Creating partnerships to help get stem cell therapies over the finish line

Lewis, Clark, Sacagawea

Lewis & Clark & Sacagawea:

Trying to go it alone is never easy. Imagine how far Lewis would have got without Clark, or the two of them without Sacagawea. Would Batman have succeeded without Robin; Mickey without Minnie Mouse? Having a partner whose skills and expertise complements yours just makes things easier.

That’s why some recent news about two CIRM-funded companies running clinical trials was so encouraging.

Viacyte Gore

First ViaCyte, which is developing an implantable device to help people with type 1 diabetes, announced a collaborative research agreement with W. L. Gore & Associates, a global materials science company. On every level it seems like a natural fit.

ViaCyte has developed a way of maturing embryonic stem cells into an early form of the cells that produce insulin. They then insert those cells into a permeable device that can be implanted under the skin. Inside the device, the cells mature into insulin-producing cells. While ViaCyte has experience developing the cells, Gore has experience in the research, development and manufacturing of implantable devices.

Gore-tex-fabricWhat they hope to do is develop a kind of high-tech version of what Gore already does with its Gore-Tex fabrics. Gore-Tex keeps the rain out but allows your skin to breathe. To treat diabetes they need a device that keeps the immune system out, so it won’t attack the cells inside, but allows those cells to secrete insulin into the body.

As Edward Gunzel, Technical Leader for Gore PharmBIO Products, said in a news release, each side brings experience and expertise that complements the other:

“We have a proven track record of developing and commercializing innovative new materials and products to address challenging implantable medical device applications and solving difficult problems for biologics manufacturers.  Gore and ViaCyte began exploring a collaboration in 2016 with early encouraging progress leading to this agreement, and it was clear to us that teaming up with ViaCyte provided a synergistic opportunity for both companies.  We look forward to working with ViaCyte to develop novel implantable delivery technologies for cell therapies.”

AMD2

How macular degeneration destroys central vision

Then last week Regenerative Patch Technologies (RPT), which is running a CIRM-funded clinical trial targeting age-related macular degeneration (AMD), announced an investment from Santen Pharmaceutical, a Japanese company specializing in ophthalmology research and treatment.

The investment will help with the development of RPT’s therapy for AMD, a condition that affects millions of people around the world. It’s caused by the deterioration of the macula, the central portion of the retina which is responsible for our ability to focus, read, drive a car and see objects like faces in fine details.

RPE

RPT is using embryonic stem cells to produce the support cells, or RPE cells, needed to replace those lost in AMD. Because these cells exist in a thin sheet in the back of the eye, the company is assembling these sheets in the lab by growing the RPE cells on synthetic scaffolds. These sheets are then surgically implanted into the eye.

In a news release, RPT’s co-founder Dennis Clegg says partnerships like this are essential for small companies like RPT:

“The ability to partner with a global leader in ophthalmology like Santen is very exciting. Such a strong partnership will greatly accelerate RPT’s ability to develop our product safely and effectively.”

These partnerships are not just good news for those involved, they are encouraging for the field as a whole. When big companies like Gore and Santen are willing to invest their own money in a project it suggests growing confidence in the likelihood that this work will be successful, and that it will be profitable.

As the current blockbuster movie ‘Beauty and the Beast’ is proving; with the right partner you can not only make magic, you can also make a lot of money. For potential investors those are both wonderfully attractive qualities. We’re hoping these two new partnerships will help RPT and ViaCyte advance their research. And that these are just the first of many more to come.

Stem cells stories that caught our eye: switching cell ID to treat diabetes, AI predicts cell fate, stem cell ALS therapy for Canada

Treating diabetes by changing a cell’s identity. Stem cells are an ideal therapy strategy for treating type 1 diabetes. That’s because the disease is caused by the loss of a very specific cell type: the insulin-producing beta cell in the pancreas. So, several groups are developing treatments that aim to replace the lost cells by transplanting stem cell-derived beta cells grown in the lab. In fact, Viacyte is applying this approach in an ongoing CIRM-funded clinical trial.

