Odorico, Jon S., MD
A tissue-specific niche to promote endocrine differentiation from human pluripotent stem cells
General Research Subject: Both Type 1 And Type 2 Diabetes
Focus: Islet Biology, Islet Biology\Beta Cell Growth and Differentiation, Stem Cell Research\Human Fetal/Embryonic, Transplantation
Type of Grant: Minority Undergraduate Internship
Project Start Date: January 1, 2013
Project End Date: December 31, 2013
Human pluripotent stem cells (hPSCs) are increasingly being considered as renewable sources for potential beta cell replacement therapies for patients with diabetes. However, despite being able to produce pancreatic progenitors from hPSCs, in vitro efforts to efficiently generate glucose-responsive insulin-secreting cells are still unsuccessful and maturation to glucose-responsive beta cells after transplantation requires a very prolonged in vivo period (e.g. 6-8 months). We hypothesize that a critical block exists, largely due to the absence of proper extracellular matrix (ECM) signals.
We have recently devised an improved method for differentiating hPSCs into pancreatic progenitors homogeneously expressing PDX1, SOX9, and Nkx6.1 based on combined growth factor treatment with Activin A, BMP4, and bFGF in chemically-defined media. Some of the cells differentiate further to beta-like cells expressing PDX1 and C-peptide, yet they exhibit low glucose-responsive insulin secretion. Realizing the importance of tissue-specific ECM in guiding the fate and behavior of stromal cells in organs, we adapted proven organ decellularization techniques to human pancreas. We hypothesize that the differentiation block in deriving functional endocrine cells from hPSCs can be overcome by exposing cells to ECM signals derived from decellularized pancreata.
Here, we will determine if human fetal pancreas ECM can provide the proper niche signals to promote and accelerate the differentiation of hPSC-derived pancreatic progenitor cells towards beta cell fate, and provide an improved environment compared to differentiation in the absence of matrix in vivo.
Mentor: Jon Odorico
Undergraduate: Joel Alvarez
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating, and curing diabetes?
This project focuses on generating replacement beta cells for lost or deficient beta cells for patients with type 1 or type 2 diabetes. Human pluripotent stem cells offer promise to provide a replenishable source of cells from which insulin-producing cells can be produced. Protocols for derivation of pancreatic beta-like cells from human pluripotent stem cells are improving, yet a block still exists in generating a sufficient number of mature, functional, glucose-responsive beta cells through culture in a petri dish. While human pluripotent stem cell derived progenitor cells can mature in a mouse and reverse diabetes, this process is quite slow and takes many months.
This project aims specifically to overcome this block and improve results in the animal by adding organ matrix, or protein scaffolding, from the pancreas to the cells. By providing a correct niche environment thereby delivering organ-specific signals to the developing cells, we hope to accelerate functional maturation.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Identify a better way to convert human pluripotent stem cells into glucose-responsive insulin-producing beta cells.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your efforts?
I have a daughter with type 1 diabetes and have seen first hand the challenges of managing this disease with insulin. In addition, as a transplant surgeon, I evaluate patients who have had long-standing diabetes for a transplant and have directly observed the tragic effects of long-standing diabetes on the eyes, kidneys, brain, nerves, intestinal function and heart. It is a devastating disease, and I would like nothing more than to help such patients and find a cure. In order to do so more rapidly, we need to engage talented young scientists and stimulate them to enter the field and devote their talents to this ever-growing health problem. The ADA, through this award, is making great strides towards attracting new enthusiastic scientists into diabetes research.
In what direction do you see the future of diabetes research going?
Diabetes research needs to continue to be broad-based, in part because it is not just one disease but has multiple causes with the end result being the same, an imbalance of the demand and supply of insulin. It also needs to be broad-based because while there are many diabetic patients currently, there are many more that are destined to develop the disease in the future and therefore some effort has to be given to both prevention and cure. Furthermore, given the myriad deleterious effects on other organs, important research needs to address the complications of diabetes and not just the disease itself. It is imperative to not lose sight of the importance of basic science research. While it is often difficult to see immediate direct benefit of such work, this research is essential to advancing our understanding of the causes of diabetes and ultimately is the backbone of future treatments and cures.
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