CIRM Board targets diabetes and kidney disease with big stem cell research awards

diabetes2

A recent study  estimated there may be more than 500 million people worldwide who have diabetes. That’s an astounding figure and makes diabetes one of the largest chronic disease epidemics in human history.

One of the most serious consequences of untreated or uncontrolled diabetes is kidney damage. That can lead to fatigue, weakness, confusion, kidney failure and even death. So two decisions taken by the CIRM Board today were good news for anyone already suffering from either diabetes or kidney disease. Or both.

The Board awarded almost $10 million to Humacyte to run a Phase 3 clinical trial of an artificial vein needed by people undergoing hemodialysis – that’s the most common form of dialysis for people with kidney damage. Hemodialysis helps clean out impurities and toxins from the blood. Without it waste will build up in the kidneys with devastating consequences.

The artificial vein is a kind of bioengineered blood vessel. It is implanted in the individual’s arm and, during dialysis, is connected to a machine to move the blood out of the body, through a filter, and then back into the body. The current synthetic version of the vein is effective but is prone to clotting and infections, and has to be removed regularly. All this puts the patient at risk.

Humacyte’s version – called a human acellular vessel or HAV – uses human cells from donated aortas that are then seeded onto a biodegradable scaffold and grown in the lab to form the artificial vein. When fully developed the structure is then “washed” to remove all the cellular tissue, leaving just a collagen tube. That is then implanted in the patient, and their own stem cells grow onto it, essentially turning it into their own tissue.

In earlier studies Humacyte’s HAV was shown to be safer and last longer than current versions. As our President and CEO, Randy Mills, said in a news release, that’s clearly good news for patients:

“This approach has the potential to dramatically improve our ability to care for people with kidney disease. Being able to reduce infections and clotting, and increase the quality of care the hemodialysis patients get could have a significant impact on not just the quality of their life but also the length of it.”

There are currently almost half a million Americans with kidney disease who are on dialysis. Having something that makes life easier, and hopefully safer, for them is a big plus.

The Humacyte trial is looking to enroll around 350 patients at three sites in California; Sacramento, Long Beach and Irvine.

While not all people with diabetes are on dialysis, they all need help maintaining healthy blood sugar levels, particularly people with type 1 diabetes. That’s where the $3.9 million awarded to ViaCyte comes in.

We’re already funding a clinical trial with ViaCyte  using an implantable delivery system containing stem cell-derived cells that is designed to measure blood flow, detect when blood sugar is low, then secrete insulin to restore it to a healthy level.

This new program uses a similar device, called a PEC-Direct. Unlike the current clinical trial version, the PEC-Direct allows the patient’s blood vessels to directly connect, or vasularize, with the cells inside it. ViaCyte believes this will allow for a more robust engraftment of the stem cell-derived cells inside it and that those cells will be better able to produce the insulin the body needs.

Because it allows direct vascularization it means that people who get the delivery system  will also need to get chronic immune suppression to stop their body’s immune system attacking it. For that reason it will be used to treat patients with type 1 diabetes that are at high risk for acute complications such as severe hypoglycemic (low blood sugar) events associated with hypoglycemia unawareness syndrome.

In a news release Paul Laikind, Ph.D., President and CEO of ViaCyte, said this approach could help patients most at risk.

“This high-risk patient population is the same population that would be eligible for cadaver islet transplants, a procedure that can be highly effective but suffers from a severe lack of donor material. We believe PEC-Direct could overcome the limitations of islet transplant by providing an unlimited supply of cells, manufactured under cGMP conditions, and a safer, more optimal route of administration.”

The Board also approved more than $13.6 million in awards under our Discovery program. You can see the winners here.

 

Scientists Make Insulin-Secreting Cells from Stem Cells of Type 1 Diabetes Patients

Stem cell research for diabetes is in a Golden Age. In the past few years, scientists have developed methods to generate insulin-secreting pancreatic beta cell-like cells from embryonic stem cells, induced pluripotent stem cells (iPS cells), and even directly from human skin. We’ve covered a number of recent studies in this area on our blog, and you can read more about them here.

