Editors' ChoiceDiabetes

Morphing Cell Identity to Treat Diabetes

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Science Translational Medicine  03 Dec 2014:
Vol. 6, Issue 265, pp. 265ec208
DOI: 10.1126/scitranslmed.aaa3411

The human body is in a constant race to replace cells, tissues, and whole organs that are lost due to injury, disease, and normal aging. Although the body has remarkable inherent regenerative capacity, it often cannot keep pace. Donor cells and tissues are available in limited quantities and are beset by problems such as immune compatibility and transplant rejection. Recently, technologies to convert one cell type into another, so-called “direct reprogramming,” have provided promise as a new source of cells for regenerative medicine. Li et al. now provide an enhanced method to directly reprogram native mouse pancreatic acinar cells into “induced” pancreatic beta cells that are functional and persist long-term.

A wave of recent studies have shown that cell identity can be readily modulated by the expression of key transcription factors. However, there remain significant uncertainties about whether the cells created by direct reprogramming will prove useful in regenerative medicine, as their long-term persistence and function in vivo are unproven. The ability to reprogram pancreatic acinar cells into induced beta cells was initially demonstrated in 2008 by adenoviral-mediated overexpression of the transcription factors Ngn3, Mafa, and Pdx1 in the mouse pancreas. The reprogramming was inefficient, and the resulting cells failed to persist much beyond 2 months. In the current study, the authors report an optimized in vivo induction protocol that enabled a 40 to 50% increase in the number of insulin-producing induced pancreatic beta cells generated from mouse acinar cells. Importantly, the induced beta cells aggregated into pancreatic islet-like structures, which enabled their persistence in vivo for more than one year. Epigenetic and transcriptional analyses showed that the induced beta cell clusters matured in vivo over the course of 2 to 7 months to reach maximal function. They exhibited proper glucose-stimulated insulin secretion and the ability to reverse hyperglycemia in diabetic mice.

Direct reprogramming technologies provide a new potential source of replacement cells to thwart disease and aging. The current paper demonstrates that reprogrammed cells can maintain their identity and function long-term in vivo, providing encouraging results that could form the basis of future clinical testing. However, significant work remains to be done to understand the epigenetic stability and safety of these reprogrammed cells. For type 1 diabetes in particular, there also exists a significant challenge to prevent the induced beta cells from succumbing to the autoimmune-mediated beta cell destruction that underlies the disease.

W. Li et al., Long-term persistence and development of induced pancreatic beta cells generated by lineage conversion of acinar cells. Nat. Biotechnol. 10.1038/nbt.3082 (2014). [Full Text]

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