skin

The Most Important Gift of All

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

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

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

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

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

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

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

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

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

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

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

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

Organs that can be donated

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

Tissue that can be donated

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

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

Using skin cells to repair damaged hearts

/ Kevin McCormack / Leave a comment

heart-muscle

Heart muscle  cells derived from skin cells

When someone has a heart attack, getting treatment quickly can mean the difference between life and death. Every minute delay in getting help means more heart cells die, and that can have profound consequences. One study found that heart attack patients who underwent surgery to re-open blocked arteries within 60 minutes of arriving in the emergency room had a six times greater survival rate than people who had to wait more than 90 minutes for the same treatment.

Clearly a quick intervention can be life-saving, which means an approach that uses a patient’s own stem cells to treat a heart attack won’t work. It simply takes too long to harvest the healthy heart cells, grow them in the lab, and re-inject them into the patient. By then the damage is done.

Now a new study shows that an off-the-shelf approach, using donor stem cells, might be the most effective way to go. Scientists at Shinshu University in Japan, used heart muscle stem cells from one monkey, to repair the damaged hearts of five other monkeys.

In the study, published in the journal Nature, the researchers took skin cells from a macaque monkey, turned those cells into induced pluripotent stem cells (iPSCs), and then turned those cells into cardiomyocytes or heart muscle cells. They then transplanted those cardiomyocytes into five other monkeys who had experienced an induced heart attack.

After 3 months the transplanted monkeys showed no signs of rejection and their hearts showed improved ability to contract, meaning they were pumping blood around the body more powerfully and efficiently than before they got the cardiomyocytes.

It’s an encouraging sign but it comes with a few caveats. One is that the monkeys used were all chosen to be as close a genetic match to the donor monkey as possible. This reduced the risk that the animals would reject the transplanted cells. But when it comes to treating people, it may not be feasible to have a wide selection of heart stem cell therapies on hand at every emergency room to make sure they are a good genetic match to the patient.

The second caveat is that all the transplanted monkeys experienced an increase in arrhythmias or irregular heartbeats. However, Yuji Shiba, one of the researchers, told the website ResearchGate that he didn’t think this was a serious issue:

“Ventricular arrhythmia was induced by the transplantation, typically within the first four weeks. However, this post-transplant arrhythmia seems to be transient and non-lethal. All five recipients of [the stem cells] survived without any abnormal behaviour for 12 weeks, even during the arrhythmia. So I think we can manage this side effect in clinic.”

Even with the caveats, this study demonstrates the potential for a donor-based stem cell therapy to treat heart attacks. This supports an approach already being tested by Capricor in a CIRM-funded clinical trial. In this trial the company is using donor cells, derived from heart stem cells, to treat patients who developed heart failure after a heart attack. In early studies the cells appear to reduce scar tissue on the heart, promote blood vessel growth and improve heart function.

The study from Japan shows the possibilities of using a ready-made stem cell approach to helping repair damage caused by a heart attacks. We’re hoping Capricor will take it from a possibility, and turn it into a reality.

If you would like to read some recent blog posts about Capricor go here and here.

Stem cell stories that caught our eye: Designer bags from human skin, large-scale stem cell production, new look at fat stem cells

/ Karen Ring / Leave a comment

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

Designer bags from human skin? I had to share a bizarre story I read this week about a UK fashion designer who is making a collection of luxury handbags from lab-grown human skin called Pure Human. What’s even weirder is that the human skin used was engineered to contain the genetic material or DNA of the famous fashion designer Alexander McQueen who passed away in 2010.

A prototype bag, made with pig skin, from Tina Gorjanc’s Pure Human collection (Credit: Tina Gorjanc)

A prototype bag, made with pig skin, from Tina Gorjanc’s Pure Human collection (Credit: Tina Gorjanc & Signals blog for caption)

I had to admit I cringed when I first read about it in CCRM’s Signals Blog, but now I am fascinated that someone is actually doing this and intrigued about the ethical conversations that this story will undoubtedly stir up.

While it isn’t possible to patent a person’s DNA, it is possible to patent a technology that uses human DNA and products made from that technology. According to Signals, “the aim of the collection is to highlight existing legal loopholes around ownership of a person’s DNA and to open the doors for tissue bioengineering into the world of fashion.”

The collection’s designer, Tina Gorjanc, explained her motivation behind Pure Human:

Tina

Tina Gorjanc

“My main goal was to show that it is possible to patent a process using human genetic information in a domain other than medicine. Biotechnology is happening at a really rapid pace and legislation has not kept up with it.”

 

She also sees her bags as an untapped resource in the global luxury goods market which is now apparently worth $1 trillion dollars.

“When it comes to bioengineering, people tend to skip the luxury goods market because they think it’s too shallow and not important, but if you look at it, it’s one of the biggest markets that we have – and one that is open to new technology.”

Imagine having the option to bypass animal leather products for engineered human skin-based products? But on the flip side, the author of the Signals blog, Jovana Drinjakovic, makes a great point at the end of her piece by saying: just because we can do this, does it mean we should?

