Diabetes’ demise? Master Switch Identified for Turning Stem Cells into Functional Insulin-Producing Cells

It’s been a good week for diabetes researchers and the over one million Americans with type 1 diabetes who are hoping for an eventual stem cell-based treatment for this incurable disease. Published a day apart, two studies reported on achieving an elusive goal for the field: creating functional insulin-producing cells in a lab dish from induced pluripotent stem cells (iPS).

My fellow Stem Cellar blogger, Karen Ring, detailed one of the studies on Tuesday which used cells from human fat tissue (aka “love handles”) to devise a novel, consistent and efficient method for generating iPS-derived insulin-producing cells.

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Salk scientists identified a master switch, ERR-gamma, for making functional beta cells from stem cells. Image: Salk Institute

The other study is a CIRM-funded project by Salk Institute scientists. Reporting in Cell Metabolism, the team compared fetal and adult insulin-producing cells in mice and uncovered a protein “switch” that stimulates human iPS cells to fully mature into insulin-producing cells in a petri dish.

Because a very specific cell type is affected, the pancreatic beta cells, developing a cell therapy for diabetes would seem pretty straight-forward. Simply transplant stem cell-derived pancreatic beta-like cells that naturally release insulin in response to glucose. But over the years, researchers found that it wasn’t so easy to make fully mature stem cell-derived beta-like cells in the lab. The cells often got stuck at an immature stage of development resembling those found in the developing fetus.

The Case of the Missing Regulator of Insulin-Producing Cells
To get past this bottleneck the Salk team studied fetal and adult beta cells in mice in hopes that a comparison would reveal key missing ingredients for making fully functional beta-like cells. In particular, they compared the levels of transcription factors, proteins that turn genes on and off and are known to play important roles in determining the cell fate of stem cells. This analysis identified a transcription factor called ERR-gamma present in higher levels in adult cells compared to the fetal cells.

If this transcription factor is really important then removing it should have a very noticeable impact on maintaining blood glucose level. To test this idea, the team genetically engineered mice that lacked ERR-gamma. Sure enough, they showed that the beta cells of these mice did not release insulin in response to a large injection of glucose.

ERR-gamma: Master Switch for Making iβeta cells
Rather than knocking out ERR-gamma production, the researchers next manipulated human iPS cells to over produce ERR-gamma. When they attempted to mature those cells into beta-like cells, the ERR-gamma worked like a charm and helped generate cells that secrete insulin when glucose was added to the petri dish. To really nail down this result, the team repeated this lab experiment in animals. They transplanted these human iPS-derived beta-like cells, which they dubbed iβeta cells, into diabetic mice. Within days of the transplantation, the mice had normal blood sugar levels.

This compelling result points to ERR-gamma as a master regulator of beta cell development and a possible answer to readily making a cell therapy product. As Evans mentions in a press release, he’s cautiously optimistic about the future:

Ron-Evans-Michael-Downes-Eiji-Yoshihara-IMG_0475e-200x300

Study authors (from left): Michael Downes, Ron Evans and Eiji Yoshihara

“Hopefully, this mirrors what would happen in the clinic—after someone is diagnosed with diabetes they could potentially get this treatment. It’s exciting because it suggests that cells in a dish are ready to go.”

For Your Consideration

And because the cells are derived from human iPS cells, each patient could potentially have beta cells tailor made from their own skin or blood sample. The advantage here is that the transplant is less likely to be rejected by the immune system. But type 1 diabetes is an autoimmune disease in which the immune system attacks the beta cells as if they were foreign to the body. So it’s possible that those transplanted cells would still be vulnerable if the autoimmune environment is still present.

A CIRM-funded clinical trial, sponsored by ViaCyte, Inc., is currently testing an embryonic stem cell-based therapy for type 1 diabetics and gets around this immune system problem by shielding the cell product inside an encapsulation device which is placed under the skin. Also, the ViaCyte product does not use fully mature beta-like cells but instead transplants earlier stage progenitor cells and lets them develop into functioning beta cells inside the patient.

Many Shots on Goal – It’s a Good Thing
Which methods will work? Are “love handle” beta cells better than ERR-gamma ones? Oh, and what about the report in January that reprogrammed skin cells directly into functional beta cells? Is that the way to go? And will the ViaCyte progenitor cells successfully develop and function inside people with diabetes?  Ultimately, only clinical testing will be able to answer these questions. It’s exciting to see so many research teams making progress toward cell therapies for diabetes. As we often say here, the more shots the field takes, the more likely someone will score the game-changing goal of curing diabetes.

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