Mesenchymal stem cells contribute to vascular growth in skeletal muscle in response to eccentric exercise

Abstract

The α(7)β(1)-integrin is an adhesion molecule highly expressed in skeletal muscle that can enhance regeneration in response to eccentric exercise. We have demonstrated that mesenchymal stem cells (MSCs), predominantly pericytes, accumulate in muscle (mMSCs) overexpressing the α(7B)-integrin (MCK:α(7B); α(7)Tg) and contribute to new fiber formation following exercise. Since vascularization is a common event that supports tissue remodeling, we hypothesized that the α(7)-integrin and/or mMSCs may stimulate vessel growth following eccentric exercise. Wild-type (WT) and α(7)Tg mice were subjected to single or multiple (3 times/wk, 4 wk) bouts of downhill running exercise. Additionally, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) -labeled mMSCs were intramuscularly injected into WT recipients. A subset of recipient mice were run downhill before injection to recapitulate the exercised microenvironment. While total number of CD31(+) vessels declined in both WT and α(7)Tg muscle following a single bout of exercise, the number of larger CD31(+) vessels with a visible lumen was preferentially increased in α(7)Tg mice following eccentric exercise training (P < 0.05). mMSC transplantation similarly increased vessel diameter and the total number of neuron-glial antigen-2 (NG2(+)) arterioles postexercise. Secretion of arteriogenic factors from mMSCs in response to mechanical strain, including epidermal growth factor and granulocyte macrophage-colony stimulating factor, may account for vessel remodeling. In conclusion, this study demonstrates that the α(7)-integrin and mMSCs contribute to increased vessel diameter size and arteriolar density in muscle in response to eccentric exercise. The information in this study has implications for the therapeutic treatment of injured muscle and disorders that result in vessel occlusion, including peripheral artery disease.

Substrate and strain alter the muscle-derived mesenchymal stem cell secretome to promote myogenesis

“…We recently defined a population of MSCs, identified by expression of stem cell antigen 1 (Sca-1 + ) and lack of expression of a hematopoietic cell surface marker (CD45 - ), that is capable of osteogenic, chondrogenic, and adipogenic differentiation and accumulate in skeletal m uscle ( m MSCs) after eccentric exercise in an α7-integrin-dependent manner [12]. We also recently demonstrated that Sca-1 + CD45 - mMSCs are involved in muscle repair after injury [12], perhaps through secretion of paracrine factors [16]. Currently, minimal information exists regarding the cues in the environment that regulate MSC paracrine factor synthesis and secretion [16].…”

“…We also recently demonstrated that Sca-1 + CD45 - mMSCs are involved in muscle repair after injury [12], perhaps through secretion of paracrine factors [16]. Currently, minimal information exists regarding the cues in the environment that regulate MSC paracrine factor synthesis and secretion [16]. …”

“…For example, MSCs derived from bone marrow are directed toward an osteogenic fate when subjected to multiple bouts of biaxial strain [23-25] and this may be dependent on the activation of focal adhesion kinase (FAK) [10]. In addition, mMSCs secrete a variety of growth factors in response to biaxial strain in the presence of LAM [16]. However, the full extent to which MSCs residing in skeletal muscle are responsive to mechanical strain in the context of substrate has yet to be determined.…”

Exercise and Stem Cells

“…147 In both studies, mMSCs did not express Pax7, form new fibers, or fuse with existing fibers. The fact that transplanted cells localized to areas of CLN + fibers and vessels and contributed to vessel remodeling following an acute bout of exercise 148 suggests the ability of mMSCs to repair multiple tissues via release of local factors. Finally, mMSCs are highly sensitive to mechanical strain and release a wide variety of growth and neurotrophic factors in a substrate-dependent manner that likely dictates their functional capacity and the ability to stimulate satellite cells throughout the lifespan.…”

“…Finally, mMSCs are highly sensitive to mechanical strain and release a wide variety of growth and neurotrophic factors in a substrate-dependent manner that likely dictates their functional capacity and the ability to stimulate satellite cells throughout the lifespan. 141,148,149 The human homologue for Sca-1 has not been determined, thus limiting the ability to use this marker for identification of mMSCs in samples of human muscle. The increase in NF-κB expression in NG2 + and ALP + pericytes 3 h posteccentric exercise suggests a role for the pericyte in the early adaptive response to exercise in human skeletal muscle.…”