scholarly journals Adipose-Derived Stem Cells Alleviate Radiation-Induced Muscular Fibrosis by Suppressing the Expression of TGF-β1

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Wei Sun ◽  
Xinchu Ni ◽  
Suping Sun ◽  
Leiming Cai ◽  
Jingping Yu ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Stem Cells ◽  
Transforming Growth Factor ◽  
Adipose Derived Stem Cells ◽  
Peripheral Tissues ◽  
Muscle Fibrosis ◽  
Muscle Tissues ◽  
Radiation Induced ◽  
Skeletal Muscle Fibrosis ◽  
Tgf Β1

We aim to investigate the effects of adipose-derived stem cells (ASCs) transplantation on irradiation-induced skeletal muscle fibrosis. Sixty-four rabbits were randomly divided into ASCs group and PBS group followed by irradiation at unilateral hip with a single dose of 80 Gy. Nonirradiated side with normal skeletal muscle served as normal control. Skeletal muscle tissues were collected from eight rabbits in each group at 1 w, 4 w, 8 w, and 26 w after irradiation. Migration of ASCs was observed in the peripheral tissues along the needle passage in the injured muscle. The proportion of the area of collagen fibers to the total area in sections of ASCs group was lower than those of PBS groups at 4 w, 8 w, and 26 w after irradiation. Significant decrease was noted in the integrated optimal density of the transforming growth factorβ1 (TGF-β1) in the ASCs group compared with those of PBS group at 4 w, 8 w, and 26 w after irradiation. Moreover, the expression of TGF-β1 was lower in the ASCs group compared to those of the PBS group at each time point determined by Western blot analysis. ASCs transplantation could alleviate irradiation fibrosis by suppressing the level of TGF-β1 in the irradiated skeletal muscle.

scholarly journals Anti-Fibrotic Effect of Human Wharton’s Jelly-Derived Mesenchymal Stem Cells on Skeletal Muscle Cells, Mediated by Secretion of MMP-1

2020 ◽  
Vol 21 (17) ◽  
pp. 6269
Author(s):  
Alee Choi ◽  
Sang Eon Park ◽  
Jang Bin Jeong ◽  
Suk-joo Choi ◽  
Soo-young Oh ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Wharton’S Jelly ◽  
Mdx Mice ◽  
Therapeutic Effects ◽  
Paracrine Factors ◽  
Wharton's Jelly ◽  
Muscle Fibrosis ◽  
Skeletal Muscle Fibrosis

Extracellular matrix (ECM) components play an important role in maintaining skeletal muscle function, but excessive accumulation of ECM components interferes with skeletal muscle regeneration after injury, eventually inducing fibrosis. Increased oxidative stress level caused by dystrophin deficiency is a key factor in fibrosis in Duchenne muscular dystrophy (DMD) patients. Mesenchymal stem cells (MSCs) are considered a promising therapeutic agent for various diseases involving fibrosis. In particular, the paracrine factors secreted by MSCs play an important role in the therapeutic effects of MSCs. In this study, we investigated the effects of MSCs on skeletal muscle fibrosis. In 2–5-month-old mdx mice intravenously injected with 1 × 105 Wharton’s jelly (WJ)-derived MSCs (WJ-MSCs), fibrosis intensity and accumulation of calcium/necrotic fibers were significantly decreased. To elucidate the mechanism of this effect, we verified the effect of WJ-MSCs in a hydrogen peroxide-induced fibrosis myotubes model. In addition, we demonstrated that matrix metalloproteinase-1 (MMP-1), a paracrine factor, is critical for this anti-fibrotic effect of WJ-MSCs. These findings demonstrate that WJ-MSCs exert anti-fibrotic effects against skeletal muscle fibrosis, primarily via MMP-1, indicating a novel target for the treatment of muscle diseases, such as DMD.

scholarly journals The Combination of Electroacupuncture and Massage Therapy Alleviates Myofibroblast Transdifferentiation and Extracellular Matrix Production in Blunt Trauma-Induced Skeletal Muscle Fibrosis