Patients with type 1 diabetes (T1D) suffer from an autoimmune response that attacks and kills the beta cells in their pancreas. Without these important cells, patients can no longer secrete insulin in response to increased glucose or sugar levels in the blood. Cell replacement is evolving into an attractive therapeutic option for patients with T1D. Replacing lost beta cells in the pancreas is a more permanent and less burdensome solution than the daily insulin shots that many T1D patients currently take.

Cell replacement therapy for type 1 diabetes

Stem cells are the latest strategy that scientists are pursuing for T1D cell replacement therapy. The strategy involves generating beta cells from pluripotent stem cells, either embryonic or iPS cells, that function similarly to beta cells found in a healthy human pancreas. Making beta cells from a patient’s own iPS cells is the ideal way to go because this autologous form (self to self) of transplantation would reduce the chances  of transplant rejection because a patient’s own cells would be put back into their body.

Scientists have generated beta cell-like cells from iPS cells derived from T1D patients previously, but the biological nature and function of these cells wasn’t up to snuff in a side by side comparison with beta cells from non-diabetic patients. They didn’t express the appropriate beta cell markers and failed to secrete the appropriate levels of insulin when challenged in a dish and when transplanted into animal models.

However, a new study published yesterday in Nature Communications has overcome this hurdle. Teams from the Washington University School of Medicine in St. Louis and the Harvard Stem Cell Institute have developed a method that makes beta cells from T1D patient iPS cells that behave very similarly to true beta cells. This discovery has the potential to offer personalized stem cell treatments for patients with T1D in the near future.

These beta cells could be the real deal

Their current work is based off of an earlier 2014 study – from the lab of Douglas Melton at Harvard – that generated functional human beta cells from both embryonic and iPS cells of non-diabetic patients. In the current study, the authors were interested in learning whether it was possible to generate functional beta cells from T1D patients and whether these cells would be useful for transplantation given that they could potentially be less functional than non-diabetic beta cells.

The study’s first author, Professor Jeffrey Millman from the Washington University School of Medicine, explained:

Jeffrey Millman

Jeffrey Millman

“There had been questions about whether we could make these cells from people with type 1 diabetes. Some scientists thought that because the tissue would be coming from diabetes patients, there might be defects to prevent us from helping the stem cells differentiate into beta cells. It turns out that’s not the case.”

After generating beta cells from T1D iPS cells, Millman and colleagues conducted a series of experiments to test the beta cells both in a dish and in mice. They found that the T1D-derived beta cells expressed the appropriate beta cell markers, secreted insulin in the presence of glucose, and responded well to anti-diabetic drugs that stimulated the beta cells to secrete even more insulin.

When T1D beta cells were transplanted into mice that lacked an immune system, they survived and functioned similarly to transplanted non-diabetic beta cells. When the mice were treated with a drug that killed off their mouse beta cells, the surviving human T1D beta cells were successful in regulating the blood glucose levels in the mice and kept them alive.

Beta cells derived from type 1 diabetes patient stem cells (top) express the same beta cell markers as beta cells derived from non-diabetic (ND) patients.

Beta cells derived from type 1 diabetes patient stem cells (top) express the same beta cell markers as beta cells derived from non-diabetic (ND) patients. (Nature Communications)

Big Picture

The authors concluded that the beta cells they generated from T1D iPS cells were indistinguishable from healthy beta cells derived from non-diabetic patients. In a news release, Millman commented on the big picture of their study:

“In theory, if we could replace the damaged cells in these individuals with new pancreatic beta cells — whose primary function is to store and release insulin to control blood glucose — patients with type 1 diabetes wouldn’t need insulin shots anymore. The cells we’ve manufactured sense the presence of glucose and secrete insulin in response. And beta cells do a much better job controlling blood sugar than diabetic patients can.”

He further commented that the T1D- derived beta cells “could be ready for human research in three to five years. At that time, Millman expects the cells would be implanted under the skin of diabetes patients in a minimally invasive surgical procedure that would allow the beta cells access to a patient’s blood supply.”

“What we’re envisioning is an outpatient procedure in which some sort of device filled with the cells would be placed just beneath the skin,” he said.

In fact, such devices already exist. CIRM is funding a type 1 diabetes clinical trial sponsored by the San Diego based company ViaCyte. They are currently testing a combination drug delivery system that implants a medical device capsule containing pancreatic progenitor cells derived from human embryonic stem cells. Once implanted, the progenitor cells are expected to specialize into mature pancreatic cells including beta cells that secrete insulin.


