The intestinal healing power of mesenchymal stem cells
Intestinal damage can lead to ulcers that penetrate the outer wall of the intestine. These penetrative ulcers can result in response to a variety of insults, including pathogenic infection, radiation therapy, chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) or VEGF inhibitors, and inflammatory bowel disease. The mechanisms that induce penetrating ulcer formation under these circumstances are not well understood and there is a dearth of clinical therapies available for the prevention or treatment of penetrating ulcers of the intestine. Nicholas Manieri and colleagues at Washington University School of Medicine now shed light on how intestinal penetrating ulcers form and examine the potential of mesenchymal stem cell (MSC) therapy to prevent ulcer development. Using a prostaglandin-deficient mouse model of colonic ulcer formation, the authors determined that penetrating ulcers form as a consequence of hypoxia-induced necrosis of smooth muscle cells underlying the initial wound site and that prostaglandin I2 (PGI2), a lipid hormone, is critical for initiating repair pathways that ultimately block penetrating ulcer formation. PGI2 signaling led to local induction of VEGF expression and subsequent de novo angiogenesis, which inhibited hypoxia-induced necrosis of cells lining the wound. The authors also investigated the use of therapeutic MSC treatment in their model and found that MSCs transplanted into the intestinal mucosa can migrate to the wound site, promote angiogenesis, and prevent necrotic ulcer formation. Importantly, de novo angiogenesis and inhibition of necrosis at the wound site was dependent upon VEGF expression in the MSCs. Together, the results of this study indicate that the application of angiogenesis-promoting MSCs may be a potential therapy for intestinal ulcerations and other conditions that feature abnormal repair. The accompanying image shows GFP-labeled colonic MSCs that have migrated to a wound site in the intestine of a PGI2 receptor-deficient mouse. Note that the MSCs surround a nearby blood vessel.
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Mucosally transplanted mesenchymal stem cells stimulate intestinal healing by promoting angiogenesis
Abstract
Mesenchymal stem cell (MSC) therapy is an emerging field of regenerative medicine; however, it is often unclear how these cells mediate repair. Here, we investigated the use of MSCs in the treatment of intestinal disease and modeled abnormal repair by creating focal wounds in the colonic mucosa of prostaglandin-deficient mice. These wounds developed into ulcers that infiltrated the outer intestinal wall. We determined that penetrating ulcer formation in this model resulted from increased hypoxia and smooth muscle wall necrosis. Prostaglandin I2 (PGI2) stimulated VEGF-dependent angiogenesis to prevent penetrating ulcers. Treatment of mucosally injured WT mice with a VEGFR inhibitor resulted in the development of penetrating ulcers, further demonstrating that VEGF is critical for mucosal repair. We next used this model to address the role of transplanted colonic MSCs (cMSCs) in intestinal repair. Compared with intravenously injected cMSCs, mucosally injected cMSCs more effectively prevented the development of penetrating ulcers, as they were more efficiently recruited to colonic wounds. Importantly, mucosally injected cMSCs stimulated angiogenesis in a VEGF-dependent manner. Together, our results reveal that penetrating ulcer formation results from a reduction of local angiogenesis and targeted injection of MSCs can optimize transplantation therapy. Moreover, local MSC injection has potential for treating diseases with features of abnormal angiogenesis and repair.
Authors
Nicholas A. Manieri, Madison R. Mack, Molly D. Himmelrich, Daniel L. Worthley, Elaine M. Hanson, Lars Eckmann, Timothy C. Wang, Thaddeus S. Stappenbeck
Copyright © 2019 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)