Diabetes enhances the proliferation of adult pancreatic multipotent progenitor cells and biases their differentiation to more ß-cell production.

Endogenous pancreatic multipotent progenitors (PMPs) are ideal candidates for regenerative approaches to compensate for ß-cell loss since their ß-cell-producing capacities as well as strategic location would eliminate unnecessary invasive manipulations. However, little is known about the status and potentials of PMPs under diabetic conditions. Here we show that ß-cell metabolic stress and hyperglycemia enhance the proliferation capacities of adult PMP cells and bias their production of progeny toward ß-cells in mouse and human. These effects are dynamic and correlate with functional ß-cell regeneration when conditions allow.

The adult mammalian pancreas contains separate precursors of pancreatic and neural crest developmental origins.

The developmental origin of a pancreatic precursor cell could provide clues to properties that may be crucial to its molecular regulation and therapeutic potential. Previously, lineage tracing experiments showed that multipotent precursors in mouse islets had a pancreatic and not a neural crest developmental origin. However, a different Cre reporter system reveals that there is, in fact, a rare population of proliferative cells in the pancreas that is descended from the Wnt1 neural crest lineage, in addition to the majority population descended from the Pdx1 pancreatic lineage. These two proliferative cell populations are distinct in their gene expression and differentiation potential. This evidence suggests that there are at least two distinct types of precursors present in adult pancreatic islets, one of pancreatic origin and one of neural crest origin.

Clonal neural stem cells from human embryonic stem cell colonies.

Clonal cell culture is crucial for experimental protocols that require growth or selection of pure populations of cells. High-density derivation of neural progenitors from human embryonic stem cells (hESCs) can lead to incomplete differentiation, and transplantation of resulting heterogeneous cell mixtures can cause proliferation of tumorigenic clusters in vivo. We have identified the neural precursor that resides among normal hESC colonies as a TRA-1-60(-)/SSEA4(-)/SOX1(+) cell and developed a method that allows for the clonal expansion of these FACS-selected progenitors to neural stem cells (NSCs) in serum-free conditions. Single TRA-1-60(-)/SSEA4(-)/SOX1(+) cells grown in serum-free media give rise to multipotent NSCs with an efficiency of 0.7%. The fate of the TRA-1-60(-)/SSEA4(-)/SOX1(+) neural precursor becomes specified in maintenance conditions by inhibition of BMP signaling. This clonal culture method can be scaled up to produce NSCs for differentiation and use in cell therapies.

The adult mouse and human pancreas contain rare multipotent stem cells that express insulin.

The search for putative precursor cells within the pancreas has been the focus of extensive research. Previously, we identified rare pancreas-derived multipotent precursor (PMP) cells in the mouse with the intriguing capacity to generate progeny in the pancreatic and neural lineages. Here, we establish the embryonic pancreas as the developmental source of PMPs through lineage-labeling experiments. We also show that PMPs express insulin and can contribute to multiple pancreatic and neural cell types in vivo. In addition, we have isolated PMPs from adult human islet tissue that are also capable of extensive proliferation, self-renewal, and generation of multiple differentiated pancreatic and neural cell types. Finally, both mouse and human PMP-derived cells ameliorated diabetes in transplanted mice. These findings demonstrate that the adult mammalian pancreas contains a population of insulin(+) multipotent stem cells and suggest that these cells may provide a promising line of investigation toward potential therapeutic benefit.