Related Links:

Diabetes’ demise? Master Switch Identified for Turning Stem Cells into Functional Insulin-Producing Cells

It’s been a good week for diabetes researchers and the over one million Americans with type 1 diabetes who are hoping for an eventual stem cell-based treatment for this incurable disease. Published a day apart, two studies reported on achieving an elusive goal for the field: creating functional insulin-producing cells in a lab dish from induced pluripotent stem cells (iPS).

My fellow Stem Cellar blogger, Karen Ring, detailed one of the studies on Tuesday which used cells from human fat tissue (aka “love handles”) to devise a novel, consistent and efficient method for generating iPS-derived insulin-producing cells.

Print

Salk scientists identified a master switch, ERR-gamma, for making functional beta cells from stem cells. Image: Salk Institute

The other study is a CIRM-funded project by Salk Institute scientists. Reporting in Cell Metabolism, the team compared fetal and adult insulin-producing cells in mice and uncovered a protein “switch” that stimulates human iPS cells to fully mature into insulin-producing cells in a petri dish.

Because a very specific cell type is affected, the pancreatic beta cells, developing a cell therapy for diabetes would seem pretty straight-forward. Simply transplant stem cell-derived pancreatic beta-like cells that naturally release insulin in response to glucose. But over the years, researchers found that it wasn’t so easy to make fully mature stem cell-derived beta-like cells in the lab. The cells often got stuck at an immature stage of development resembling those found in the developing fetus.

The Case of the Missing Regulator of Insulin-Producing Cells
To get past this bottleneck the Salk team studied fetal and adult beta cells in mice in hopes that a comparison would reveal key missing ingredients for making fully functional beta-like cells. In particular, they compared the levels of transcription factors, proteins that turn genes on and off and are known to play important roles in determining the cell fate of stem cells. This analysis identified a transcription factor called ERR-gamma present in higher levels in adult cells compared to the fetal cells.

If this transcription factor is really important then removing it should have a very noticeable impact on maintaining blood glucose level. To test this idea, the team genetically engineered mice that lacked ERR-gamma. Sure enough, they showed that the beta cells of these mice did not release insulin in response to a large injection of glucose.

ERR-gamma: Master Switch for Making iβeta cells
Rather than knocking out ERR-gamma production, the researchers next manipulated human iPS cells to over produce ERR-gamma. When they attempted to mature those cells into beta-like cells, the ERR-gamma worked like a charm and helped generate cells that secrete insulin when glucose was added to the petri dish. To really nail down this result, the team repeated this lab experiment in animals. They transplanted these human iPS-derived beta-like cells, which they dubbed iβeta cells, into diabetic mice. Within days of the transplantation, the mice had normal blood sugar levels.

This compelling result points to ERR-gamma as a master regulator of beta cell development and a possible answer to readily making a cell therapy product. As Evans mentions in a press release, he’s cautiously optimistic about the future:

Ron-Evans-Michael-Downes-Eiji-Yoshihara-IMG_0475e-200x300

Study authors (from left): Michael Downes, Ron Evans and Eiji Yoshihara

“Hopefully, this mirrors what would happen in the clinic—after someone is diagnosed with diabetes they could potentially get this treatment. It’s exciting because it suggests that cells in a dish are ready to go.”

For Your Consideration

And because the cells are derived from human iPS cells, each patient could potentially have beta cells tailor made from their own skin or blood sample. The advantage here is that the transplant is less likely to be rejected by the immune system. But type 1 diabetes is an autoimmune disease in which the immune system attacks the beta cells as if they were foreign to the body. So it’s possible that those transplanted cells would still be vulnerable if the autoimmune environment is still present.

A CIRM-funded clinical trial, sponsored by ViaCyte, Inc., is currently testing an embryonic stem cell-based therapy for type 1 diabetics and gets around this immune system problem by shielding the cell product inside an encapsulation device which is placed under the skin. Also, the ViaCyte product does not use fully mature beta-like cells but instead transplants earlier stage progenitor cells and lets them develop into functioning beta cells inside the patient.