Drinjakovic finishes her piece with a reality-check quote from Dr. Marc Jeschke, the leader of a burn research and skin regeneration lab in Toronto:

“We are trying to find a way to make skin that is functional and won’t be rejected after a transplant. But just to grow skin for fashion – I don’t think that’s very useful.”

 

Large-Scale Stem Cell Production in Texas. A nonprofit company in San Antonio, Texas, called BioBridge, has big plans to produce large amounts of clinical-grade stem cells for regenerative medicine purposes. The company recently received $7.8 million in funding from the Medical Technology Enterprise Consortium to pursue this effort.

BioBridge will work with GenCure, a subsidiary company, to develop the technology to manufacture different types of stem cells at a large scale. These stem cells will be clinical-grade, meaning that they can be used for cell therapy applications in patients. BioBridge’s goal is to provide enough stem cells for both academic researchers and companies who need more than their current lab resources can generate.

The CEO of GenCure, Becky Cap, explained the need for this type of large-scale stem cell manufacturing technology in an interview with Xconomy:

“The capabilities in this sector right now are at a scale that’s appropriate for bench research and some clinical research, depending on the indication and volume of cells we need. We’re talking about moving from hundreds of millions of cells to billions of cells. You need billions of cells to do tissue regeneration and scaffold reengineering.”

Two other companies with expertise in cell manufacturing, StemBioSys from San Antonio and RoosterBio in Maryland, will be working with BioBridge and GenCure over the next three years on specific projects. StemBioSys plans to develop materials that will be used to promote stem cell growth. RoosterBio will take stem cell culturing from small-scale petri dishes to large-scale bioreactors that can produce billions of cells.

It will be interesting to see how the BioBridge collaboration works out. Xconomy concluded:

“This sort of large-scale manufacturing is still years out. The results that come from the work will be incorporated into a contract manufacturing operation that BioBridge is opening within GenCure.”

 

A new way to look at fat stem cells. (By Todd Dubnicoff)

Human fat stem cells, scientifically known as human adipose stem cells (hASC), are an attractive cell source for regenerative medicine. Their low tendency to cause tissue rejection and their ability to transform into bone cells make them particularly well-suited for developing cell-based treatments for osteoporosis, a disease that weakens bones and makes them susceptible to fractures. And thanks to the numerous liposuction procedures performed in the U.S. each year, hASCs are readily available to researchers.

Electron microscope image showing the eroded, inner structure of a back bone in an 89 year old woman with osteoposis. Image courtesy the Bone Research Society

Electron microscope image showing the eroded, inner structure of a back bone in an 89 year old woman with osteoposis. Image courtesy the Bone Research Society.

But a lingering problem with hASCs as a reliable cell source for future therapies is their extreme patient-to-patient variability. Studies have shown that all sorts of factors like gender, body mass index (BMI) and age can have profound effects on the ability of hASCs to multiply and to specialize into bone cells.

Now, University of Missouri researchers describe the novel use of a measuring device to make more quantitative comparisons of different sets of donor hASCs. The instrument, called an electrical cell-substrate impedance spectroscopy (ECIS) – try saying that three times fast! – sends a very weak, noninvasive current through the cells and can measure changes in the cells’ shape in real-time. Other studies had shown that ECIS can quantitatively detect differences between hASCs and human bone marrow-derived mesenchymal stem cells as they mature into their respective cell types.

In the current Stem Cells Translational Medicine study, picked up this week by Health Canal, hASCs were obtained from young (24–36 years old), middle-aged (48–55 years old), and elderly (60–81 years old) donors. The ECIS results showed that stem cells from older donors matured into bone cells much quicker (~ 1day) than the younger cell of cells (~10 day). You might have intuitively thought the youngest stem cells would mature the fastest. But the end result of the difference is that the young set of stem cells multiplied much more than the cells from older donor and they accumulated more calcium over time.

This noninvasive, quantitative tool for predicting a fat stem cell’s potential to specialize into bone has the promise to improve quality control for manufacturing cell therapies, and it also provides researchers a means to better observe the underlying biological basis for this patient-to-patient variability in human fat cells.

Stem cells provide promising skin in the game for treating burn victims

/ Todd Dubnicoff / Leave a comment

For severe burn victims and others in need of skin transplants, current treatments using artificial skin grafts made from sheets of lab-grown skin cells aren’t ideal because they lack the complex structures needed to fully restore many of the skin’s critical functions.

Blausen_0810_SkinAnatomy_01 cropped

The skin isn’t just a layer of covering for our body. It’s a complex organ with many structures that work together to protect us from infection, regulate our body temperature and allow us to sense the outside world.
Image credit: Wikimedia Commons

For example, artificial skin doesn’t contain oil-producing sebaceous glands and forces burn victims to relentlessly apply oil to their skin grafts in order to prevent them from drying out and losing their natural cushioning and waterproof properties.  Without the replacement of sweat glands and hair follicles within the skin tissue, the graft regions don’t adequately regulate body temperature. And the sense of touch is often lost as disrupted nerve fibers aren’t reconnected to transplanted skin.