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Na Zhao ◽  
Bo Liu ◽  
Si-Wen Liu ◽  
Wei Zhang ◽  
Hua-Nan Li ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Extracellular Matrix ◽  
Growth Factor ◽  
Blunt Trauma ◽  
Massage Therapy ◽  
Muscle Fibrosis ◽  
Extracellular Matrix Production ◽  
Matrix Production ◽  
Skeletal Muscle Fibrosis ◽  
Tgf Β1

Complementary therapies, such as acupuncture and massage, had been previously reported to have therapeutic effects on skeletal muscle contusions. However, the recovery mechanisms on skeletal muscles after blunt trauma via the combination of electroacupuncture (EA) and massage therapy remain unclear. In the present study, a rat model of the skeletal muscle fibrosis following blunt trauma to rat skeletal muscle was established, and the potential molecular mechanisms of EA + massage therapy on the skeletal muscle fibrosis were investigated. The results suggested that EA + massage therapy could significantly decrease inflammatory cells infiltration and collagenous fiber content and ameliorate the disarrangement of sarcomeres within myofibrils compared to the model group. Further analysis revealed that EA + massage therapy could reduce the degree of fibrosis and increase the degree of myofibroblast apoptosis by downregulating the mRNA and protein expression of transforming growth factor- (TGF-) β1 and connective tissue growth factor (CTGF). Furthermore, the fibrosis of injured skeletal muscle was inhibited after treatment through the normalization of balance between matrix metalloproteinase- (MMP-) 1 and tissue inhibitor of matrix metalloproteinase (TIMP). These findings suggested that the combination of electroacupuncture and massage therapy could alleviate the fibrotic process by regulating TGF β1-CTGF-induced myofibroblast transdifferentiation and MMP-1/TIMP-1 balance for extracellular matrix production.

scholarly journals Cellular Mechanisms of Tissue Fibrosis. 4. Structural and functional consequences of skeletal muscle fibrosis

2013 ◽  
Vol 305 (3) ◽  
pp. C241-C252 ◽  
Author(s):  
Richard L. Lieber ◽  
Samuel R. Ward
Keyword(s):  
Skeletal Muscle ◽  
Structural Model ◽  
Transforming Growth Factor ◽  
Clinical Problem ◽  
Transforming Growth Factor Β ◽  
Common Mechanism ◽  
Cellular Mechanisms ◽  
Muscle Fibrosis ◽  
Activated Fibroblasts ◽  
Skeletal Muscle Fibrosis

Skeletal muscle fibrosis can be a devastating clinical problem that arises from many causes, including primary skeletal muscle tissue diseases, as seen in the muscular dystrophies, or it can be secondary to events that include trauma to muscle or brain injury. The cellular source of activated fibroblasts (myofibroblasts) may include resident fibroblasts, adult muscle stem cells, or inflammatory or perivascular cells, depending on the model studied. Even though it is likely that there is no single source for all myofibroblasts, a common mechanism for the production of fibrosis is via the transforming growth factor-β/phosphorylated Smad3 pathway. This pathway and its downstream targets thus provide loci for antifibrotic therapies, as do methods for blocking the transdifferentiation of progenitors into activated fibroblasts. A structural model for the extracellular collagen network of skeletal muscle is needed so that measurements of collagen content, morphology, and gene expression can be related to mechanical properties. Approaches used to study fibrosis in tissues, such as lung, kidney, and liver, need to be applied to studies of skeletal muscle to identify ways to prevent or even cure the devastating maladies of skeletal muscle.

scholarly journals Human Umbilical Cord Mesenchymal Stem Cells Extricate Bupivacaine-Impaired Skeletal Muscle Function via Mitigating Neutrophil-Mediated Acute Inflammation and Protecting against Fibrosis

2019 ◽  
Vol 20 (17) ◽  
pp. 4312 ◽  
Author(s):  
Wen-Hong Su ◽  
Ching-Jen Wang ◽  
Hung-Chun Fu ◽  
Chien-Ming Sheng ◽  
Ching-Chin Tsai ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Growth Factor ◽  
Umbilical Cord ◽  
Muscle Injury ◽  
Acute Inflammation ◽  
Transforming Growth Factor ◽  
Skeletal Muscle Injury ◽  
Tgf Β1