Many Shots on Goal – It’s a Good Thing
Which methods will work? Are “love handle” beta cells better than ERR-gamma ones? Oh, and what about the report in January that reprogrammed skin cells directly into functional beta cells? Is that the way to go? And will the ViaCyte progenitor cells successfully develop and function inside people with diabetes?  Ultimately, only clinical testing will be able to answer these questions. It’s exciting to see so many research teams making progress toward cell therapies for diabetes. As we often say here, the more shots the field takes, the more likely someone will score the game-changing goal of curing diabetes.

Stem cells from “love-handles” could help diabetes patients

Love handles usually get a bad rap, but this week, a study from Switzerland claims that stem cells taken from the fat tissue of “love handles” could one day benefit diabetes patients.

An islet of a mouse pancreas containing beta cells shown in green. (wikipedia)

An islet of a mouse pancreas containing beta cells shown in green. (wikipedia)

The study, which was published in Nature Communications, generated the much coveted insulin-secreting pancreatic beta cells from human induced pluripotent stem cells (iPS cells) in a dish. When exposed to glucose (sugar), beta cells secrete the hormone insulin, which can tell muscle and fat tissue to absorb excess glucose if there is too much around. Without these important cells, your body wouldn’t be able to regulate the sugar levels in your blood, and you would be at high risk for getting diabetes.

Diabetic patients can take daily shots of insulin to manage their disease, but scientists are looking to stem cells for a more permanent solution. Their goal is to make bonafide beta cells from human pluripotent stem cells in a dish that behave exactly the same as ones living in a normal human pancreas. Current methods to make beta cells from stem cells are complex, too often yield inconsistent results and generate multiple other cell types.

Turning fat tissue into pancreatic cells

The Switzerland study developed a novel method for making beta cells from iPS cells that is efficient and gives more consistent results. The iPS cells were genetically reprogrammed from mesenchymal stem cells that had been extracted from the fat tissue of a 50-year old woman. To create insulin-secreting beta cells, the group developed a synthetic control network that directed the iPS cells step by step down the path towards becoming pancreatic beta cells.

The synthetic control network coordinated the expression of genes called transcription factors that are important for pancreatic development. The network could be thought of as an orchestra. At the start of a symphony, the conductor signals to different instrument groups to begin and then directs the tempo and sound of the performance, making sure each instrument plays at the right time.

In the case of this study, the synthetic gene network coordinates expression of three pancreatic transcription factors: Ngn2, Pdx1, and MafA. When the expression of these genes was coordinated in a precise way that mimicked natural beta cell development, the pancreatic progenitor cells developed into functioning beta-like cells that secreted insulin in the presence of glucose.

The diagram shows the dynamics of the most important growth factors during differentiation of human induced pluripotent stem cell to beta-like cells. Credit: ETH Zurich

The diagram shows the dynamics of the most important transcription factors during differentiation of human induced pluripotent stem cell to beta-like cells. Credit: ETH Zurich

Pros of love handle-derived beta cells

This technology has advantages over current stem cell-derived beta cell generating methods, which typically use combinations of genetic reprogramming factors, chemicals, or proteins. Senior author on the study, Martin Fussenegger, explained in a news release that his study’s method has more control over the timing of pancreatic gene expression and as a result is more efficient, having the ability to turn three out of four fat stem cells into functioning beta cells.

Another benefit to this technology is the potential for making personalized stem cell treatments for diabetes sufferers. Patient-specific beta cells derived from iPS cells can be transplanted without fear of immune rejection (it’s what’s called an autologous stem cell therapy). Some diabetes patients have received pancreatic tissue transplants from donors, but they have to take immunosuppressive drugs and even then, there is no guarantee that the transplant will survive and work properly for an extended period of time.

Fussenegger commented:

“With our beta cells, there would likely be no need for this action, since we can make them using endogenous cell material taken from the patient’s own body. This is why our work is of such interest in the treatment of diabetes.”

More work to do

While these findings are definitely exciting, there is still a long road ahead. The authors found that their beta cells did not perform at the same level as natural beta cells. When exposed to glucose, the stem cell-derived beta cells failed to secrete the same amount of insulin. So it sounds like the group needs to do some tweaking with their method in order to generate more mature beta cells.

Lastly, it’s definitely worth looking at the big picture. This study was done in a culture dish, and the beta cells they generated were not tested in animals or humans. Such transplantation experiments are necessary to determine whether love-handle derived beta cells will be an appropriate and effective treatment for diabetes patients.

