Odorico, Jon S.
Epigenetic control of reprogramming and differentiation to pancreatic beta cells
General Research Subject: Type 1 Diabetes
Focus: Islet Biology\Beta Cell Growth and Differentiation, Islet Biology\Beta Cell Transcription Regulation
Type of Grant: Innovation
Project Start Date: July 1, 2011
Project End Date: June 30, 2013
In Type I diabetes, beta cells within islets of the pancreas are permanently damaged. Insulin-replacement therapies, including islet and pancreas transplantation, are largely successful in restoring normal glucose metabolism, but the scarcity of donor organs restricts their use. Embryonic stem cells (ESC) can proliferate indefinitely in culture, yet are able to turn into many distinct mature cell types under appropriate conditions, and could thus potentially be used to generate an abundant supply of islet tissue. New techniques enable generation of induced pluripotent stem cells (iPSC) from adult tissues; these cells are similar to ESC in their differentiation capabilities.
Our lab developed a protocol resulting in differentiation of nearly all human ESC into early pancreatic progenitors, but very few cells progress to mature insulin-producing cells. Epigenetics, heritable changes to the genome that do not alter the genetic code, may be one mechanism responsible for this block in maturation. Methylation of CpG sites in promoters and certain histone methylation sites at gene loci, two types of epigenetic marks, typically result in gene repression. Our hypothesis is that the promoters of insulin and other important pancreatic genes are methylated in the human ESC-derived pancreatic progenitors. Recent evidence suggests iPSC retain the methylation marks of the cells from which they were derived. Here, iPSC will be generated from human adult islet cells. Our prediction is that these cells will have the appropriate epigenetic marks to allow expression of genes required for maturation of pancreatic precursors to insulin-producing cells after differentiation.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
This research seeks to understand the role epigenetics plays in beta cell development. Epigenetics refers to heritable alterations in the genome that do not involve base pair mutations or changes in the primary structure of DNA. Such non-DNA based changes can profoundly influence gene expression profiles, and therefore fates of cells during differentiation and development. We specifically wish to understand if these types of alterations to the genome, focused on several key genes, affect how human pluripotent stem cells are able to or not able to become insulin-secreting beta cells in culture. The results derived from these experiments may enlighten our future ability to generate glucose-responsive mature beta cells from pluripotent stem cells, like induced pluripotent stem cells (iPSCs). This may ultimately provide a better long-term beta cell replacement therapy for insulin-deficient patients with Type 1 and Type 2 diabetes without the need for chronic immunosuppressive medications.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
These experiments should teach us whether epigenetic changes in cells from our body affect the ability of pluripotent stem cells derived from them to become glucose-responsive, insulin-producing beta cells. If we have a better understanding of the role that epigenetic changes might play in gene activation and cell fates, then we can better manipulate pluripotent stem cells to our advantage to produce beta cells that can be used to replace lost beta cells for patients with Type 1 and Type 2 diabetes. Progress in this area will be highly relevant to both cell replacement therapies and to beta cell regeneration efforts.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
The proportion of the US population affected by diabetes is increasing at alarming rates. In some regions, more than 10% of the population is affected. Therapies which can achieve perfect glycemic control with minimal morbidity are urgently needed for patients to forestall the secondary complications which are so prevalent, costly and life-threatening. This research has direct translational potential to influence diabetes care for many millions of afflicted individuals.
This innovative award allows us to ask some preliminary questions which may stimulate more in depth analysis and generate new hypotheses. To some extent this award also allows our laboratory to explore a new potential explanation for the widely observed finding of insufficient pluripotent stem cell to beta cell differentiation in culture.
In what direction do you see the future of diabetes research going?
These studies may define some of the epigenetic mechanisms regulating beta cell formation and maturation genes during beta cell development from stem cells. While we hope to make important discoveries, it is anticipated that these studies will only 'scratch the surface' of our understanding of the critical epigenetic changes that are involved in the beta cell development process. More studies with more advanced reagents will likely be needed. As it is largely epigenetics that determines the differentiation state of cells, there is no doubt that a better understanding of the epigenetic state of cells at various times in development and the mechanisms directing these alterations will be essential to future progress in both cell replacement therapies and to beta cell regeneration efforts.
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