Quest for beta understanding

Biologists patiently unravel the mysteries of insulin-producing cells.

While we stay tuned to Covid-19, biomedical researchers keep reporting major progress on other fronts. Here are three recent papers on key questions about the insulin-producing pancreatic beta cells that are wiped out in type 1 diabetes.

1. Why are beta cells so prone to autoimmune attack? “There is mounting evidence that type 1 diabetes is a disease not only of autoimmunity, but also of the target beta cell itself,” say Roberto Mallone of the University of Paris and Decio Eizirik of the Free University of Brussels.

In a Diabetologia paper, the scientists analyze three main weaknesses of beta cells.

First, cranking out insulin and other proteins in high volume “is a stressful job,” so the cells are likely to show signs of inflammation and compensate in various ways that are not healthy in the long run, thus worrying the immune system. Second, the pancreatic islets where beta cells live are closely embraced by blood vessels, “which favours face-to-face encounters between immune cells and beta cells.” Third, insulin and related proteins flow directly into the networks of blood vessels and can raise alarms at a distance.

“Agents aimed at limiting the autoimmune vulnerability of beta cells should find their place in the search for disease-modifying treatments, either alone or in combination with immunotherapies,” the authors suggest.

2. Can we create islet organoids with not only beta cells but their islet buddies? Beta cells probably live most happily in pancreatic islet neighborhoods with their homies—other endocrine cells. So, ideally, we would replace the beta cells destroyed in type 1 diabetes with complete islets. Good news, we now can create organoids, 3D tissues with multiple cell types derived from stem cells.

In a Nature paper, Ron Evans of the Salk Institute and colleagues report human islet-like organoids (HILOs) that indeed act very much like islets in controlling blood glucose levels when transplanted into mouse models of type 1 diabetes.

More dramatically, HILOs can do this even in mice with working immune systems, by expressing a cell-surface protein called PD-L1. (An enormous amount of cancer research has laid out how proteins such as PD-L1 can ward off immune-system cells.)

3. Are there better methods to transplant beta cells and other islet cells? For decades, researchers have struggled to find practical ways to embed these cells into people with type 1 diabetes. The most successful route has been the “Edmonton protocol” developed more than 20 years ago at the University of Alberta. Here, islet cells from cadavers are infused into a vein going into the livers of people with particularly difficult-to-control disease. These recipients then are put on immunosuppressive drugs. The treatment is often initially successful but the cells typically die within a few years. And donor islets will always be in extremely short supply.

Fortunately, with stem cell technologies engineered by Doug Melton’s Harvard lab and other groups, we now can grow remarkably beta-like cells in high volumes. These cells release hormones directly into the bloodstream, so they could in theory work well enough in many locations around the body. The transplants would be tiny.

But keeping the implanted cells well and active raises many tough challenges—especially in guarding them from the immune system while they stay full connected to blood vessels.

Many labs have grappled with this paradox for many years. Startup companies are building clever encapsulation devices but none of these capsules has proven itself in clinical trials. (One intriguing candidate made by Semma Therapeutics, which Melton cofounded, vanished from public view after biotech giant Vertex Therapeutics paid almost $1 billion for the startup.)

Last week in a Nature Metabolism paper, Ali Naji and coworkers at the University of Pennsylvania gave details on an unusual approach with no device at all. Instead, islets were harbored within a mixture mostly made up of collagen (connective protein). This “islet viability matrix” (IVM) then was injected under the skin—a very handy site for transplants, if workable.

IVM proved highly promising in experiments with mouse, pig and human islet cells in various animal models of diabetes, including some animals with working immune systems. One part of the recipe is that the matrix seems to activate a molecular pathway with multiple mechanisms that protect beta cells. IVM “represents a simple, safe and reproducible method, paving the way for a new therapeutic paradigm for type 1 diabetes,” the UPenn team claims.

In an accompanying commentary, Thierry Berney and Ekaterine Berishvili of the University of Geneva School of Medicine note that the IVM strategy could include beta cell protective measures that might range from novel biomaterials to amniotic cells that act as shields. “This method is technically simple, minimally invasive in easily accessible sites and acceptable from a regulatory standpoint,” they conclude. “The door is now wide open for the initiation of a pilot clinical trial.”

Beta cells image courtesy the lab of Douglas Melton at Harvard.

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