A CIRM funded team at San Diego-based company ViaCyte seems to have successfully gotten around the issue of maturing beta cells from stem cells and is already testing their therapy in clinical trials. Their study involves transplanting so-called pancreatic progenitor cells (derived from embryonic stem cells) that are only part way down the path to becoming beta cells. They transplant these cells in an encapsulated medical device placed under the skin where they receive natural cues from the surrounding tissue that direct their growth into mature beta cells. Several patients have been transplanted with these cells in a CIRM funded Phase 1/2 clinical trial, but no data have been released as yet.


Related Links:

Stem cell stories that caught our eye: sexual identity of organs, upping the game of muscle stem cells, mini guts produce insulin

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.

A new sexual identity crisis—in our organs. With the transition from Mr. to Ms. Jenner and other transsexual news this year, it seems inevitable that a research paper would come out suggesting we may all have some mosaic sexual identity. A team in the U.K. found that the stem cells that develop our organs can have varying sexual identities and that can impact the function of the organ.

The organ in question in this case, intestines in fruit flies, is smaller in males than in females. By turning on and off certain genes the researchers at the Medical Research Council’s Clinical Science Centre found that making stem cells in the gut more masculine reduced their ability to multiply and produced smaller intestines. They also found that female intestines were more prone to tumors, just as many diseases are more common in one sex than the other.

In an interview with Medical News Today, Bruno Hudry, the first author on the paper, which is published in Nature, talked about the likelihood that we all have some adult cells in us with genes of the opposite sex.

 “This study shows that there is a wider spectrum than just two sexes. You can be chromosomally, hormonally or phenotypically female but still having some specific adult stem cells (here the stem cells of the intestine) acting like male. So it is hard to say if someone is “really” male or female. Some people are simply a mosaic of male and female cells within a phenotypically ‘male’ or ‘female’ body.”

Hurdry speculated that if the results are duplicated in humans it could provide a window into other sex-linked differences in diseases and could be a matching factor added to the standard protocol for blood and organ donations.

 

Reprogramming stomach to produce insulin.  The stem cells in our gut show an efficiency not seen in most of our organs. They produce a new lining for our stomach and intestine every few days. On the opposite end of the spectrum, the insulin-producing cells in our pancreas rank poorly in self renewal. So, what if you could get some of those vigorous gut stem cells to make insulin producing beta cells? Turns out you can and they can produce enough insulin to allow a diabetic mouse to survive.

mini stomach

A mini-gut with insulin-producing cells (red) and stem cells (green).

A team at the Harvard Stem Cell Institute manipulated three genes known to be associated with beta cell development and tested the ability of many different tissues—from tail to snout—to produce beta cells. A portion of the stomach near the intestine, which naturally produces other hormones, easily reprogrammed into insulin producing cells. More important, if the first batch of those cells was destroyed by the team, the remaining stem cells in the tissue quickly regenerated more beta cells. Since a misbehaving immune system causes type 1 diabetes, this renewal ability could be key to preventing a return of the disease after a transplant of these cells.

In the lab the researchers pushed the tissue from the pylorous region of the stomach to self-organize into mini-stomachs along with the three genetic factors that drive beta cell production.  When transplanted under the skin of mice that had previously had their beta cells destroyed, the mice survived. The genetic manipulations used in this research could not be used in people, but the team is working on a system that could.

 “What is potentially really great about this approach is that one can biopsy from an individual person, grow the cells in vitro and reprogram them to beta cells, and then transplant them to create a patient-specific therapy,” said Qiao Zhou, the senior author. “That’s what we’re working on now. We’re very excited.”

Medicalxpress ran a story about the work published in Cell Stem Cell.

 

muscle stem cells

Muscle stem cells generate new muscle (green) in a mouse.

Better way to build muscle.  Stem cells behave differently depending on what environment they find themselves in, but they are not passive about their environment. They can actively change it. A CIRM-funded team at Sanford Burnham Prebys Medical Discovery Institute (SBP) found that fetal muscle stem cells and adult muscle stem cells make very different changes in the micro-environment around them.

Fetal muscle stem cells become very good at generating large quantities of new muscle, while the adult stem cells take the role of maintaining themselves for emergencies. As a result, when major repair is needed like in muscular dystrophies and aging, they easily get overwhelmed. So the SBP team looked for ways to make the adult stem cells behave more like their fetal predecessors.