In preliminary animal studies published late last week, a Stanford research team has shown another approach may be possible which generates beta cells inside the body instead of relying on cells grown in a petri dish. The CIRM-funded Cell Metabolism report focused on alpha cells, another cell type in pancreas which produces the hormone glucagon.

glucagon

Microscopy of islet cells, round clusters of cells found in the pancreas. The brown stained cells are glucagon-producing alpha cells. Credit: Wikimedia Commons

After eating a meal, insulin is critical for getting blood sugar into your cells for their energy needs. But glucagon is needed to release stored up sugar, or glucose, into your blood when you haven’t eaten for a while. The research team, blocked two genes in mice that are critical for maintaining an alpha cell state. Seven weeks after inhibiting the activity of these genes, the researchers saw that many alpha cells had converted to beta cells, a process called direct reprogramming.

Does the same thing happen in humans? A study of cadaver donors who had been recently diagnosed with diabetes before their death suggests the answer is yes. An analysis of pancreatic tissue samples showed cells that produced both insulin and glucagon, and appeared to be in the process of converting from beta to alpha cells. Further genetic tests showed that diabetes donor cells had lost activity in the two genes that were blocked in the mouse studies.

It turns out that there’s naturally an excess of alpha cells so, as team lead Seung Kim mentioned in a press release, this strategy could pan out:

image-img-620-high

Seung Kim. Credit: Steve Fisch, Stanford University

“This indicates that it might be possible to use targeted methods to block these genes or the signals controlling them in the pancreatic islets of people with diabetes to enhance the proportion of alpha cells that convert into beta cells.”

Using computers to predict cell fate. Deep learning is a cutting-edge area of computer science that uses computer algorithms to perform tasks that border on artificial intelligence. From beating humans in a game of Go to self-driving car technology, deep learning has an exciting range of applications. Now, scientists at Helmholtz Zentrum München in Germany have used deep learning to predict the fate of cells.

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Using deep learning, computers can predict the fate of these blood stem cells.
Credit: Helmholtz Zentrum München.

The study, published this week in Nature Methods, focused on blood stem cells also called hematopoietic stem cells. These cells live in the bone marrow and give rise to all the different types of blood cells. This process can go awry and lead to deadly disorders like leukemia, so scientists are very interested in exquisitely understanding each step that a blood stem cell takes as it specializes into different cell types.

Researchers can figure out the fate of a blood stem cells by adding tags, which glow with various color, to the cell surface . Under a microscope these colors reveal the cells identity. But this method is always after the fact. There no way to look at a cell and predict what type of cell it is turning into. In this study, the team filmed the cells under a microscope as they transformed into different cell types. The deep learning algorithm processed the patterns in the cells and developed cell fate predictions. Now, compared to the typical method using the glowing tags, the researchers knew the eventual cell fates much sooner. The team lead, Carsten Marr, explained how this new technology could help their research:

“Since we now know which cells will develop in which way, we can isolate them earlier than before and examine how they differ at a molecular level. We want to use this information to understand how the choices are made for particular developmental traits.”

Stem cell therapy for ALS seeking approval in Canada. (Karen Ring) Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disease that kills off the nerve cells responsible for controlling muscle movement. Patients with ALS suffer from muscle weakness, difficulty in speaking, and eventually breathing. There is no cure for ALS and the average life expectancy after diagnosis is just 2 – 5 years. But companies are pursuing stem cell-based therapies in clinical trials as promising treatment options.

One company in particular, BrainStorm Cell Therapeutics based in the US and Israel, is testing a mesenchymal stem cell-based therapy called NurOwn in ALS patients in clinical trials. In their Phase 2 trials, they observed clinical improvements in slowing down the rate of disease progression following the stem cell treatment.

In a recent update from our friends at the Signals Blog, BrainStorm has announced that it is seeking regulatory approval of its NurOwn treatment for ALS patients in Canada. They will be working with the Centre for Commercialization of Regenerative Medicine (CCRM) to apply for a special regulatory approval pathway with Health Canada, the Canadian government department responsible for national public health.

In a press release, BrainStorm CEO Chaim Lebovits, highlighted this new partnership and his company’s mission to gain regulatory approval for their ALS treatment:

“We are pleased to partner with CCRM as we continue our efforts to develop and make NurOwn available commercially to patients with ALS as quickly as possible. We look forward to discussing with Health Canada staff the results of our ALS clinical program to date, which we believe shows compelling evidence of safety and efficacy and may qualify for rapid review under Canada’s regulatory guidelines for drugs to treat serious or life-threatening conditions.”

Stacey Johnson who wrote the Signals Blog piece on this story explained that while BrainStorm is not starting a clinical trial for ALS in Canada, there will be significant benefits if its treatment is approved.

