Editors' ChoiceRegenerative Medicine

A soothing MSC-based ulcer treatment

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Science Translational Medicine  26 Aug 2015:
Vol. 7, Issue 302, pp. 302ec147
DOI: 10.1126/scitranslmed.aad1825

Gastrointestinal ulceration, a complication of chronic NSAID use, radiation therapy, or inflammatory bowel disease, is a painful problem for patients. Understanding the molecular pathophysiology of gastrointestinal ulceration and applying this knowledge to the development of new therapeutic approaches is an active area of research. Manieri and colleagues shed light on the molecular underpinnings of ulcer formation and apply mesenchymal stem cell (MSC) therapy in a mouse model of this disorder.

Using the prostaglandin-deficient mouse (Ptgs2–/–) as a model of penetrating ulcer formation—that is, ulcers that penetrate the muscularis propria—these authors demonstrated extensive necrosis of the colon mucosa and underlying muscle after biopsies were taken. They were able to ameliorate the damage to the colon by treating the mice with stable prostaglandin-I2 (PGI2) analogs. Taking colon biopsies from Ptgir–/– mice lacking the receptor for PGI2 also resulted in extensive colon muscle injury, further supporting a role for PGI2 in minimizing muscle wall damage. When the researchers analyzed the ulcer beds in the Ptgs2–/– and Ptgir–/– mice, they observed a lack of CD31+ endothelial cells, suggesting that reduced angiogenesis may be a key driver of penetrating ulcer formation. When the authors stained the wound sites for vascular endothelial growth factor (VEGF), they saw fewer VEGF+ cells in the Ptgs2–/– and Ptgir–/– mice compared with wild-type animals, further suggesting that impaired angiogenesis contributed to ulceration. Moreover, suppression of angiogenesis in wild-type mice using tivozanib (a VEGF receptor antagonist) resulted in colon smooth muscle necrosis after biopsy injury.

The team then injected mouse colon MSCs, showing increased expression of VEGF, into the ulcerated colonic submucosa of Ptgir–/– mice and found that the MSCs migrated to the ulcer beds. Notably, the MSCs rescued the muscle necrosis phenotype. These early results represent a soothing treatment prospect for patients battling gastrointestinal ulceration.

N. A. Manieri et al., Mucosally transplanted mesenchymal stem cells stimulate intestinal healing by promoting angiogenesis. J. Clin. Invest. 10.1172/JCI81423 (2015). [Abstract]

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