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.

scholarly journals PO-232 The Regulation of Vimentin in Skeletal Muscle Fibrosis Affected by High-load Exercise

2018 ◽  
Vol 1 (5) ◽  
Author(s):  
Xiaoran Liu
Keyword(s):  
Skeletal Muscle ◽  
Connective Tissue ◽  
Muscle Fiber ◽  
Tissue Growth ◽  
High Load ◽  
Control Group ◽  
Vimentin Expression ◽  
Muscle Fibrosis ◽  
Skeletal Muscle Fibrosis ◽  
Tgf Β1

Objective Long-term movement could induce micro-damage of skeletal muscle, increase collagen significantly, and appear skeletal muscle fibrosis. Vimentin is one of the most important proteins in evaluating the fibrosis after muscle injury. TGF-β1 could up-regulate Vimentin expression, promoting cell migration and accelerating fibrosis and injury repair. This study mainly explored the role of TGF-β1/Vim in skeletal muscle fibrosis affected by a bout of high-load exercise. And we tried to find whether the expression of vimentin could regulate the regeneration of muscle fiber and the remodeling of connective tissue. Methods SD rats were divided into 7groups: control group, immediately, 6-hour, 12-hour, 24-hour, 48-hour and 72-hour after group. Western Blot was used to detect TGF-β1, vimentin, RhoA, ROCK1 and CTGF(connective tissue growth factor) expressions. Electron microscopy was used to observe the changes of collagen in skeletal muscle. Results Vimentin protein exprsssion increased quickly at 6-hour after exerciese. At 48-hour, the vimentin expression reached the peak. And then the expression of vimentin gradually decreased. The expressions of TGF-β1, RhoA, ROCK1 and CTGF gradually increased after exercise. The peak of these expressions appeared at 12-hour respectively. Then these protein expressions declined slowly. Collagen in skeletal muscle became long and thick in 48-hour and 72-hour after exercise. Conclusions A bout of high-load exercise could induce skeletal muscle fibrosis. RhoA-ROCK1 maybe affect TGF-β1/Vim expressions as main regulators, and then the protein expression vimentin could regulate the regeneration of muscle fiber and the remodeling of connective tissue as an important evaluation factor.  

scholarly journals Role of Transforming Growth Factor-β in Skeletal Muscle Fibrosis: A Review

2019 ◽  
Vol 20 (10) ◽  
pp. 2446 ◽  
Author(s):  
Ahmed Ismaeel ◽  
Jeong-Su Kim ◽  
Jeffrey S. Kirk ◽  
Robert S. Smith ◽  
William T. Bohannon ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Muscle Fibrosis ◽  
Cellular Processes ◽  
Targeted Treatments ◽  
Skeletal Muscle Fibrosis

Transforming growth factor-beta (TGF-β) isoforms are cytokines involved in a variety of cellular processes, including myofiber repair and regulation of connective tissue formation. Activation of the TGF-β pathway contributes to pathologic fibrosis in most organs. Here, we have focused on examining the evidence demonstrating the involvement of TGF-β in the fibrosis of skeletal muscle particularly. The TGF-β pathway plays a role in different skeletal muscle myopathies, and TGF-β signaling is highly induced in these diseases. In this review, we discuss different molecular mechanisms of TGF-β-mediated skeletal muscle fibrosis and highlight different TGF-β-targeted treatments that target these relevant pathways.

scholarly journals A High-Fat Diet Promotes Mammary Gland Myofibroblast Differentiation through MicroRNA 140 Downregulation

2016 ◽  
Vol 37 (4) ◽  
Author(s):  
Benjamin Wolfson ◽  
Yongshu Zhang ◽  
Ramkishore Gernapudi ◽  
Nadire Duru ◽  
Yuan Yao ◽  
...  
Keyword(s):  
Stem Cells ◽  
Adipose Tissue ◽  
High Fat Diet ◽  
Transforming Growth Factor ◽  
Early Stage ◽  
Myofibroblast Differentiation ◽  
Adipose Derived Stem Cells ◽  
High Fat ◽  
Breast Adipose Tissue ◽  
Tgf Β1

