MicroRNA-29a Exhibited Pro-Angiogenic and Anti-Fibrotic Features to Intensify Human Umbilical Cord Mesenchymal Stem Cells—Renovated Perfusion Recovery and Preventing against Fibrosis from Skeletal Muscle Ischemic Injury

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.

miRNA-Guided Regulation of Mesenchymal Stem Cells Derived from the Umbilical Cord: Paving the Way for Stem-Cell Based Regeneration and Therapy

“…Transplantation of UCMSC-exosomes, specifically enhanced with silk fibroin hydrogel and carrying miR-675, was also proposed as a novel strategy for the treatment of vascular disease, with miR-675 significantly inhibiting the aging-related vascular dysfunction and promoting blood perfusion in an ischemic hindlimb mouse model [124]. Similar results were reported in the case of skeletal muscle ischemic injury, since combined treatment with WJMSCs and miR-29a has shown a particularly efficient therapeutic potential by greatly enhancing the angiogenetic potential of vein endothelial cells and reversing the impaired blood perfusion in the hindlimb of BPVC-injured mice [85]. Treatment of co-cultured UCMSCs and endothelial colony-forming cells (ECFCs) with hyaluronic acid was shown to cause significant downregulation of miR-139-5p through CD44 activation in order to facilitate the blood flow in the tissues of ischemic hindlimb rats as well as to enhance their angiogenetic properties [100].…”

Obesity affects mitochondrial metabolism and proliferative potential of equine endometrial progenitor cells

“…Those molecules are not only essential regulators of the self-renewal potential of MSCs, but they also promote the wound healing capacity of tissues [68]. Furthermore, miR-29a promotes angiogenesis and protects against fibrosis post-injury, regulating biological activity of MMPs and vascular endothelial growth factors (VEGFs) [69]. Down-regulation of miR-20a-5p and miR-133b-3p are observed in mesenchymal stem cells as a result of oxidative stress damage [70,71].…”

Research progress and prospects of benefit-risk assessment methods for umbilical cord mesenchymal stem cell transplantation in the clinical treatment of spinal cord injury

“…Antifibrotic activity: hUMSCs stimulate the apoptosis of fibrosis-related cells and the secretion of cytokines with antifibrotic functions to reduce the degree of tissue fibrosis. At the same time, the antifibrotic effect of hUMSCs can also be achieved by regulating relevant signalling pathways and promoting vascular remodelling [ 5 , 20 – 24 ]. Paracrine effects: hUMSCs can secrete soluble molecules such as keratinocyte growth factor (KGF), fibroblast growth factor (FGF), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF) and other cytokines to promote tissue regeneration [ 6 , 25 – 28 ].…”