 “We found that fetal MuSCs remodel their microenvironment by secreting specific proteins, and then examined whether that same microenvironment can encourage adult MuSCs to more efficiently generate new muscle. It does, which means that how adult MuSCs normally support muscle growth is not an intrinsic characteristic, but can be changed,” said Matthew Tierney, first author of the study in an institute press release distributed by Newswise.

The results point to paths for developing therapies for a number of muscle wasting conditions.

Protective cell therapy could mean insulin independence for diabetic patients

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.”


Related Links:

A Win for Diabetes: Scientists Make Functional Pancreatic Cells From Skin

Today is an exciting day for diabetes research and patients. For the first time, scientists have succeeded in making functional pancreatic beta cells from human skin. This new method for making the insulin-producing cells of the pancreas could produce a new, more effective treatment for patients suffering from diabetes.

Researchers at the Gladstone Institutes and the University of California, San Francisco published these promising findings today in the journal Nature Communications.

Making pancreatic cells from skin

They used a technique called direct reprogramming to turn human skin cells directly into pancreatic beta cells without having to go all the way back to a pluripotent stem cell state. The skin cells were treated with factors used to generate induced pluripotent stem cells (iPSCs) and with pancreatic-specific molecules. This cocktail of factors and molecules shut off the skin genes and turned on genes of the pancreas.

The end product was endoderm progenitor cells, which are like stem cells but can only generate cell types specific to organs derived from the endoderm layer (for example: lungs, thyroid, pancreas). The scientists took these endoderm progenitors and further coaxed them into mature, pancreatic beta cells after treatment with another cocktail of molecules.

Functioning human pancreatic cells after they’ve been transplanted into a mouse. (Image: Saiyong Zhu, Gladstone)

Functioning human pancreatic cells after they’ve been transplanted into a mouse. (Image: Saiyong Zhu, Gladstone)

While the pancreatic cells they made looked and acted like the real thing in a dish (they were able to secrete insulin when exposed to glucose), the authors needed to confirm that they functioned properly in animals. They transplanted the mature beta cells into mice that were engineered to have diabetes, and observed that the human beta cells protected the mice from becoming diabetic by properly regulating their blood glucose levels.

Importantly, none of the mice receiving human cells got tumors, which is always a concern when transplanting reprogrammed cells or cells derived from pluripotent stem cells.

What does this mean?

This study is groundbreaking because it offers a new and more efficient method to make functioning human beta cells in mass quantities.

Dr. Sheng Ding, a CIRM funded senior investigator at the Gladstone and co-senior author, explained in a Gladstone news release:

Sheng Ding

Sheng Ding

“This new cellular reprogramming and expansion paradigm is more sustainable and scalable than previous methods. Using this approach, cell production can be massively increased while maintaining quality control at multiple steps. This development ensures much greater regulation in the manufacturing process of new cells. Now we can generate virtually unlimited numbers of patient-matched insulin-producing pancreatic cells.”

 

Matthias Hebrok, director of the Diabetes Center at UCSF and co-senior author on paper discussed the potential research and clinical applications of their findings:

Mattias Hebrok

Matthias Hebrok

“Our results demonstrate for the first time that human adult skin cells can be used to efficiently and rapidly generate functional pancreatic cells that behave similar to human beta cells. This finding opens up the opportunity for the analysis of patient-specific pancreatic beta cell properties and the optimization of cell therapy approaches.”

 

The study does mention the caveat that their direct reprogramming approach wasn’t able to generate all the cell types of the pancreas. Having these support cells would better recreate the pancreatic environment and likely improve the function of the transplanted beta cells.

Lastly, I find this study exciting because it kills two birds with one stone. Scientists can use this technique to make better cellular models of diabetes to understand why the disease happens, and they could also develop new cell replacement therapies in humans. Already, stem cell derived pancreatic beta cells are being tested in human clinical trials for type 1 diabetes (one of them is a CIRM-funded clinical trial by Viacyte) and it seems likely that beta cells derived from skin will follow suit.


Related links:

Type 1 Diabetes Trial Explained Whiteboard Video Style

There’s a saying, a picture is worth a thousand words. With complicated science however, pictures don’t always do these topics justice. Here’s where videos come to the rescue.

