“Wow, my mouth just got diabetes.” Such are my immediate thoughts after taking a bite out of a red velvet cupcake. Though I must qualify: by cupcake, I mean a skyscraper of frosting carefully balanced on a minimal crumbly foundation.
Making such a hyperbolic statement heightens our awareness that diabetes involves intolerably high blood sugar levels. And yet, for most of us, even after indulging in what seems like concentrated sucrose, our blood sugar remains relatively steady. Such a feat involves a complex process of glucose (one of the components of sugar) being sensed by our pancreatic β-cells, leading to the opening of ion channels and the subsequent release of insulin. Insulin then helps us tuck our excess blood glucose away into various tissues and storage depots in our body.
The problem experienced by Type I diabetics is that their bodies launch an autoimmune assault on their β–cells, and without insulin, they can’t shift glucose from the blood to their tissues for use.
It is not surprising, then, that using stem cells to make replacement β-cells as a cell therapy for diabetes has long been a goal in the field of regenerative medicine. However, scientists have been challenged in identifying the series of molecular signals needed to turn stem cells into cells that secrete insulin (vs. multiple hormones), specifically in response to glucose.
The Kieffer group at the University of British Columbia may have just broken through this barrier. In an article published in last month’s Nature Biotechnology, the group sets out to determine a program of differentiation that takes cells closer to mature pancreatic β-cells than ever before.
Their current system involves stepwise differentiation of embryonic stem cells through seven stages (S1-S7). Without getting too far into the details, the goal for the S7 cells was to find compounds that led to the expression of a protein called MAFA, since this is known to be involved in β-cell maturation. After testing several molecules, they ultimately created a medium with four special additives (AXL inhibitor, N-Cys, ALK5iII, T3) that upregulated MAFA mRNA levels by a factor of 16.
Having achieved this expression goal, they next sought to address the most important questions: 1) Do their cells respond to glucose like mature β-cells? And 2) can their cells reverse diabetes in a mouse model?
To answer the first question, the investigators found that the ion channels in their S7 channels were responsive to glucose (part of insulin release process) but not in a completely identical way to mature β-cells. In terms of insulin release, extensive experimentation showed that the cells were able to package insulin into vesicles for cellular release, and a subpopulation of cells would do so in response to glucose.
Despite these S7 cells still being slightly less mature than adult β-cells, in vivo experiments were highly promising. Upon transplanting their cells into diabetic mice, they observed normal fasting blood glucose levels by 40 days, and this process required a quarter of the cells as compared to when less mature cells have been transplanted (S4). Once the graft was removed, the mice quickly returned to a state of hyperglycemia.
Furthermore, in another experiment, when the mice were injected with exogenous insulin causing blood glucose levels to drop, the grafted cells withheld their secretion of insulin (as determined by reduced C-peptide levels), to prevent dangerous hypoglycemia. Thus, the transplanted S7 cells seem to appropriately modulate their insulin release in both high and low glucose environments, which is critical to our body’s glucose homeostasis.
I see there being two major achievements from this research. By creating a subpopulation of glucose-sensitive, insulin secreting β-cells, this advances our ability to develop in vitro platforms for studying both type I and type II diabetes. We are also closer to understanding how to make cells that could be used for cell therapy for these diseases.
Since the cells used in this study were derived from embryonic stem cells, there is still the issue of potential immune rejection. The investigators do note that they have had some success in using their protocol with iPSCs, which would be patient specific; however, it is unclear to what extent these cells would then be protected from autoimmunity.
Given the many debilitating consequences of having chronic diabetes, including retinal and kidney disease, as well as peripheral vascular disease, there will undoubtedly be continued thrusts to advance the presented research into a directly translatable outcome. But generating the cells that function appropriately is a very significant first step.
Rezania A., Payal Arora, Allison Rubin, Irina Batushansky, Ali Asadi, Shannon O’Dwyer, Nina Quiskamp, Majid Mojibian, Tobias Albrecht & Yu Hsuan Carol Yang & (2014). Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells, Nature Biotechnology, DOI: http://dx.doi.org/10.1038/nbt.3033
Update (10-06): Edited paragraph nine to correct word transposition between glucose and insulin.
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