The lack of a genuine skin replacement has emotional consequences too since skin grafts often don’t match up with surrounding skin and leaves victims disfigured. So, while current treatments help, the field is busily looking for new and better solutions.

New skin in the game
As reported in the latest issue of Science Advances, a research team from the RIKEN Center for Developmental Biology in Japan has taken a major step in the right direction by generating a fully functional 3D skin organ system in mice using stem cells.

The team accomplished this feat by first collecting gum cells from the mouth of the mouse and reprogramming them into induced pluripotent stem cells (iPS) which can specialize into any cell type of the body. After a few days in a petri dish, the iPS cells formed into embryoid bodies, clumps of cells that contain a random mix of cell types that would be seen in a developing embryo, including those that give rise to skin. Then, using a novel transplantation method, a cluster of several embryoid bodies were encased together in a gel and then transplanted into mice where they could grow for later testing.

Skin that sweats and grows hair

normal-and-ips-skin

Image credit: Tsuji et al./RIKEN

The embryoid body clusters were allowed to further develop in the mice for a month. The transplants were then taken out and their cellular structure and gene activity were analyzed. The results confirmed the formation of a complex, three-dimensional skin organ system complete with all three skin layers as well as hair follicles, sweat glands, oil-producing sebaceous glands and fat tissue.

In follow up experiments, small pieces of this tissue were transplanted into the skin of another set of mice. After 14 days, the researchers observed new hair growth from the follicles of the transplanted tissue. They also showed that the hair follicles had made the necessary connections to muscle tissue and nerve fibers of the host mice.

Future directions
Translating this method for humans is years away but this data provides an important step toward a new generation of regenerative skin grafts that are fully functional as a complex organ system and not as just a two dimensional sheet of skin cells.

As study leader Takashi Tsuji mentions in a press release, skin transplants are not the only potential application of their technique:

skin blog tsuji

Takashi Tsuji

“With this new technique, we have successfully grown skin that replicates the function of normal tissue. We are coming ever closer to the dream of being able to recreate actual organs in the lab for transplantation, and also believe that tissue grown through this method could be used as an alternative to animal testing of chemicals.”

 

And with the restoration of functional hair follicles, maybe my fellow bald brethren could one day get back a full set of hair.

Molecular Trick Diminishes Appearance of Scars, Stanford Study Finds

/ cirmweb / Leave a comment

Every scar tells a story, but that story may soon be coming to a close, as new research from Stanford University reveals clues to why scars form—and offers clues on how scarring could become a thing of the past.

Reported last week in the journal Science, the research team pinpointed the type of skin cell responsible for scarring and, importantly, also identified a molecule that, when activated, can actually prevent the skin cells from forming a scar. As one of the study’s senior authors Michael Longaker explained in a press release, the biomedical burden of scarring is vast.

Scars, both internal and external, present a significant biomedical burden.

Scars, both internal and external, present a significant biomedical burden.

“About 80 million incisions a year in this country heal with a scar, and that’s just on the skin alone,” said Longaker, who also co-directs Stanford’s Institute for Stem Cell Biology and Regenerative Medicine. “Internal scarring is responsible for many medical conditions, including liver cirrhosis, pulmonary fibrosis, intestinal adhesions and even the damage left behind after a heart attack.”

Scars are normally formed when a type of skin cell called a fibroblast secretes a protein called collagen at the injury site. Collagen acts like a biological Band-Aid that supports and stabilizes the damaged skin.

In this study, which was funded in part by a grant from CIRM, Longaker, along with co-first authors Yuval Rinkevich and Graham Walmsley, as well as co-senior author and Institute Director Irving Weissman, focused their efforts on a type of fibroblast that appeared to play a role in the earliest stages of wound healing.

This type of fibroblast stands out because it secretes a particular protein called engrailed, which initial experiments revealed was responsible for laying down layers of collagen during healing. In laboratory experiments in mouse embryos, the researchers labeled these so-called ‘engrailed-positive fibroblast cells,’ or EPF cells, with a green fluorescent dye. This helped the team track how the cells behaved as the mouse embryo developed.

Interestingly, these cells were also engineered to self-destruct—activated with the application of diphtheria toxin—so the team could monitor what would happen in the absence of EPF cells entirely.

Their results revealed strong evidence that EPF cells were critical for scar formation. The scarring process was so tied to these EPF cells that when the team administered the toxin to shut them down, scarring reduced significantly.

Six days later the team found continued differences between mice with deactivated EPF cells, and a group of controls. Indeed, the experimental group had repaired skin that more closely resembled uninjured skin, rather than the distinctive scarring pattern that normally occurs.

Further examination of EPF cells’ precise function revealed a protein called CD26 and that blocking EPF’s production of CD26 had the same effect as shutting off EPF cells entirely. Wounds treated with a CD26 inhibitor had scars that covered only 5% of the original injury site, as opposed to 30%.

Pharmaceutical companies Merck and Novartis have already manufactured two types of CD26 inhibitor, originally developed to treat Type II diabetes, which could be modified to block CD26 production during wound healing—a prospect that the research team is examining more closely.