“If BrainStorm qualifies for this pathway and its market authorization request is successful, it is possible that NurOwn could be available for patients in Canada by early 2018.  True access to improved treatments for Canadian ALS patients would be a great outcome and something we are all hoping for.”

CIRM is also funding stem cell-based therapies in clinical trials for ALS. Just yesterday our Board awarded Cedars-Sinai $6.15 million dollars to conduct a Phase 1 trial for ALS patients that will use “cells called astrocytes that have been specially re-engineered to secrete proteins that can help repair and replace the cells damaged by the disease.” You can read more about this new trial in our latest news release.

Don’t Sugar Coat it: A Patient’s Perspective on Type 1 Diabetes

John Welsh

John Welsh

“In the weeks leading up to my diagnosis, I remember making and drinking Kool-Aid at the rate of about a gallon per day, and getting up to pee and drink Kool-Aid several times a night. The exhaustion and constant thirst and the weight loss were pretty scary. Insulin saved my life, and it’s been saving my life every day for the past 40 years.” – John Welsh

 

In honor of diabetes awareness month, we are featuring a patient perspective on what it’s like to live with type 1 diabetes (T1D) and what the future of stem cell research holds in terms of a cure.

T1D is a chronic disease that destroys the insulin producing cells in your pancreas, making it very difficult for your body to maintain the proper levels of sugar in your blood. There is no cure for T1D and patients take daily shots of insulin and closely monitor their blood sugar to stay healthy and alive.

Stem cell research offers an alternative strategy for treating T1D patients by potentially replacing their lost insulin producing cells. We’ve written blogs about ongoing stem cell research for diabetes on the Stem Cellar (here) but we haven’t focused on the patient side of T1D. So today, I’m introducing you to John Welsh, a man whose has lived with T1D since 1976.

John Welsh is a MD/PhD scientist and currently works at a company called Dexcom, which make a continuous glucose monitoring (CGM) device for diabetes patients. He is also an enrolled patient in CIRM-funded stem cell clinical trial (also funded by JDRF) for T1D sponsored by the company ViaCyte. The trial is testing a device containing stem cell-derived pancreatic cells that’s placed under the skin to act as a transplanted pancreas. You can learn more about it here.

I reached out to John to see if he wanted to share his story about living with diabetes. He was not only willing but enthusiastic to speak with me. As you will read later, one of John’s passions is a “good story”. And he sure told me a good one. So before you read on, I recommend grabbing some coffee or tea, going to a quiet room, and taking the time to enjoy his interview.


Q: Describe your career path and your current job.

JW: I went to college at UC Santa Cruz and majored in biochemistry and molecular biology. I then went into the medical scientist training program (combined MD/PhD program) at UC San Diego followed by research positions in cell biology and cancer biology at UC San Francisco and Novartis. I’ve been a medical writer specializing in medical devices for type 1 diabetes since 2009. At Dexcom, I help study the benefits of CGM and get the message out to healthcare professionals.

Q: How has diabetes affected your life and what obstacles do you deal with because of diabetes?

JW: I found out I had T1D at the age of 13, and it’s been a part of my life for 40 years. It’s been a big deal in terms of what I’m not allowed to do and figuring out what would be challenging if I tried. On the other hand, having diabetes is a great motivator on a lot of levels personally, educationally and professionally. Having this disease made me want to learn everything I could about the endocrine system. From there, my interests turned to biology – molecular biology in particular – and understanding how molecules in cells work.

The challenge of having diabetes also motivated me to do things that I might not have thought about otherwise – most importantly, a career that combined science and medicine. Having to stay close to my insulin and insulin-delivery paraphernalia (early on, syringes; nowadays, the pump and glucose monitor) meant that I couldn’t do as many ridiculous adventures as I might have otherwise.

Q: Did your diagnosis motivate you to pursue a scientific career?

JW: Absolutely. If I hadn’t gotten diabetes, I probably would have gone into something like engineering. But my parents were both healthcare professionals, so a career in medicine seemed plausible. The medical scientist MD/PhD training program at UC San Diego was really cool, but very competitive. Having first-hand experience with this disease may have given me an inside track with the admissions process, and that imperative – to understand the disease and how best to manage it – has been a great motivator.

There’s also a nice social aspect to being surrounded by people whose lives are affected by T1D.

Q: Describe your treatment regimen for T1D?