Florie Mar, founder of Youreka Science.

Florie Mar, founder of Youreka Science.

Today’s topic is type 1 diabetes and a CIRM-funded clinical trial headed by the San Diego company ViaCyte hoping to develop a cure for patients with this disease. Instead of writing an entire blog about the latest on this clinical trial, we are featuring an excellent video by Youreka Science. This nonprofit organization is the brainchild of former University of California, San Francisco graduate student Florie Mar who has a passion to bring scientific concepts to life to reach both students and the general public.

Youreka’s style uses whiteboard videos to explain disease and basic science research with drawings, words, and lay person-friendly narrative. This particular video, “Progress and Promise of Stem Cell Research: Type 1 Diabetes” was developed in collaboration with Americans for Cures and explains how CIRM-funded stem cell research is “leading to groundbreaking advances in diabetes.”

We are also excited about this ViaCyte trial as it’s being conducted in one of the CIRM Alpha Stem Cell Clinics located at the University of California, San Diego. The goal of the Alpha Clinics is to accelerate the development and delivery of stem cell therapies to patients by providing stem-cell focused clinics for conducting high quality trials.

In brief, the video explains ViaCyte’s stem cell derived therapy that replaces the insulin-producing cells that are lost in type 1 diabetes patients. For more details, check out the video!

 

And to hear from Viacyte’s chief scientific officer as well as two people living with type 1 diabetes, check out a CIRM video we produced a few years ago.


Related Links:

New type of diabetes caused by old age may be treatable

I’m going to tell you a secret: I love sugar. I love it so much that as a little kid my mom used to tell me scary stories about how my teeth would fall out and that I might get diabetes one day if I ate too many sweets. Thankfully, none of these things happened. I have a full set of teeth (and they’re real), my blood sugar level is normal, and I’ve become one with the term “everything in moderation”.

I am not out of the woods, however: a newly discovered type of diabetes could strike in a few decades. A research team has found the cause of a type of diabetes that occurs because of old age, and a potential cure, at least in mice.

Diabetes comes in different flavors

People who suffer from diabetes (which is almost 30 million Americans) lack the ability to regulate the amount of sugar in their blood. The pancreas is the organ that regulates blood sugar by producing a hormone called insulin. If blood has a high sugar level, the pancreas releases insulin, which helps muscle, liver, and fat cells to absorb the excess sugar until the levels in the blood are back to normal.

There are two main forms of diabetes, type 1 and 2, both of which cause hyperglycemia or high blood sugar. Type 1 is an autoimmune disorder where the immune system attacks and kills the insulin-producing cells in the pancreas. As a result, these type 1 diabetics aren’t able to produce insulin and endure a lifetime of daily insulin shots to manage their condition. Type 2 diabetes is the more common form of the disease and occurs when the body’s cells become unresponsive, or resistant, to insulin and stop absorbing sugar from the bloodstream.

The cause of type 1 diabetes is not known although genetic factors are sure to be involved. Type 2 diabetes can be caused by a combination of factors including poor diet, obesity, genetics, stress, and old age. Both forms of the disease can be fatal if not managed properly and raise the risk of other medical complications such as heart disease, blindness, ulcers, and kidney failure.

While type 1 or 2 diabetes make up the vast majority of the cases, there are actually other forms of this disease that we are only just beginning to understand. One of them is type 3, which is linked to Alzheimer’s disease. (To learn more about the link between AD and diabetes, read this blog.)

Old age can cause diabetes

Another form of diabetes, which is in the running for the title of type 4, is caused by old age. Unlike type 2 diabetes which also occurs in adults, type 4 individuals don’t have the typical associated risk factors like weight gain. The exact mechanism behind age-related type 4 diabetes in humans isn’t known, but a CIRM-funded study published today in Nature identified the cause of diabetes in older, non-obese mice.

Scientists from the Salk Institute compared the immune systems of healthy mice to lean mice with age-associated insulin resistance or mice with obesity-associated insulin resistance (the equivalent to type 2 diabetes in humans). When they studied the fat tissue in the three animal models, they noticed a striking difference in the number of immune cells called T regulatory cells (Tregs). These cells are the “keepers of the immune system”, and they keep inflammation and excessive activity of other immune cells to a minimum.

