Shortly after I started my PhD in 2009, Time magazine profiled a Harvard Stem Cell Institute researcher, Doug Melton, who dedicated his research program to understanding the development and biology of pancreatic beta cells following the diagnosis of his children with type I diabetes. Over the years, I have followed Melton’s progress towards creating functional pancreatic beta cells (the cells affected in type I diabetes) from pluripotent stem cells.
As I reflect on the first few days of the annual ISSCR meeting, the highlight for me thus far has been Melton’s progress update on the quest to develop functional pancreatic beta cells (I missed Hongwei Chen’s musical poster teaser). But in all seriousness, Melton has made significant headway in the pancreatic beta cell differentiation field.
Pancreatic beta cells secrete insulin, a protein that regulates blood glucose levels. Following an increase in blood glucose levels, beta cells secrete insulin, causing glucose uptake and normalization of blood glucose levels. In a type I diabetes patient, beta cells do not sufficiently secrete insulin, leaving diabetic patients unable to regulate blood glucose levels. Stem cell researchers, including Melton, hope that one day pluripotent stem cells will be a source of functional beta cells that could be transplanted into the pancreas of individuals with type I diabetes.
In his talk, Melton described the greatest challenge the beta cell differentiation field faces: the ability to create a functional beta cell that is capable of sensing glucose.
To date, there has been much success creating insulin-producing beta cells from human pluripotent stem cells however, these cells cannot accurately detect blood glucose. To overcome this challenge, Melton’s team performed a chemical screen in hopes of identifying a small molecule that would induce the ability of pluripotent stem cell-derived beta cells to sense glucose. They found that the combination of four chemical compounds can convert glucose-unresponsive pluripotent stem cell-derived beta cells to glucose-responsive cells.
Following chemical treatment, beta cells underwent a sequential glucose challenge in a petri dish. As the concentration of glucose increased, the level of insulin secretion increased. When these cells were transplanted into mice, human insulin could be detected in vivo following a glucose challenge, suggesting that these cells can respond to glucose levels following transplantation.
To end his talk, Melton outlined his vision for the future of diabetes research and treatment:
- stem cell-derived functional beta cells used as research tools to understand the pathophysiology of this condition, and
- transplantation of functional beta cells into patients, giving these individuals the ability to regulate blood glucose levels.
Transplantation of beta cells has stem cell researchers excited but as Melton outlined, there are still many challenges ahead. Type I diabetes is an autoimmune condition. The immune system attacks beta cells in these patients and would also attack transplanted beta cells. One potential solution could be to encapsulate beta cells, protecting them from the immune system. Melton pointed out that his lab is not focused on bioengineering but he challenged the audience to think about this.
Who’s up for the challenge?
Angela C. H. McDonald
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