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.
Highlights
Mesenchymal stem cells (MSCs) are multipotent stem cells that possess the potential to self-renew and differentiate into a variety of specialized cell types, such as osteocytes, adipocytes, chondrocytes, fibroblasts, and endothelial cells (ECs) [1,2,3,4]
In this study, using stem cell tracking approaches in an experimental mouse hind limb ischemia (HI) model with genetic Plg ablation, we reveal that Plg is critical for MSC survival and persistence in ischemic tissues and regulates MSC-mediated neovascularization and tissue repair
Considering that cysteinerich protein 61 (Cyr61) secreted by MSCs promotes EC migration and vascular morphogenesis [22], we investigated the role of the Plg-mediated cleavage of Cyr61 in the MSC-mediated neovascularization
Summary
Mesenchymal stem cells (MSCs) are multipotent stem cells that possess the potential to self-renew and differentiate into a variety of specialized cell types, such as osteocytes, adipocytes, chondrocytes, fibroblasts, and endothelial cells (ECs) [1,2,3,4]. In addition to their ability of pleiotropic differentiation, MSCs exhibit a set of fairly unique properties, including antiapoptosis, proangiogenesis, production of growth factors, neuroprotection, antifibrosis, and chemoattraction [5]. Clinical trial failures have been frequently reported, largely due to low retention and survival of the transplanted MSCs in the ischemic environment, compromising long-term efficacy of MSC therapy [13,14,15]
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