Editors' ChoiceType 1 Diabetes

Restoring the Hormone-Making Machinery

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Science Translational Medicine  26 Jun 2013:
Vol. 5, Issue 191, pp. 191ec103
DOI: 10.1126/scitranslmed.3006769

More than 30 million people worldwide suffer from type 1 (autoimmune) diabetes, and insulin therapy is not a cure. Most often diagnosed in childhood, a lifetime of the disease and of insulin treatment can damage the kidneys, eyes, nerves, and blood vessels and cause hypoglycemia and substantial weight gain (with all of its comorbidities), respectively. Despite advances in disease management, no existing treatment permanently restores the body’s glucose-responsive insulin-production machinery—the pancreatic β cells. Stem cell–based strategies that enable β cell replacement might be the answer. But what progenitor cell is the most suitable source?

In a recent study, Kumar et al. provided an exceptionally detailed characterization of a strategy for in vitro differentiation of two sources of multipotent progenitor cells to differentiated ones that resembled pancreatic β cells. The progenitor cells were isolated from embryonic and adult rats (blastocysts and bone marrow, respectively) and over a 3-week period were subjected to a series of differentiation steps, from their original multipotent state to a β cell–like phenotype. At every stage of the four-step process, gene and protein expression moved closer to that of a naïve insulin-secreting β cell, with some notable exceptions: In the most differentiated cell pool, C-peptide staining per cell was low, glucagon was undetectable, and the MafA protein was expressed in the perinuclear region, all of which are hallmarks of immature cells. Yet, the cells responded in vitro to high glucose concentrations by secreting C-peptide.

Studies performed in nude Balb/C type 1 diabetic mice revealed that implantation of a population of either type of cells after the four-stage differentiation protocol resulted in normalization of serum glucose concentrations in half of the mice. Normoglycemia was achieved 1 month after transplantation of the cell grafts, whereas previous recent reports needed 4 months of in vivo maturation of the progenitor cells to achieve glucose control. Immunohistological analysis of the excised grafts revealed that the progeny of the implanted cell population were able to mature in vivo to generate the three major endocrine hormones: insulin, glucagon, and somatostatin. Glucose levels were normal for 1 week, even in the absence of treatment with subcutaneous insulin pellets. Why only half of the animals responded to cell transplantation is not yet known. What is known, however, is that the search for a cure must go on. Thirty million people are depending on it.

A. Kumar et al., Reversal of hyperglycemia by insulin-secreting rat bone marrow-and blastocyst-derived hypoblast stem cell-like cells. PLoS One 8, e63491(2013). [Full text]

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