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 5

Mucosally injected cMSCs migrate to wounds and prevent penetrating ulcers in injured Ptgir–/– mice.

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Mucosally injected cMSCs migrate to wounds and prevent penetrating ulcer...
(A and C) Fluorescent image of Ptgir–/– wound 5 days after (A) intravenous or (C) mucosal injection of GFP-expressing cMSCs (n = 8 wounds from 4 mice in 4 experiments). (B) Section from A and (D) from C stained with β-catenin and α-SMA antisera. (E) Relative α-SMA staining in the outer muscle layer underlying wounds from indicated groups of mice. P = 0.0159, 1-way ANOVA. *P < 0.05, Tukey’s post-test. n = 8 wounds per group. (F) Colon section (n = 6 wounds from 3 mice in 3 experiments) from Ptgir–/– mice 3 days after intramucosal cMSC injection stained with CD31 and β-catenin antisera. (G) Number of blood vessels per wound bed length and (H) number of VEGF-positive cells per wound bed 4 days after injury in Ptgir–/– or Ptgir–/– plus intramucosal cMSCs. *P < 0.05, **P < 0.01, Student’s t test, n = 6 wounds per group. (I and J) Fluorescent image of (I) day 6 Ptgir–/– wound given intramucosal cMSCs and CXCR4 inhibitor AMD3100 (n = 6 wounds from 3 mice in 3 experiments) and (J) the injection site from mouse in I. (K) Section from I stained with β-catenin and α-SMA antisera. (L) Relative α-SMA staining in the outer muscle layer underlying Ptgir–/– wounds (n = 6–10 wounds per group). *P < 0.05, Student’s t test. White boxes indicate areas shown at high magnification. Scale bar: 1 mm (A, C, I, and J); 100 μm (B, D, F, and K); 125 μm (C, inset; I, inset; and J, inset). Mean ± SEM.