Improved Method for Converting Stem Cells into Pancreatic Islet Progenitor Cells Detailed in iScience

Left panel: Abundant production of Cx43 in definitive endoderm cells. Middle and right panels: pancreatic islet progenitors derived from stem cells in the presence of the AAP10 activator of Cx43. They are identified by the simultaneous expression of progenitors markers Sox9, Pdx1 and Nkx6.1 (in yellow).

Type 1 diabetes is a disease that occurs when the immune system attacks and kills the cells that produce insulin in the pancreas, known as beta-cells. People living with type 1 diabetes require daily injections of insulin to survive and are at risk of both life-threatening hypoglycemia (low blood sugar) and lifelong cardiovascular and neurological health complications that include increased heart diseases, kidney failure, and blindness. Approximately 1.25 million children and adults in the United Sates have type 1 diabetes. An additional 30 million Americans have type 2 diabetes, a condition in which the pancreas produces insulin unreliably. The combined national healthcare costs of type 1 and type 2 diabetes exceed $320 billion a year.

Cell replacement therapy offers one of the most promising prospects for treating or even curing type 1 diabetes. Investigators at the Institute for Stem Cell and Regenerative Medicine (ISCRM) are among the many researchers attempting to use stem cells to replace lost or dysfunctional pancreatic islet cells and restore the production of insulin and glucagon – the hormones responsible for regulating blood sugar.  However, current protocols for differentiating stem cells into rare cell types, including pancreatic islet cells, remain inefficient.

Now, an article published recently in the journal iScience details how promoting the function of a protein, known as Cx43, helped an ISCRM research team to more efficiently convert stem cells into pancreatic islet progenitor cells. The research team, led by ISCRM faculty members Vincenzo Cirulli MD, PhD and Laura Crisa MD, PhD, with first author Wendy Yang, PhD (Department of Pharmacology), set out to answer a pivotal question. Starting with stem cells, how can scientists produce a higher quality yield of the definitive endoderm cells that more efficiently give rise to the pancreatic cells lost when type 1 diabetes strikes?

“We know we can derive immature pancreatic cells from stem cells,” says Cirulli. “The problem is that too few of the cells we produce are the beta-cells we need. The goal of this investigation was to test if enhancing the innate ability of stem cells to talk to one another through a mechanism of direct cell-to-cell communication would foster a more efficient derivation of pancreatic islet progenitors.”

The investigation led Cirulli and Crisa to look closely at a protein, known as Cx43, that represents the building block of gap junction channels – essentially, the portholes that enable intercellular communication and influence cell fate and cell maturation. They found that supplementing pluripotent stem cells with a peptide (AAP10) that enhances Cx43-mediated cell-to-cell communication, led to a more fertile output of definitive endoderm cells, and subsequently to a more than five-fold increase in the number of pancreatic islet progenitors, the immature cells that eventually mature into islet cells.

The study, conducted in collaboration with Dr. Paul Lampe at the Fred Hutchinson Cancer Research Center, lays the groundwork for the development of more efficient protocols of stem cell differentiation into pancreatic islet cells that produce insulin and glucagon, an important stepping stone toward cell replacement therapies for type 1 and possibly type 2 diabetes.

Acknowledgements:

The research published in iScience (https://doi.org/10.1016/j.isci.2019.07.033) was supported by R01 DK103711, by the WA State Life Sciences Discovery Fund Program Grant #4553677, and by an Innovation Pilot Award from the UW Institute for Stem Cell and Regenerative Medicine, with funds contributed by the State of Washington.