Funding opportunities

Engineered matrices for control of lineage commitment in human pancreatic stem cells

Funding Type: 
Basic Biology V
Grant Number: 
RB5-07398
Principle Investigator: 
Funds requested: 
$526 896
Funding Recommendations: 
Recommended if funds allow
Grant approved: 
Yes
Public Abstract: 
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.
Statement of Benefit to California: 
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.
Review Summary: 
In this Exploratory Concepts Track proposal, The applicant intends to engineer an in vitro extracellular matrix-based culture system, which can regulate lineage differentiation in adult human pancreatic progenitor cells from human embryonic stem cell (hESC). These cells have the potential to provide a cell source for allogeneic islet transplantation. The first aim tests whether artificial extracellular matrix (ECM) proteins will direct differentiation of adult human pancreatic progenitor cells into beta-like cells. The second aim seeks to optimize physical properties of matrices to enhance beta-cell differentiation and cell harvest. Significance and Innovation - Though the hypothesis is not novel, this application is unique in that it proposes to identify putative human pancreatic progenitor cells. - The proposed engineered artificial ECM culture system is novel. The role of ECM in cell differentiation is poorly understood, and studies outlined in this proposal utilize a promising approach. - If successful, could lead to cell-based therapy to treat diabetes. Feasibility and Experimental Design - Reviewers stated that one of the critical flaw in this study is the lack of evidence that the pancreatic progenitor-like cells are clonal and arise from a collection of cells from the dissociated pancreata. - Reviewers criticized that the assays proposed at the end of the application are not robust and do not adequately test for functionality. They considered this to be an additional critical flaw. - The beta cells that arise from the progenitor cells do not appear any more functional than those that have been differentiated from pluripotent cells. - The applicant presents extensive preliminary data suggesting the existence of pancreatic progenitor cells in mice and preliminary studies using human cells to demonstrate some differentiation into insulin-expressing cells. - Reviewers praised the bioengineering component of this application and considered it a strength. Principal Investigator (PI) and Research Team - The PI is an outstanding bioengineer with expertise in modifying polymers and has been studying artificial extracellular matrices for over a decade. - The PI and research team have complementary skills required to perform the proposed studies. Responsiveness to the RFA - The application expands preliminary data developed in mice to focus on the role of ECM in expanding human pancreatic progenitors and thus, it is responsive to the RFA.
Conflicts: 

© 2013 California Institute for Regenerative Medicine