New Research Proves the Pancreas Can Regenerate

Type 1 diabetes is caused by an autoimmune attack that destroys the beta cells, the part of the body that produces the essential hormone insulin. It is generally supposed that once these cells have been lost, they are gone forever. In the search for a cure, the most advanced research has concentrated on the transplantation of new beta cells — either from an organ donor or grown in a laboratory — to replace the cells that have been irrevocably lost.

But what if your body could be directed to regrow its own new beta cells? A lead investigator at the Diabetes Research Institute believes that the pancreas can regenerate beta cells, and that his lab has discovered how to make it happen.

A Century of Questions

Many human cells can regenerate themselves. You may have heard that, due to constant cell regrowth, the entire human body is replaced every seven years. That’s not quite right — while most of your skin cells turn over within months, you also have brain cells that never have been and never will be replaced.

The pancreas, like most other internal organs, is slow to regenerate and has a very limited ability to heal itself. But doctors have long suspected that the pancreas harbors the ability to regenerate the islet cells, which contain the insulin-producing beta cells. “The concept has been around for more than 100 years,” since even before the discovery of insulin, says Juan Dominguez-Bendala, PhD. It’s always been a controversial idea, but he believes that the debate has now been settled.

Dr. Dominguez-Bendala is the Director of Stem Cell & Pancreatic Regeneration and Research at the Diabetes Research Institute. His team, in a collaborative effort with his colleague Dr. Ricardo Pastori, recently published a report in Cell Metabolism that finally proves that the adult human body is capable of growing new beta cells:

“I think that this is very definitive. We’re looking at regeneration in the real thing, the real human pancreas. We see this happening in real-time. It’s unequivocal.”

New Evidence

The islet cells that contain both the beta cells and other important exocrine cells only make up a small minority of the pancreas’ mass. Most of the organ is devoted to a ductal system that helps synthesize digestive juices and transport them to the intestines. In the embryo, though, this part of the pancreas also creates the islet cells.

“There are lots of people that don’t believe that this is a process that happens during normal adult life. But what we and others contend is that when there’s extensive damage to the pancreas, there’s a partial reactivation of the embryonic program that brought about islet cells in the first place. There are stem cells in the ducts that give rise to new islets.”

For years, however, the evidence in favor of human islet regeneration only came in the form of samples from the pancreases of deceased people. It had never been possible to observe the regeneration of islet cells in real-time, and “the evidence was rather circumstantial.” There was supporting evidence from mouse models, but Dominguez-Bendala admits that this was of limited value: “We have cured diabetes in mice hundreds of different ways, and none of them have ever worked in humans.”

Scientists received a new tool with the establishment of nPOD, the Network for Pancreatic Organ Donors with Diabetes. Founded and supported by the leading charity JDRF, nPOD encourages people with diabetes to sign up as organ donors and donate their pancreases to science. This national network is the only way for American researchers to receive a reliable supply of viable organs from people with type 1 diabetes.

Dominguez-Bendala’s lab began receiving donations of pancreas slices in 2018. It took some tinkering, but they found a medium that “could extend the life and functionality in vitro for about two weeks, which was plenty for us to start seeing if there’s regeneration.” It provided, for the first time, “a window into the real pancreas.”

How to Stimulate Beta Cell Regeneration

If pancreatic regeneration does occur naturally, it’s obviously not enough to substantially heal people with diabetes or pancreatitis. To make a difference, Dominguez-Bendala would have to find a way to accelerate and amplify the regeneration process. His secret ingredient may be a natural human growth factor named BMP7.

BMP7 is “like a fuel for stem cells across the body,” and Dominguez-Bendala wanted to see if it could have the same effect in the pancreas. The substance is well-studied and is already approved for an unrelated condition: “It’s already in clinical use. It regrows bone, and is used to fuse vertebrae when you have spinal surgery.”

