Plasminogen regulates mesenchymal stem cell–mediated tissue repair after ischemia through Cyr61 activation
Hao Duan, … , Yi Fan, Yanqing Gong
Hao Duan, … , Yi Fan, Yanqing Gong
Published August 11, 2020; First published August 6, 2020
Citation Information: JCI Insight. 2020;5(15):e131376. https://doi.org/10.1172/jci.insight.131376.
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Research Article Vascular biology

Plasminogen regulates mesenchymal stem cell–mediated tissue repair after ischemia through Cyr61 activation

Abstract

Stem cell transplantation has emerged as a promising strategy in regenerative medicine. However, the poor survival and persistence of the transplanted cells, including mesenchymal stem cells (MSCs), in the hostile ischemic microenvironments represents a major therapeutic barrier. Here we report that plasminogen (Plg) stimulated MSC functions and promoted MSC survival during tissue repair after ischemia. Genetic Plg ablation abolished MSC survival, migration, and proliferation in mouse ischemic limbs, and abrogated MSC-mediated blood reperfusion, neovascularization, and tissue repair after ischemia, suggesting a critical role for Plg in MSC-mediated tissue repair. Furthermore, multiplex cytokine array analysis identified that Plg cleaved and activated cysteine-rich protein 61 (Cyr61), an ECM-associated growth factor, to stimulate MSC survival and migration. Overexpression with truncated Cyr61 in MSCs rescued blood reperfusion after hind limb ischemia in Plg-deficient mice. Finally, Plg-mediated Cyr61 cleavage promoted endothelial cell migration and neovascularization in vitro and in vivo. Our study reveals that Plg promotes MSC survival, persistence, and paracrine effects and improves postischemic neovascularization and tissue repair through Cyr61 cleavage and activation. Thus, targeting Plg/Cyr61 may offer exciting therapeutic opportunities for strengthening MSC therapy in ischemic diseases.

Authors

Hao Duan, Zhenqiang He, Maohuan Lin, Yanling Wang, Fan Yang, R. Alan Mitteer, Hyun-Jun Kim, Eujing Yeo, Hongyu Han, Ling Qin, Yi Fan, Yanqing Gong

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Figure 1

Plg promotes MSC proliferation and migration under normoxia and improves MSC survival under hypoxia.

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Plg promotes MSC proliferation and migration under normoxia and improves...
(A) MSCs were cultured with serum-free medium and treated with or without Plg under normoxia. Cell proliferation was determined by MTS-based assay (n = 4–8, mean ± SEM). Statistical analysis by 1-way ANOVA (compared with control). (B) MSCs were suspended in serum-free medium supplemented with or without Plg and seeded on Transwell membranes precoated with Matrigel. Plg-depleted FBS was used as the attractant to induce the migration through Matrigel. Cell migration was determined after 4-hour incubation. Top, representative images. Bottom, quantified results (n = 12, mean ± SEM). Statistical analysis by unpaired Student’s t test. (C) MSCs were cultured with serum-free medium and treated with or without Plg under hypoxia (2% O2). Cell proliferation was determined by MTS-based assay (n = 3, mean ± SEM). Statistical analysis by 1-way ANOVA (compared with control). (D) MSCs were cultured with serum-free medium and treated with or without Plg under hypoxia (2% O2) for 24 hours. Cell apoptosis was analyzed by using FITC-annexin V–based flow cytometry. Left, representative sorting. Right, quantified results (n = 3, mean ± SEM). Statistical analysis by 1-way ANOVA. Experiments were repeated 3 times and representative results are shown.