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MicroRNA-29a Exhibited Pro-Angiogenic and Anti-Fibrotic Features to Intensify Human Umbilical Cord Mesenchymal Stem
Wen-Hong Su1,2, Ching-Jen Wang3,4, Yi-Yung Hung5
1Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan.
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.
Insights
microRNA-29a (miR-29a) promotes skeletal muscle healing by enhancing blood vessel formation and reducing fibrosis. Combining miR-29a with umbilical cord-derived mesenchymal stem cells (uMSCs) offers a potent therapeutic strategy for muscle injury recovery.
Area of Science:
- Regenerative Medicine
- Molecular Biology
- Biomedical Engineering
Background:
- Skeletal muscle injuries often involve impaired healing, angiogenesis, and fibrosis.
- microRNA-29a (miR-29a) dysregulation is observed during muscle healing.
- Mesenchymal stem cells (MSCs) show potential in tissue repair.
Purpose of the Study:
- To investigate the role of miR-29a in skeletal muscle healing.
- To evaluate the therapeutic potential of miR-29a and/or umbilical cord-derived mesenchymal stem cells (uMSCs) in a mouse model of muscle injury.
- To elucidate the molecular mechanisms underlying miR-29a's effects on angiogenesis and fibrosis.
Main Methods:
- Established a bupivacaine-induced skeletal muscle ischemic injury model in C57BL/6 mice.
- Assessed miR-29a expression levels during muscle healing phases.
- Utilized in vitro assays to study endothelial cell proliferation and tube formation with miR-29a.
- Administered miR-29a mimics and/or uMSCs to injured mice.
- Quantified blood flow perfusion using Laser Doppler.
- Analyzed collagen deposition and expression of extracellular matrix components.
Main Results:
- miR-29a was downregulated in injured skeletal muscle.
- Overexpression of miR-29a promoted endothelial cell proliferation and angiogenesis in vitro.
- miR-29a administration improved blood flow perfusion by inhibiting TIMP-2 and releasing MMPs.
- Engrafted uMSCs also restored perfusion and increased VEGF expression.
- Combination therapy of miR-29a and uMSCs yielded the greatest improvement in perfusion.
- miR-29a reduced collagen deposition and suppressed fibrosis.
Conclusions:
- miR-29a acts as a pro-angiogenic and anti-fibrotic factor, enhancing skeletal muscle healing.
- uMSCs contribute to perfusion recovery and vascular repair.
- The combined strategy of miR-29a and uMSCs represents a promising approach for accelerating skeletal muscle regeneration post-injury.
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