Planting the right seeds

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Science Translational Medicine  09 Mar 2016:
Vol. 8, Issue 329, pp. 329ec41
DOI: 10.1126/scitranslmed.aaf3861

The cells of the gastrointestinal (GI) epithelium are ripe for reprogramming to create replacements for the insulin-secreting β cells lost in type 1 diabetes. For these cellular seeds to grow into a diabetes-fighting forest, the right cells must be planted. Ariyachet et al. discovered that it is antral stomach cells—endocrine cells that line the distal stomach—that can be reprogrammed to yield insulin-positive replacement cells. Like a forest comprising strong, sturdy trees, these remodeled stomach cells regenerate and regrow, providing long-term protection against diabetes in a mouse model.

The researchers constructed a new triple-transgenic mouse that expressed a key insulin-inducing set of transcription factors in stomach cells. This engineered mouse was then exposed to a chemical that induced robust reprogramming of GI endocrine cells into mostly monohormonal insulin-producing cells. Induction occurred most efficiently and completely in the antral stomach cells, likely a result of their transcriptional similarity to pancreatic β cells. Induction of insulin-positive cells in the GI tract reversed hyperglycemia sufficiently to keep diabetic test mice alive for the entire 6-month study, while all control animals died within 8 weeks. Even wiping out insulin-positive cells with a toxin could not keep the cells down, as they regenerated in the stem cell compartment, resuppressing hyperglycemia. These robust cells worked in vivo, too: Ariyachet et al. created and transplanted into the mice bioengineered stomach mini-organs containing renewable insulin-positive cells and found that they reversed β cell death in a mouse diabetes model.

To improve and translate these results, we will need to determine why antral stomach cells reprogram better than antral intestinal cells and to scale up the technique to yield a clinically useful cell mass. Nevertheless, these promising results suggest that transplanted stomach spheres, combined with improved gene therapies, could continuously guard against diabetes and perhaps other disorders. Plant the right seeds, and the forest can withstand any weather.

C. Ariyachet et al., Reprogrammed stomach tissue as a renewable source of functional β cells for blood glucose regulation. Cell Stem Cell 18, 1–12 (2016). [Abstract]

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