Abstract
Skeletal muscle injury presents a challenging traumatological dilemma, and current therapeutic options remain mediocre. This study was designed to delineate if engraftment of mesenchymal stem cells derived from umbilical cord Wharton’s jelly (uMSCs) could aid in skeletal muscle healing and persuasive molecular mechanisms. We established a skeletal muscle injury model by injection of myotoxin bupivacaine (BPVC) into quadriceps muscles of C57BL/6 mice. Post BPVC injection, neutrophils, the first host defensive line, rapidly invaded injured muscle and induced acute inflammation. Engrafted uMSCs effectively abolished neutrophil infiltration and activation, and diminished neutrophil chemotaxis, including Complement component 5a (C5a), Keratinocyte chemoattractant (KC), Macrophage inflammatory protein (MIP)-2, LPS-induced CXC chemokine (LIX), Fractalkine, Leukotriene B4 (LTB4), and Interferon-γ, as determined using a Quantibody Mouse Cytokine Array assay. Subsequently, uMSCs noticeably prevented BPVC-accelerated collagen deposition and fibrosis, measured by Masson’s trichrome staining. Remarkably, uMSCs attenuated BPVC-induced Transforming growth factor (TGF)-β1 expression, a master regulator of fibrosis. Engrafted uMSCs attenuated TGF-β1 transmitting through interrupting the canonical Sma- And Mad-Related Protein (Smad)2/3 dependent pathway and noncanonical Smad-independent Transforming growth factor beta-activated kinase (TAK)-1/p38 mitogen-activated protein kinases signaling. The uMSCs abrogated TGF-β1-induced fibrosis by reducing extracellular matrix components including fibronectin-1, collagen (COL) 1A1, and COL10A1. Most importantly, uMSCs modestly extricated BPVC-impaired gait functions, determined using CatWalk™ XT gait analysis. This work provides several innovative insights into and molecular bases for employing uMSCs to execute therapeutic potential through the elimination of neutrophil-mediated acute inflammation toward protecting against fibrosis, thereby rescuing functional impairments post injury.
Highlights
Musculoskeletal disorders and diseases are the leading causes of physical disabilities [1]
We previously demonstrated that mesenchymal stem cells (MSCs) are present in human umbilical cord blood (HUCB) and that they can differentiate into bone nodules in vitro, as well as into bony callus when transplanted in the femoral segment of a mice model [17]
We report a study designed to elucidate if the transplantation of MSCs derived from umbilical cord Wharton’s jelly has regulatory properties on the skeletal muscle healing process, especially through restriction of neutrophil-derived acute inflammation toward protecting against fibrosis, restoring functional impairment post muscle injury
Summary
Musculoskeletal disorders and diseases are the leading causes of physical disabilities [1]. Skeletal muscle has a good regenerative capacity; extensive muscle injury, such as that instigated by trauma associated with a loss of healthy muscular tissues or development of fibrous scar tissue, might prevent complete regeneration, in terms of functional recovery [2]. This highlights the need to comprehensively understand how pathologic muscle processes occur, with a focus on delineating therapeutic interventions to facilitate muscle healing along with improving the extent of functional recovery post injury. The development of molecular signaling-based strategies that can block individual trophic factors [10,11] These strategies either did not elicit the desired response or failed to completely restore the impaired function in response to muscle injury
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