Engineered matrices for control of lineage commitment in human pancreatic stem cells
Patients with end-stage type 1 diabetes (T1D) can be effectively managed by allogeneic islet transplantation. However, a severe cadaveric organ shortage greatly limits use of this promising procedure. Stem cells have the potential to provide a solution to this bottleneck because of their ability to self-renew and differentiate into islet β-cells. Although progress has been made in coaxing human embryonic stem (ES) cells to differentiate into pancreatic progenitor-like cells in culture, there are safety concerns regarding ES cell-derived products because of their ability to form teratomas in vivo. In contrast, adult tissue cells lack teratoma potential. Our goal is to develop, for transplantation, insulin-expressing cells derived from adult human pancreatic progenitor-like cells. If successful, the proposed research will establish a new paradigm for the development of cell products derived from adult pancreata and enable important advances in cell replacement therapy for T1D. This research will allow human cadaveric adult pancreatic tissues, which are largely discarded after islet isolation, to be used to maximum efficiency in transplantation. Moreover, the results of these studies will be applicable to the treatment of end-stage type 2 diabetes patients, in whom islet β-cells are exhausted and dysfunctional.
In type 1 and some type 2 diabetic patients, the pancreatic β-cells, which secrete insulin in response to elevated glucose concentrations in the blood, are insufficient or dysfunctional. Insulin injection is the most common form of therapy to control diabetes. However, insulin injection cannot match the physiological response conferred by endogenous β-cells, and complications inevitably develop over time. Allogeneic islet transplantation is beneficial to those diabetic patients who have developed end-stage complications. However, it is estimated that fewer than 1% of Californians most in need of islet transplantation can benefit from the procedure because there is a severe shortage of human cadaveric pancreas organs. This dire situation has led to the search for alternative sources of β-cells for transplantation. If human adult pancreatic stem and progenitor cells can be coaxed to differentiate into β-like cells in culture, they would provide large numbers of cells for replacement therapy. This proposal addresses the important challenge of producing β-cells through differentiation of human pancreatic stem and progenitor cells, with the ultimate objective of developing new treatments for diabetic patients.
This award has supported the development of several new classes of artificial proteins designed to facilitate production of glucose-sensitive cells for the treatment of Type 1 diabetes. We are exploring methods for controlled differentiation of glucose-sensitive cells from progenitor cells isolated from adult human pancreas. In our first year, we have prepared two new classes of artificial extracellular matrix (aECM) proteins, achieved targeted levels of elasticity in aECM gels to be used for cell encapsulation, demonstrated that cells can be encapsulated in and released from aECM gels without loss of viability, and shown that encapsulated cells maintain their insulin expression levels for at least 24 hours. These experiments lay the groundwork for the development of an important new source of cells for treatment of diabetic patients.
- Stem Cell Res (2016) Cells with surface expression of CD133(high)CD71(low) are enriched for tripotent colony-forming progenitor cells in the adult murine pancreas. (PubMed: 26691820)
- Stem Cells Dev (2015) Postnatal Pancreas of Mice Contains Tripotent Progenitors Capable of Giving Rise to Duct, Acinar, and Endocrine Cells In Vitro. (PubMed: 25941840)
- Integr Biol (Camb) (2015) Quantifying cell-induced matrix deformation in three dimensions based on imaging matrix fibers. (PubMed: 26021600)