DRI Takes a Big Step Forward with Reprogramming Cells to Create Islets

DRI’s Dr. Juan Dominguez-Bendala and Dr. Ricardo Pastori are reprogramming the non-endocrine cells of the pancreas to create insulin-producing islets.

People with kidney issues can get a kidney transplant from a donor. 

People with heart issues can get a heart transplant from a donor. 

People with liver issues … Well, you get the picture.

People with type 1 diabetes have “pancreas issues.” More specifically, they have issues with the endocrine, or insulin-producing, function of the pancreas because their immune systems have destroyed the islet cells (even more specifically, the beta cells of pancreatic islets) that produce this vital hormone.

Transplantation using donor islets has been available for a while now. Several type 1s have had the procedure and are living free of insulin injections for more than a decade. One of the shortcomings, however, is that there has always been a limited supply of islets because there has been a shortage of pancreas donors. 

BMP-7: Offering a new hope
DRI scientists now have new research that might be the solution to the cell shortage. They have successfully turned non-insulin producing cells of the pancreas into insulin-producing cells. 

As published in the December 2015 issue of Diabetes, the DRI used an FDA-approved agent called bone morphogenetic protein-7 (BMP-7). It was the first time that HUMAN non-endocrine pancreatic tissue (NEPT) was “reprogrammed” to respond to blood glucose without the use of genetic manipulation.

This new, non-invasive way of reprogramming cells may increase the limited supply of islets for transplantation into people with type 1 diabetes. Even better, it may even allow patients to regenerate their own insulin-producing cells, alleviating the need for a transplant altogether.

A Clearer Path to the Clinic
BMP-7 is approved by the Food and Drug Administration for clinical use, and its history as a regenerative agent is distinguished.

In the past, BMP-7 has been used to form bone and cartilage. In fact, as far back as December 2003, the American Journal of Physiology reported that BMP-7 improved kidney function in mice that were in kidney failure.  

So if it worked for the regeneration of bone, cartilage and kidney function, why not for the production of insulin-producing cells. Right?

“We thought it would perhaps improve the results that we were getting using another method. It was surprising to observe that BMP-7 did induce the conversion by itself, and without the need for anything else,” says Juan Dominguez-Bendala, MSc, Ph.D., Research Associate Professor and head of the DRI’s Pancreatic Development & Stem Cell Laboratory. “At that point, we hypothesized that BMP-7 could be inducing resident progenitors within the human pancreas. We tested this second hypothesis, and it turned out to be correct.” 

He added, “BMP-7 and small molecules that act like BMP-7 are already in clinical use for a variety of conditions, making the path to the clinic an easier one from a regulatory perspective.” 

“If we could reactivate these stem cells within the pancreas of the patient, while administering [accompanying] treatments to prevent the autoimmune response that caused the disease in the first place, we would be allowing the pancreas to heal itself,” says Dr. Dominguez-Bendala. 

The use of a clinically approved product like BMP-7 to achieve this goal, coupled with what so far appears to be an excellent safety profile, made using BMP-7 a no-brainer for clinical translation in people with type 1. 

DRI Director Camillo Ricordi, M.D., touts BMP-7’s safety profile and its ability to allow DRI researchers to work on targeted delivery to the progenitor cells that can be converted into islets.

“It would be like smart-bomb technology,” says Dr. Ricordi. “Not to destroy, but to selectively target only the cells that can become new insulin-producing cells.” 

Making Good Use of Discarded Tissue
About 98 percent of the pancreas consists of exocrine (or non-endocrine) tissue that produces enzymes for digestion (acinar) and collects those secretions (ductal). The remaining tissue consists of “endocrine” cells (A.K.A. islets) which are composed of alpha cells (which release glucagon), beta cells (which release insulin) and delta cells (which inhibit the release on glucagon and insulin). 

Non-endocrine pancreatic tissue (NEPT) is highly adaptable, and can be turned into other cell types or tissues. Additionally, it is not a primary target of autoimmunity (the immune system’s attack on its own cells and tissues) in type 1 diabetes.

Scientists have long known that non-endocrine pancreatic cells can be turned into other cell types or tissues. However, this type of “cell reprogramming” typically involves genetic manipulation, which can create health risks to patients. 