JW: I travel around with two things stuck on my belly, a Medtronic pump and a Dexcom Continuous Glucose Monitor (CGM) sensor. The first is an infusion port that can deliver insulin into my body. The port lasts for about three days after which you have to take it out. The port that lives under the skin surface is nine millimeters long and it’s about as thick as a mechanical pencil lead. The port is connected to a tube and the tube is connected to a pump, which has a reservoir with fast-acting insulin in it.

The insulin pump is pretty magical. It’s conceptually very simple, but it transforms the way a lot of people take insulin. You program it so that throughout the day, it squirts in a tiny bit of basal insulin at the low rate that you want. If you’re just cruising through your day, you get an infusion of insulin at a low basal rate. At mealtimes, you can give yourself an extra squirt of insulin like what happens with normal people’s pancreas. Or if you happen to notice that you have a high sugar level, you can program a correction bolus which will help to bring it back to towards the normal range. The sensor continuously interrogates the glucose concentration in under my skin. If something goes off the rails, it will beep at me.

dexcom_g4_platinum_man

Dexcom continuous glucose monitor.

As good as these devices are, they’re not a cure, they’re not perfect, and they’re not cheap, so one of my concerns as a physician and as a patient is making these transformative devices better and more widely available to people with the disease.

Q: What are the negative side effects associated with your insulin pump and sensor?

JW:  If you have an insulin pump, you carry it everywhere because it’s stuck onto you. The pump is on you for three days and it does get itchy. It’s expensive and a bit uncomfortable. And when I take my shirt off, it’s obvious that I have certain devices stuck on me.  This is a big disincentive for some of my type 1 friends, especially those who like to wear clothes without pockets. And every once-in-a-while, the pump will malfunction and you need a backup plan for getting insulin when it breaks.

On the other hand, the continuous glucose monitoring (CGM) is wonderful especially for moms and dads whose kids have T1D. CGM lets parents essentially spy on their kids. You can be on the sidelines watching your kid play soccer and you get a push notification on your phone saying that the glucose concentration is low, or is heading in that direction. The best-case scenario is that this technology helps people avoid dangerous and potentially catastrophic low blood sugars.

Q: Was the decision easy or hard to enroll in the ViaCyte trial?

JW: It was easy! I was very excited to learn about the ViaCyte trial and equally pleased to sign up for it. When I found out about it from a friend, I wanted to sign up for it right away. I went to clinicaltrials.gov and contacted the study coordinator at UC San Diego. They did a screening interview over the phone, and then they brought me in for screening lab work. After I was selected to be in the trial, they implanted a couple of larger devices (about the size of a credit card) under the skin of my lower back, and smaller devices (about the size of a postage stamp) in my arm and lower back to serve as “sentinels” that were taken out after two or three months.

ViaCyte device

ViaCyte device

I’m patient number seven in the safety part of this trial. They put the cell replacement therapy device in me without any pre-medication or immunosuppression. They tested this device first in diabetic mice and found that the stem cells in the device differentiated into insulin producing cells, much like the ones that usually live in the mouse pancreas. They then translated this technology from animal models to human trials and are hoping for the same type of result.

I had the device transplanted in March of 2015, and the plan is for in the final explant procedure to take place next year at the two-year anniversary. Once they take the device out, they will look at the cells under the microscope to see if they are alive and whether they turned into pancreatic cells that secrete insulin.

It’s been no trouble at all having this implant. I do clinic visits regularly where they do a meal challenge and monitor my blood sugar. My experience being a subject in this clinical study has been terrific. I met some wonderful people and I feel like I’m helping the community and advancing the science.

Q: Do you think that stem cell-derived therapies will be a solution for curing diabetes?

JW: T1D is a great target for stem cell therapy – the premise makes a lot of sense — so it’s logical that it’s one of the first ones to enter clinical trials. I definitely think that stem cells could offer a cure for T1D. Even 30 years ago, scientists knew that we needed to generate insulin producing cells somehow, protect them from immunological rejection, and package them up and put them somewhere in the body to act like a normal pancreas. The concept is still a good concept but the devil is in the implementation. That’s why clinical trials like the one CIRM is funding are important to figure these details out and advance the science.

Q: What is your opinion about the importance of stem cell research and advancing stem cell therapies into clinical trials?

JW: Understanding how cells determine their fate is tremendously important. I think that there’s going to be plenty of payoffs for stem cell research in the near term and more so in the intermediate and long term. Stem cell research has my full support, and it’s fun to speculate on how it might address other unmet medical needs. The more we learn about stem cell biology the better.

