Dedifferentiation for Replication of Human β-Cells

Abstract

Human β-cells, generated in ample quantities, are a prerequisite in order to realize a wider application of β-cell replacement therapy for diabetes. Theoretically, there are several potential sources of new β-cells, including embryonic or adult stem/progenitor cells, transdifferentiation of nonislet tissues such as liver, or the proliferation of fully differentiated β-cells (1). Because it has been demonstrated that all β-cells could theoretically be induced to proliferate (2,3), a significant increase in β-cell number might be achieved by simply stimulating the proliferation of existing β-cells through application of specific growth factors, as has been achieved for cultured rat and mouse β-cells (4). Unfortunately, stimulation of human β-cell proliferation in culture has proven to be much more difficult than for rodent cells. In a recent comparison, the conditions leading to efficient proliferation of rat β-cells were not found to have an effect on human β-cells (5). However, it should be emphasized that this does not preclude the possibility that unidentified culture conditions for human β-cell expansion could exist. Another potential source of β-cells that has recently received much attention is the fibroblast-like cells that become evident following the gradual loss of endocrine cells in long-term cultures of human islets (6,7). The nature and origin of these fibroblast-like cells emerging from islets have been closely examined because of their proposed capacity to function as endocrine precursors (7–9). These cells are not only able to proliferate and expand, but are also able to retain their ability to produce at least small amounts of insulin following induction of differentiation (7). Some studies have suggested that these …