution to this problem. In a CIRM-funded study published today in journal Cell Stem Cell, UCSF professor Holger Willenbring details a new approach to repairing damaged livers in mice – one that generates good, healthy liver cells from bad, scar-tissue forming cells already present in the damaged liver.

The bad cells in this case are called myofibroblasts. Initially, these cells play an important role in repairing injuries in the liver. They secrete proteins called collagen that form a support structure that helps maintain composition of the liver as it repairs itself. However, if liver damage persists as is the case with chronic injury, the excess buildup of collagen secreted by myofibroblasts causes the accumulation of permanent scar tissue or fibrosis, which can negatively impact liver function.

Reducing damage by improving function

Cirrhosis causing myofibroblast cells (red) are converted into healthy liver cells (green) to regenerate the damaged liver. (Willenbring lab)

Cirrhosis causing myofibroblast cells (red) are converted into healthy liver cells (green) to regenerate the damaged liver. (Willenbring lab)

In an “Ah-Ha” moment, Willenbring proposed that they could stop myofibroblasts in the damaged livers of mice from causing more fibrosis by turning them into healthy liver cells. Willenbring and his team used a specific type of virus called an adeno-associated virus that only infects myofibroblasts to deliver a cocktail of liver-specific genes that have the ability to transform cells into liver cells called hepatocytes. When they treated mice with end-stage liver disease with their viral cocktail, they observed that a small percentage of myofibroblasts were converted into hepatocytes that developed into new healthy liver tissue, which improved the overall liver function of these mice. They also tested their viral method on human myofibroblasts and found that it was successful in converting these cells into functional hepatocytes.

Willenbring explained the science behind their new technique in a UCSF news release:

“Part of why this works is that the liver is a naturally regenerative organ, so it can deal with new cells very well. What we see is that the converted cells are not only functionally integrated in the liver tissue, but also divide and expand, leading to patches of new liver tissue.”

Solution to a healthy liver?

It’s important to realize that these studies are still in their early stages. The UCSF team has plans to expand on their human cell studies and to improve their viral delivery method so that it is more specific to myofibroblasts and more efficient at converting these cells into functioning hepatocytes.

They also recognize that their strategy will not be the panacea for liver disease and cirrhosis. Willenbring commented:

“A liver transplant is still the best cure. This is more of a patch. But if it can boost liver function by just a couple percent, that can hopefully keep patients’ liver function over that critical threshold, and that could translate to decades more of life.”

However, their study does offer a number of advantages over cell transplant therapies for liver disease including repairing the liver and improving its function from within the organ itself and also offering a simpler and cheaper form of treatment that would be accessible to more patients.

Willenbring puts it best:

Holger Willenbring, UCSF

Holger Willenbring, UCSF

“The new results suggest that in the fibrotic liver, this approach could produce a more efficient and stable improvement of liver function than cell transplant approaches. Once the viral packaging is optimized, such a treatment could be done cheaply at a broad range of medical facilities, not just in the specialized research hospitals where stem-cell transplants could be conducted.”

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