Q: What advice do you have for other patients dealing with diabetes or who are recently diagnosed?

JW: Don’t give up, don’t be ashamed or discouraged, and gather as much data as you can. Make sure you know where the fast-acting carbohydrates are!

Q: What are you passionate about?

JW: I love a good story, and I’m a fan of biological puzzles. It’s great having a front-row seat in the world of diabetes research, and I want to stick around long enough to celebrate a cure.


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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.


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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.


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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.”


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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.


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Stem cell stories that caught our eye: new ways to reprogram, shifting attitudes on tissue donation, and hockey legend’s miracle questioned

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.

Insulin-producing cells produced from skin. Starting with human skin cells a team at the University of Iowa has created iPS-type stem cells through genetic reprogramming and matured those stem cells into insulin-producing cells that successfully brought blood-sugar levels closer to normal when transplanted in mice.

University of Iowa researchers reprogrammed human skin cells to create iPS cells, which were then differentiated in a stepwise fashion to create insulin-producing cells. When these cells were transplanted into diabetic mice, the cells secreted insulin and reduced the blood sugar levels of the mice to normal or near-normal levels. The image shows the insulin-producing cells (right) and precursor cells (left). [Credit: University of Iowa]

University of Iowa researchers reprogrammed human skin cells to create iPS cells, which were then differentiated in a stepwise fashion to create insulin-producing cells. When these cells were transplanted into diabetic mice, the cells secreted insulin and reduced the blood sugar levels of the mice to normal or near-normal levels. The image shows the insulin-producing cells (right) and precursor cells (left).
[Credit: University of Iowa]

The cells did not completely restore blood-sugar levels to normal, but did point to the possibility of achieving that goal in the future, something the team leader Nicholas Zavazava noted in an article in the Des Moines Register, calling the work an “encouraging first step” toward a potential cure for diabetes.

The Register discussed the possibility of making personalized cells that match the genetics of the patient and avoiding the need for immune suppression. This has long been a goal with iPS cells, but increasingly the research community has turned to looking for options that would avoid immune rejection with donor cells that could be off-the-shelf and less expensive than making new cells for each patient.

Heart cells from reprogramming work in mice. Like several other teams, a group in Japan created beating heart cells from iPS-type stem cells. But they went the additional step of growing them into sheets of heart muscle that when transplanted into mice integrated into the animals own heart and beat to the same rhythm.

The team published the work in Cell Transplantation and the news agency AlianzaNews ran a story noting that it has previously been unclear if these cells would get in sync with the host heart muscle. The result provides hope this could be a route to repair hearts damaged by heart attack.

Patient attitudes on donating tissue. A University of Michigan study suggests most folks don’t care how you use body tissue they donate for research if you ask them about research generically. But their attitudes change when you ask about specific research, with positive responses increasing for only one type of research: stem cell research.

On the generic question, 69 percent said go for it, but when you mentioned the possibility of abortion research more than half said no and if told the cells might lead to commercial products 45 percent said nix. The team published their work in the Journal of the American Medical Association and HealthCanal picked up the university’s press release that quoted the lead researcher, Tom Tomlinson, on why paying attention to donor preference is so critical:

“Biobanks are becoming more and more important to health research, so it’s important to understand these concerns and how transparent these facilities need to be in the research they support.”

CIRM has begun building a bank of iPS-type stem cells made from tissue donated by people with one of 11 diseases. We went through a very detailed process to develop uniform informed consent forms to make sure the donors for our cell bank knew exactly how their cells could be used. Read more about the consent process here.

Mainstream media start to question hockey legend’s miracle. Finally some healthy skepticism has arrived. Hockey legend Gordie Howe’s recovery from a pair of strokes just before the holidays was treated by the general media as a true Christmas miracle. The scientific press tried to layer the coverage with some questions of what we don’t know about his case but not the mainstream media. The one exception I saw was Brad Fikes in the San Diego Union Tribune who had to rely on a couple of scientists who were openly speaking out at the time. We wrote about their concerns then as well.

Now two major outlets have raised questions in long pieces back-to-back yesterday and this morning. The Star in hockey-crazed Canada wrote the first piece and New York Magazine wrote today’s. Both raise serious questions about whether stem cells could have been the cause of Howe’s recovery and are valuable additions to the coverage.