Mucosally transplanted mesenchymal stem cells stimulate intestinal healing by promoting angiogenesis
Nicholas A. Manieri, … , Timothy C. Wang, Thaddeus S. Stappenbeck
Nicholas A. Manieri, … , Timothy C. Wang, Thaddeus S. Stappenbeck
Published August 17, 2015
Citation Information: J Clin Invest. 2015;125(9):3606-3618. https://doi.org/10.1172/JCI81423.
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Research Article Gastroenterology

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

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Figure 3

Ptgs2–/– and Ptgir–/– mice have hypoxia and defective angiogenesis after mucosal injury.

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Ptgs2–/– and Ptgir–/– mice have hypoxia and defective angiogenesis afte...
(A–F) Representative images of colons (3 mice per group in 3 experiments) from (A) WT (n = 7 wounds), (C) Ptgs2–/– (n = 5 wounds), and (E) Ptgir–/– (n = 5 wounds) mice 4 days after injury stained with anti–HIF-1α antisera (green, hypoxic cells) and bisbenzimide (blue, nuclei). Dashed white lines outline wound beds, dashed yellow lines outline muscularis propria, and dashed white boxes indicate the areas shown at higher magnification in B, D, and F. (G) Number of HIF-1α–positive cells per wound bed length (n = 5–7 wounds per group). P = 0.0056, 1-way ANOVA; P < 0.001, Bartlett’s test for unequal variance. (H–J) Representative images of colons (n = 5–6 wounds per group from 3 mice per group in 3 experiments) from (H) WT (n = 5 wounds), (I) Ptgs2–/– (n = 6 wounds), and (J) Ptgir–/– (n = 5 wounds) mice 4 days after colonic biopsy injury stained with anti-CD31 (red, blood vessels) and anti–β-catenin antisera (green, epithelium). (K) Number of blood vessels found in the wound bed divided by the width of the wound bed in indicated groups of mice 4 days after injury (n = 5–6 wounds per group). P = 0.0038, 1-way ANOVA. (L) Number of VEGF-positive cells per wound bed from WT (n = 5 wounds), Ptgs2–/– (n = 5 wounds), and Ptgir–/– (n = 7 wounds) mice. n = 5–7 wounds per group from 3 mice per group in 3 experiments. P = 0.0013, 1-way ANOVA; P = 0.0021, Bartlett’s test for unequal variance. *P < 0.05, **P < 0.01, Tukey’s post-test. Scale bar: 100 μm (A, C, E, and H–J); 25 μm (B, D, and F). Mean ± SEM.