The team at Dominguez-Bendala’s lab would take multiple pancreatic slices from a single donor and treated some with BMP7. When they took a closer look, they saw exactly what they had hoped: new hybrid cells emerging from the ductal mass of the pancreas and creating a bridge towards the area where islet cells are born. A trajectory analysis showed that some of the new hybrid cells “became new islet cells.”

“We showed for the first time, in a human-based model, how regeneration works.”

“We discovered that progenitor cells inside the ducts respond to BMP7 by proliferating, and then when you remove the BMP7, they differentiate into all the different cell types of the pancreas.”

“To me, it doesn’t get any more promising than that,” Dominguez-Bendala said. “You can cure diabetes left and right in mice, but to show that you can induce beta cell regeneration in a type 1 diabetes donor? That’s something really major.”

Next, they had to prove that the new islet cells were actually functional. Could they respond to high blood sugar levels, secrete insulin, and correct hyperglycemia? “When we look at the neogenic cells, the cells that have been formed as a result of BMP7 stimulation, we can see that they respond to glucose stimulation by making insulin.”

It will take several years and “a lot of boring experiments” to convince the FDA that the therapy is safe to try in humans. Studies of mice, at least, show that BMP7 causes no other dysfunctional tissue growth. It also doesn’t stimulate islet cell growth in healthy mice, suggesting that the substance naturally targets injuries: “We think it takes an extreme degree of damage to the pancreas for this very primitive regeneration program to be activated.” Studies in humans help show that BMP7 is safe for general use, including when used to help heal kidney disease.

The Immunity Problem

Beta cell regeneration has the same big problem that every other proposed type 1 diabetes cure has: the immune system. Transplanted islet cells — whether they come from an organ donor or a laboratory manufacturing process — can correct hyperglycemia and grant insulin independence, but thus far nobody has figured out how to protect them from the immune system without the use of powerful drugs (with potentially powerful side effects).

“This doesn’t work unless we do something about the immune system, or else the new cells will be destroyed again and again,” says Dominguez-Bendala. “We envision this as a combination therapy alongside immunotherapies.”

Dominguez-Bendala is gambling, along with the rest of the diabetes world, that better immunotherapies are coming soon. In the meanwhile, the first patient population likely to benefit from any beta cell regeneration therapy are people who have received a kidney transplant, patients who therefore already require anti-rejection medications.

There is at least some hope, however, that naturally regenerated beta cells will be easier to protect from the immune system than transplanted cells, which the body’s defenses identify as foreign. We won’t know yet how the body will respond to neogenic cells: “The truth is that we don’t know. I have spoken to immunologists who believe that the new cells may be able to sneak in and won’t be destroyed as quickly as the ones that were destroyed in the first place. I’m hopeful that it will happen, but I’m not counting on that.”

Timeline

Beta cell regeneration is in its infancy as a therapy, and will require many years of experimentation before it gets anywhere close to FDA approval. I asked Dominguez-Bendala if a more advanced potential cure — such as Vertex’s VX-264 — might succeed first and render his work obsolete. Dominguez-Bendala doesn’t see Vertex as a competitor — his lab has helped contribute to progress in the field of stem cell differentiation — but he is emphatic that VX-264 will not be a full cure and will not end the search for better type 1 diabetes remedies:

“It’s not a cure by any stretch of the imagination. It’s a brute force strategy, putting things in the body, and the body is attacking them. What we are proposing is fundamentally different, to harness the very natural ability of the pancreas to heal itself. That’s a much more holistic approach.”

Several other research groups are investigating parallel therapies. In France, a startup named DiogenX believes it has found another way to regenerate the beta cells. And just last week, an Australian team published a study of another method that could stimulate beta cell regeneration.

“I’m hopeful that it will be available sooner rather than later. We could spend twenty years exploring the little details of the mechanisms, but that’s not what the Diabetes Research Institute is about. We want to have therapies in the clinic as soon as possible. That’s our mission, and that’s what we are going to do.”

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