Directly Reprogramming Gut Cells into Beta Cells to Treat Diabetes


Type 1 diabetes mellitus results from destruction of insulin-producing beta cells in the pancreas. Diabetics have to give themselves routine shots of insulin. The hope that stem cells offer is the production of cells that can replace the lost beta cells. “We are looking for ways to make new beta cells for these patients to one day replace daily insulin injections,” says Ben Stanger, MD, PhD, assistant professor of Medicine in the Division of Gastroenterology, Perelman School of Medicine at the University of Pennsylvania.

Some diabetics have had beta cells from cadavers transplanted into their bodies to replace the missing beta cells. Such a procedure shows that replacement therapy is, in principle possible. Therefore, transplanting islet cells to restore normal blood sugar levels in type 1 diabetics could treat and even cure disease. Unfortunately, transplantable islet cells are in short supply, and stem cell-based approaches have a long way to go before they reach the clinic. However, Stanger and his colleagues have tried a different strategy for treating type 1 diabetes. “It’s a powerful idea that if you have the right combination of transcription factors you can make any cell into any other cell. It’s cellular alchemy,” comments Stanger.

New research from Stanger and a postdoctoral fellow in his laboratory, Yi-Ju Chen that was published in Cell Reports, describes the production of new insulin-making cells in the gut of laboratory animals by introducing three new transcription factors. This experiment raises the prospect of using directly reprogrammed adult cells as a source for new beta cells.

In 2008, Stanger and others in Doug Melton’s laboratory used three beta-cell reprogramming factors (Pdx1, MafA, and Ngn3, collectively called PMN) to convert pancreatic acinar cells (the cells in the pancreas that secrete enzymes rather than hormones) into cells that had many of the features of pancreatic beta cells.

Following this report, the Stanger and his team set out to determine if other cells types could be directly reprogrammed into beta cells. “We expressed PMN in a wide spectrum of tissues in one-to-two-month-old mice,” says Stanger. “Three days later the mice died of hypoglycemia.” It was clear that Stanger and his crew were on to something. Further work showed that some of the mouse cells were making way too much extra insulin and that killed the mice.

When the dead mice were autopsied, “we saw transient expression of the three factors in crypt cells of the intestine near the pancreas,” explained Stanger.

They dubbed these beta-like, transformed cells “neoislet” cells. These neoislet cells express insulin and show outward structural features akin to beta cells. These neoislets also respond to glucose and release insulin when exposed to glucose. The cells were also able to improve hyperglycemia in diabetic mice.

Stanger and his co-workers also figured out how to turn on the expression of PMN in only the intestinal crypt cells to prevent the deadly whole-body hypoglycemia side effect that first killed the mice.

In culture, the expression of PMN in human intestinal ‘‘organoids,’ which are miniature intestinal units grown in culture, also converted intestinal epithelial cells into beta-like cells.

“Our results demonstrate that the intestine could be an accessible and abundant source of functional insulin-producing cells,” says Stanger. “Our ultimate goal is to obtain epithelial cells from diabetes patients who have had endoscopies, expand these cells, add PMN to them to make beta-like cells, and then give them back to the patient as an alternate therapy. There is a long way to go for this to be possible, including improving the functional properties of the cells, so that they more closely resemble beta cells, and figuring out alternate ways of converting intestinal cells to beta-like cells without gene therapy.”

This is hopefully a grand start to what might be a cure for type 1 diabetes.

Reactivation of Hair Follicle Stem Cells Restarts Hair Growth


Sarah Millar and her team at the Perelman School of Medicine at the University of Pennsylvania have exploited a known property of hair follicle stem cells to restart hair growth in laboratory animals.

The Wnt signaling pathway is an important regulator of hair follicle proliferation, but does not seem to be required for hair follicle survival. Wnt signaling in cells culminated in the activation of a protein called beta-catenin, which goes to the nucleus of the cell and causes changes in gene expression.

wnt signaling

Millar and her colleagues disrupted Wnt signaling in laboratory animals by expressed an inhibitor called Dkk1 in hair follicles. Dkk1 expression prevented hair growth, and when the hair follicles were examined, they still had their stem cell populations, but these stem cells were dormant. Removal of Dkk1 resumed Wnt/beta-catenin signaling, and restored hair growth.

Dkk1 activity

Interestingly, Millar’s group found Wnt activity in non-hairy regions of the skin, such as palms, soles of feet, and so on. Therefore, in order for Wnt signaling to induce hair growth, it must occur within specific cell types.

This work also has additional applications: skin tumors often show over-active beta-catenin. Removing beta-catenin could prevent the growth of skin tumors, just as removing beta-catenin in the skin of these mice prevented proliferation of any hair follicles. However, agents that can activate beta-cateinin in hair follicles could reactivate dormant hair follicles and induce new hair growth.

Finding ways to safely reactivating the Wnt pathway in particular cells in the skin is a major focus of Millar’s research group.  Such work may lead to treatments for male pattern baldness.