The Epithelial-to-Mesenchymal Transition of Human Pancreatic β−Cells: Inductive Mechanisms and Implications for the Cell-Based Therapy of Type I Diabetes

摘要

As a therapy for type I diabetes, islet transplantation provides clear benefits in terms of increased insulin-nindependence and a reduced risk of hypoglycemia. However, a critical shortage of donor pancreata means that few can nbenefit from this approach. The ex vivo expansion of human β-cells prior to transplantation could ameliorate this problem, nhowever, attempts to grow large numbers of β-cells that retain their native phenotype have thus far failed. Recent lineage ntracing studies suggest that this problem is due to the inherent tendency of cultured human β-cells to undergo a process nreminiscent of epithelial-to-mesenchymal transition (EMT). EMT describes a highly complex process that culminates in a nloss of epithelial cell polarity, severance of intercellular adhesive junctions and the acquisition of a highly motile nmesenchymal phenotype. Interestingly, recent evidence suggests that a transient EMT-like process may also contribute to nthe delamination of endocrine progenitors and subsequent islet neogenesis. The inherent susceptibility of cultured human nβ-cells to EMT, and the potential involvement of this process during islet neogenesis, raises important questions as to how nthis process is triggered and subsequently regulated. The primary purpose of this review is to describe those factors, npathways or processes that are complicit in inducing or regulating the mesenchymal transition of human β-cells. This nincludes addressing the role of the extracellular matrix, the contribution of select signaling pathways, and the regulatory nfunction of microRNAs. We propose that manipulation of these cues and pathways offers the greatest potential for nrestoring β-cell function after ex vivo expansion.