ABSTRACT Human breast adipose tissue is a heterogeneous cell population consisting of mature white adipocytes, multipotent mesenchymal stem cells, committed progenitor cells, fibroblasts, endothelial cells, and immune cells. Dependent on external stimulation, adipose-derived stem cells differentiate along diverse lineages into adipocytes, chondrocytes, osteoblasts, fibroblasts, and myofibroblasts. It is currently not fully understood how a high-fat diet reprograms adipose-derived stem cells into myofibroblasts. In our study, we used mouse models of a regular diet and of high-fat-diet-induced obesity to investigate the role of dietary fat on myofibroblast differentiation in the mammary stromal microenvironment. We found that a high-fat diet promotes myofibroblast differentiation by decreasing microRNA 140 (miR-140) expression in mammary adipose tissue through a novel negative-feedback loop. Increased transforming growth factor β1 (TGF-β1) in mammary adipose tissue in obese mice activates SMAD3 signaling, causing phospho-SMAD3 to bind to the miR-140 locus and inhibit miR-140 transcription. This prevents miR-140 from targeting SMAD3 for degradation, resulting in amplified TGF-β1/SMAD3 signaling and miR-140 downregulation-dependent myofibroblast differentiation. Using tissue and coculture models, we found that myofibroblasts and the fibrotic microenvironment created by myofibroblasts impact the stemness and proliferation of normal ductal epithelial cells and early-stage breast cancer invasion and stemness.

scholarly journals Tenotomy immobilization as a model to investigate skeletal muscle fibrosis (with emphasis on Secreted frizzled-related protein 2)

2016 ◽  
Vol 48 (6) ◽  
pp. 397-408 ◽  
Author(s):  
Uğur Akpulat ◽  
İlyas Onbaşılar ◽  
Y. Çetin Kocaefe
Keyword(s):  
Skeletal Muscle ◽  
Extracellular Matrix ◽  
Transforming Growth Factor ◽  
Fatty Infiltration ◽  
Muscle Fibrosis ◽  
Clear Cut ◽  
Extracellular Matrix Components ◽  
Transcriptional Changes ◽  
Slow Twitch Fibers ◽  
Skeletal Muscle Fibrosis

The pathological endpoint of congenital and senile myopathies is chronic muscle degeneration characterized by the atrophy of contractile elements, accompanied by fibrosis and fatty infiltration of the interstitium. Tenotomy is the release of preload that causes abrupt shortening of the muscle and models atrophy and fibrosis without prominent inflammatory response. Fibrosis in the skeletal muscle is known to be triggered by transforming growth factor (TGF)-β, which is activated by inflammatory events. As these were lacking, tenotomy provided an opportunity to investigate transcriptional events on a background without inflammation. An unbiased look at the transcriptome of tenotomy-immobilized soleus muscle revealed that the majority of the transcriptional changes took place in the first 4 wk. Regarding atrophy, proteasomal and lysosomal pathways were actively involved in accompanying cathepsins and calpains in the breakdown of the macromolecular contractile machinery. The transcriptome provided clear-cut evidence for the upregulation of collagens and several extracellular matrix components that define fibrotic remodeling of the skeletal muscle architecture as well as activation of the fibro-adipogenic precursors. Concomitantly, Sfrp2, a Wnt antagonist as well as a procollagen processor, accompanied fibrosis in skeletal muscle with an expression that was stringently confined to the slow-twitch fibers. An interpreted mechanistic scenario construed the kinetic events initiated through the abnormal shortening of the muscle fibers as enough to trigger the resident latent TGF-β in the extracellular matrix, leading to the activation of fibroadipogenic precursors. As in the heart, Sfrp2 shows itself to be a therapeutic target for the prevention of irreversible fibrosis in degenerative skeletal muscle conditions.

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