Engineering human pluripotent stem cell-derived, self-renewing endocrine and ductal transplants for treatment of type I diabetes

The Parashurama Research Group

Image of a pancreas

Building the pancreas, from human pluripotent stem cells, is also an enormous scientific challenge, and could help for diseases like type I insulin-dependent diabetes.

Overview

    Glucose homeostasis is central to carbohydrate metabolism. Unfortunately, this is disrupted in patients with type 1 diabetes mellitus (T1DM), who undergo autoimmune destruction of β-cells of the pancreatic islets. These β-cells secrete insulin, which enables whole body intracellular glucose uptake and carbohydrate metabolism, and so the autoimmune loss of β-cells, due to unknown and complex mechanisms, results in major metabolic and pathological derangements, primarily due to the inability to control blood glucose levels. Therapies include the direct intramuscular injection of insulin, and many types of medical devices which mediate controlled injection of insulin. Nevertheless, these approaches do not mimic the physiological control of insulin secretion is ideal, and require constant attention from clinicians and patients.

    Pancreatic regenerative medicine has been defined by understanding, discovering and developing new cell-based treatments for T1DM. Isolation and transplantation of allogeneic pancreatic islets is one approach which has led to short term but not long term efficacy, and is limited by cell source, long term cell survival and function, and the need for immunosuppression. The development of human pluripotent stem cells (hPSC) has enabled the possibility of generating an unlimited amount of personalized mature β-cells for therapy. Current clinical trials employ the transplantation of encapsulated hPSC-derived pancreatic endoderm, the earliest committed endoderm progenitor cell. While promising, safe, and immunoprotective, the greatest problem with these approaches has been intratransplant cellular heterogeneity, intertransplant heterogeneity, and lack of maturity. Our approach is to use our knowledge of development and regenerative medicine to engineer new cell sources of mature islet cells, to prevent transplant heterogeneity for functional improvement of β-cell differentiation, transplantation, and in vivo function.

Resulting Publications

  • Parashurama N, Nahmias Y, Cho CH, Berthiaume F, Tilles AW, Yarmush ML. Activin alters kinetics of (hepatic) endoderm induction in collagen gel cultures of embryonic stem cells. Stem Cells. 2008 Feb; 26(2): 474-84. Citations: 25
  • Banerjee I, Spandan M, Parashurama N, Yarmush ML. An integer programming formulation to identify the sparse network architecture governing differentiation of embryonic stem cells. Bioinformatics. 2010 May 15; 26(10): 1332-9. Citations: 8

Students on This Projects

  • Mitch Maloy (PhD)