The Dangers of Genetic Manipulation
“Genetic manipulation requires the introduction of foreign genes, so that the cells receiving them are forced to do things that they normally wouldn’t [such as making insulin],” says Dr. Dominguez-Bendala. “If the cells were computers, these foreign genes would be the equivalent of a new software. However, the only way that this new software can be introduced into cells is through viruses.” 

Dr. Dominguez-Bendala explains that viruses may be helpful in some instances because nature designed them so that they could very effectively infect every cell they come in contact with, but he raises some concerns.

“We can use them as ‘Trojan horses’ to effectively introduce foreign genes into cells. However, they tend to elicit immune responses of their own, and also may release their cargo in uncontrolled fashion … That is why extreme caution is necessary on the design of clinical trials involving genetic manipulation.”

So, he and his team wanted to pursue a method that didn’t involve the use of viruses. By using BMP-7, the scientists were able to “reprogram” the NEPT cells to respond to blood glucose without the use of genetic manipulation.

‘Fuel’ for the Cells
Dr. Dominguez-Bendala explains that BMP-7 acts as “fuel” for stem-like cells throughout the body. 

“The pancreas contains cells such as these, but they usually remain dormant or have little activity. BMP-7 awakens them, making them regenerate the endocrine cells that were lost because of the autoimmune attack.”

Dr. Dominguez-Bendala adds that we have to keep in mind that any treatment aimed at replenishing these cells would only work if simultaneous steps were taken to prevent autoimmunity from hitting them again.

A Safer Way to Increase the Limited Supply of Islets for Transplantation
According to our scientists, using this non-invasive procedure is a safer and more efficient method to increase the limited supply of insulin-producing islet cells for transplantation into people with type 1 diabetes. 

Exposure of human pancreatic exocrine cells to BMP-7 alone resulted in conversion to insulin-producing clusters that respond to glucose both in the laboratory setting and after transplantation into diabetic rodents.

According to Dr. Dominguez-Bendala, cells generated in this manner produced insulin levels between 50 and 250 times higher than previously published by other teams. 

“What we’ve accomplished, a non-genetic conversion of human pancreatic exocrine-to-endocrine cells, is a safer and simpler alternative to genetic reprogramming,” says Dr. Dominguez-Bendala. “We also saw the formation of other cells typical of the islet, not just beta cells.” 

He continues, “The relative simplicity of our approach, coupled with its high efficiency, makes it a prime candidate for translation to patients with diabetes.” 

Taking it in Two Directions
Dr. Dominguez-Bendala explains that the DRI team is now developing research in two directions:

  1. The first one is the conversion of the 90-plus percent of the pancreas (the exocrine pancreas) that is routinely discarded after islet isolation. This may potentially allow the scientists to treat multiple patients from the same organ. 
  2. The second is the activation of these stem cells within the pancreas of the very patient they intend to treat, without the need for transplantation. 

“The most appealing aspect of our research is that the means to achieve this conversion is non-genetic, i.e., does not require the forced expression of [external] genes in order to ‘reprogram’ exocrine cells,” says Dr. Dominguez-Bendala. “BMP-7 is naturally occurring protein, and one that is already in clinical use for other conditions.”

Transplantation vs. Regeneration: Where Do We Go from Here? 
When asked about the direction of “transplantation” versus “regeneration” strategies, Dr. Ricordi says that in the coming years there will be “parallel tracks” for both transplantation and regeneration and/or expansion of residual-insulin-producing cells, which are still present in many people with type 1 diabetes.

“There is a common path, however, which is restoration of self-tolerance and prevention of immune destruction of either the transplanted or regenerated/expanded insulin-producing cells,” says Dr. Ricordi.

The importance of tolerance-induction research should be emphasized in future studies, according to Dr. Ricordi, who calls tolerance-reduction research a “key pillar” for future development of other transplantation and/or regeneration strategies. 

“ … Especially in the case of regeneration where we will not have the possibility to protect the newly formed insulin-producing cells within the native pancreas with semipermeable barriers such as [protective chemical] coating encapsulation.”

Dr. Ricordi adds that encapsulation technologies will remain an option for cells prepared outside the body. Among these would be insulin-producing cells derived in the lab from other pancreatic precursor cells.

By Daniel Trecroci
March 2016 

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