Lean mice with age-related diabetes, had a substantially larger number of Tregs in their fat tissue compared to obesity-related diabetic and normal mice. Instead of being their usual helpful selves, the overabundance of Tregs in the age-related diabetic mice caused insulin resistance.

Salk researchers show that diabetes in elderly, lean animals is caused by an overabundance of immune cells in fat. In this graphic, fat tissue is shown with representations of the immune cells called Tregs (orange). In aged mice with diabetes (represented on the right), Tregs are overexpressed in fat tissue and trigger insulin resistance. When Tregs are blocked, the fat cells in mice become insulin sensitive again. (Image courtesy of Salk Institute)

Diabetes in elderly, lean animals is caused by an overabundance of immune cells called Tregs (orange)  in fat tissue (brown cells). In aged mice with diabetes (right), Tregs are overexpressed in fat tissue and trigger insulin resistance. When Tregs are blocked, the fat cells in mice become insulin sensitive again. (Image courtesy of Salk Institute)

In a Salk Institute press release, lead author Sagar Bapat explained:

Normally, Tregs help calm inflammation. Because fat tissue is constantly broken down and built back up as it stores and releases energy, it requires low levels of inflammation to constantly remodel itself. But as someone ages, the new research suggests, Tregs gradually accumulate within fat. And if the cells reach a tipping point where they completely block inflammation in fat tissue, they can cause fat deposits to build up inside unseen areas of the body, including the liver, leading to insulin resistance.

A cure for type 4 diabetes, but in mice…

After they identified the cause, the authors next searched for a solution. They blocked the build up of Tregs in the fat tissue of age-related diabetic mice using an antibody drug that inhibits the production of Tregs. The drug successfully cured the age-related diabetic mice of their insulin resistance, but didn’t do the same for the obesity-related diabetic mice. The authors concluded that the two forms of diabetes have different causes and type 4 can be cured by removing excessive Tregs from fat tissue.

This study is only the beginning for understanding age-related diabetes. The authors next want to find out why Tregs accumulate in the fat tissue of older mice, and if they also build up in other tissues and organs. They are also curious to know if the same phenomenon happens in elderly humans who become diabetic but don’t have type 2 diabetes.

Understanding the cause of age-related diabetes in humans is of upmost importance to Ronald Evans who is the director of the Gene Expression Lab at the Salk Institute, and senior author on the study.

Ron Evans

Ron Evans

A lot of diabetes in the elderly goes undiagnosed because they don’t have the classical risk factors for type 2 diabetes, such as obesity. We hope our discovery not only leads to therapeutics, but to an increased recognition of type 4 diabetes as a distinct disease.

For more on this exciting study, check out a video interview of Dr. Evans from the Salk Institute:


Related links:

Seeing is believing: using video to explain stem cell science

People are visual creatures. So it’s no surprise that many of us learn best through visual means. In fact a study by the Social Science Research Network found that 65 percent of us are visual learners.

That’s why videos are such useful tools in teaching and learning, and that’s why when we came across a new video series called “Reaping the rewards of stem cell research” we were pretty excited. And to be honest there’s an element of self-interest here. The series focuses on letting people know all about the research funded by CIRM.

We didn’t make the videos, a group called Youreka Science is behind them. Nor did we pay for them. That was done by a group called Americans for Cures (the group is headed by Bob Klein who was the driving force behind Proposition 71, the voter-approved initiative that created the stem cell agency). Nonetheless we are happy to help spread the word about them.

The videos are wonderfully simple, involving just an engaging voice, a smart script and some creative artwork on a white board. In this first video they focus on our work in helping fund stem cell therapies for type 1 diabetes.

What is so impressive about the video is its ability to take complex ideas and make them easily understandable. On their website Youreka Science says they have a number of hopes for the videos they produce:

“How empowering would it be for patients to better understand the underlying biology of their disease and learn how new treatments work to fight their illness?

How enlightening would it be for citizens to be part of the discovery process and see their tax dollars at work from the beginning?

How rewarding would it be for scientists to see their research understood and appreciated by the very people that support their work?”

What I love about Youreka Science is that it began almost by chance. A PhD student at the University of California San Francisco was teaching some 5th graders about science and thought it would be really cool to have a way of bringing the textbook to life. So she did. And now we all get to benefit from this delightful approach.