Abstract
This study was conducted to elucidate whether microRNA-29a (miR-29a) and/or together with transplantation of mesenchymal stem cells isolated from umbilical cord Wharton’s jelly (uMSCs) could aid in skeletal muscle healing and putative molecular mechanisms. We established a skeletal muscle ischemic injury model by injection of a myotoxin bupivacaine (BPVC) into gastrocnemius muscle of C57BL/6 mice. Throughout the angiogenic and fibrotic phases of muscle healing, miR-29a was considerably downregulated in BPVC-injured gastrocnemius muscle. Overexpressed miR-29a efficaciously promoted human umbilical vein endothelial cells proliferation and capillary-like tube formation in vitro, crucial steps for neoangiogenesis, whereas knockdown of miR-29a notably suppressed those endothelial functions. Remarkably, overexpressed miR-29a profitably elicited limbic flow perfusion and estimated by Laser Dopple. MicroRNA-29a motivated perfusion recovery through abolishing the tissue inhibitor of metalloproteinase (TIMP)-2, led great numbers of pro-angiogenic matrix metalloproteinases (MMPs) to be liberated from bondage of TIMP, thus reinforced vascular development. Furthermore, engrafted uMSCs also illustrated comparable effect to restore the flow perfusion and augmented vascular endothelial growth factors-A, -B, and -C expression. Notably, the combination of miR29a and the uMSCs treatments revealed the utmost renovation of limbic flow perfusion. Amplified miR-29a also adequately diminished the collagen deposition and suppressed broad-wide miR-29a targeted extracellular matrix components expression. Consistently, miR-29a administration intensified the relevance of uMSCs to abridge BPVC-aggravated fibrosis. Our data support that miR-29a is a promising pro-angiogenic and anti-fibrotic microRNA which delivers numerous advantages to endorse angiogenesis, perfusion recovery, and protect against fibrosis post injury. Amalgamation of nucleic acid-based strategy (miR-29a) together with the stem cell-based strategy (uMSCs) may be an innovative and eminent strategy to accelerate the healing process post skeletal muscle injury.
Highlights
Skeletal muscle repair post injury comprises a complex and well-coordinated regenerative response and involves phases of degeneration and inflammation, angiogenesis and vascularization, regeneration of myofibers, as well as the formation of connective scar tissue [1,2]
We recenly demonstrated that employing human umbilical cord mesenchymal stem cells is an aid to suppress the early-onset of inflammation by restraining the neutrophils
BPVC were injected into the left hind (LH) limb gastrocnemius muscles of C57BL/6 mice to induce ischemic muscle injury (BPVC group)
Summary
Skeletal muscle repair post injury comprises a complex and well-coordinated regenerative response and involves phases of degeneration and inflammation, angiogenesis and vascularization, regeneration of myofibers, as well as the formation of connective scar tissue [1,2]. Proliferating and differentiating satellite cells stimulate endothelial cells proliferation and migration joins together to form the new blood vessels and endorse the microvascular fragments to establish the new capillary sprouts to sustain the muscle homeostasis or regeneration of muscle post injury [5,15]. These evidences support that successful muscle regeneration depends on reinstallation of the vascular network. We recenly demonstrated that employing human umbilical cord mesenchymal stem cells (uMSCs) is an aid to suppress the early-onset of inflammation by restraining the neutrophils
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