scholarly journals Dynamics of skeletal muscle-resident stem cells during myogenesis in fibrodysplasia ossificans progressiva

2022 ◽  
Vol 7 (1) ◽  
Author(s):  
Alexandra Stanley ◽  
Elisia D. Tichy ◽  
Jacob Kocan ◽  
Douglas W. Roberts ◽  
Eileen M. Shore ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Stem Cells ◽  
Skeletal Muscles ◽  
Skeletal Muscle Regeneration ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Type I ◽  
Heterotopic Bone ◽  
Differentiation Potential ◽  
Resident Stem Cells

AbstractFibrodysplasia ossificans progressiva (FOP) is a rare genetic disease in which extraskeletal (heterotopic) bone forms within tissues such as skeletal muscles, often in response to injury. Mutations in the BMP type I receptor ACVR1/ALK2 cause FOP by increasing BMP pathway signaling. In contrast to the growing understanding of the inappropriate formation of bone tissue within the muscle in FOP, much is still unknown about the regenerative capacity of adult diseased muscles. Utilizing an inducible ACVR1R206H knock-in mouse, we found that injured Acvr1R206H/+ skeletal muscle tissue regenerates poorly. We demonstrated that while two resident stem cell populations, muscle stem cells (MuSCs) and fibro/adipogenic progenitors (FAPs), have similar proliferation rates after injury, the differentiation potential of mutant MuSCs is compromised. Although MuSC-specific deletion of the ACVR1R206H mutation does not alter the regenerative potential of skeletal muscles in vivo, Acvr1R206H/+ MuSCs form underdeveloped fibers that fail to fuse in vitro. We further determined that FAPs from Acvr1R206H/+ mice repress the MuSC-mediated formation of Acvr1R206H/+ myotubes in vitro. These results identify a previously unrecognized role for ACVR1R206H in myogenesis in FOP, via improper interaction of tissue-resident stem cells during skeletal muscle regeneration.

scholarly journals Tenogenic Contribution to Skeletal Muscle Regeneration: The Secretome of Scleraxis Overexpressing Mesenchymal Stem Cells Enhances Myogenic Differentiation In Vitro

2020 ◽  
Vol 21 (6) ◽  
pp. 1965
Author(s):  
Maximilian Strenzke ◽  
Paolo Alberton ◽  
Attila Aszodi ◽  
Denitsa Docheva ◽  
Elisabeth Haas ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Regeneration ◽  
Skeletal Muscles ◽  
Myogenic Differentiation ◽  
Muscular Contraction ◽  
Myoblast Fusion ◽  
Skeletal Muscle Regeneration ◽  
Potential Candidate ◽  
Musculoskeletal Tissue

Integrity of the musculoskeletal system is essential for the transfer of muscular contraction force to the associated bones. Tendons and skeletal muscles intertwine, but on a cellular level, the myotendinous junctions (MTJs) display a sharp transition zone with a highly specific molecular adaption. The function of MTJs could go beyond a mere structural role and might include homeostasis of this musculoskeletal tissue compound, thus also being involved in skeletal muscle regeneration. Repair processes recapitulate several developmental mechanisms, and as myotendinous interaction does occur already during development, MTJs could likewise contribute to muscle regeneration. Recent studies identified tendon-related, scleraxis-expressing cells that reside in close proximity to the MTJs and the muscle belly. As the muscle-specific function of these scleraxis positive cells is unknown, we compared the influence of two immortalized mesenchymal stem cell (MSC) lines—differing only by the overexpression of scleraxis—on myoblasts morphology, metabolism, migration, fusion, and alignment. Our results revealed a significant increase in myoblast fusion and metabolic activity when exposed to the secretome derived from scleraxis-overexpressing MSCs. However, we found no significant changes in myoblast migration and myofiber alignment. Further analysis of differentially expressed genes between native MSCs and scleraxis-overexpressing MSCs by RNA sequencing unraveled potential candidate genes, i.e., extracellular matrix (ECM) proteins, transmembrane receptors, or proteases that might enhance myoblast fusion. Our results suggest that musculotendinous interaction is essential for the development and healing of skeletal muscles.

Murine Osteochondral Stem Cells Express Collagen Type I More Strongly on PDMS Substrates Than on Tissue Culture Plastic

2013 ◽  
Author(s):  
William S. Van Dyke ◽  
Ozan Akkus ◽  
Eric Nauman
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Bone Cells ◽  
Stem Cell Differentiation ◽  
Collagen Type I ◽  
Fiber Formation ◽  
Substrate Stiffness ◽  
Type I ◽  
Differentiation Potential

The discovery of the multipotent lineage of mesenchymal stem cells has dawned a new age in tissue engineering, where an autologous cell-seeded scaffold can be implanted into different therapeutic sites. Mesenchymal stem cells have been reported to differentiate into numerous anchorage-dependent cell phenotypes, including neurons, adipocytes, myoblasts, chondrocytes, tenocytes, and osteoblasts. A seminal work detailing that mesenchymal stem cells can be directed towards differentiation of different cell types by substrate stiffness alone [1] has led to numerous studies attempting to understand how cells can sense the stiffness of their substrate [2–3] Substrate stiffness has been shown to be an inducer of stem cell differentiation. MSCs on extremely soft substrates (250 Pa), similar to the stiffness of bone marrow, became quiescent but still retained their multipotency [4]. Elastic substrates in the stiffness range of 34 kPa revealed MSCs with osteoblast morphology, and osteocalcin along with other osteoblast markers were expressed [1]. However, osteogenesis has been found to increase on much stiffer (20–80 kPa) [5–6] (400 kPa) [7] as well as much softer substrates (75 Pa) [8]. Overall, cells have increased projected cell area and proliferation on stiffer substrates, leading to higher stress fiber formation. This study seeks to understand if the stiffness of the substrate has any effect on the differentiation potential of osteochondral progenitor cells into bone cells, using an in vitro dual fluorescent mouse model.

scholarly journals In Vivo Activation of STAT3 Signaling in Satellite Cells and Myofibers in Regenerating Rat Skeletal Muscles

2002 ◽  
Vol 50 (12) ◽  
pp. 1579-1589 ◽  
Author(s):  
Katsuya Kami ◽  
Emiko Senba
Keyword(s):  
Skeletal Muscle ◽  
Satellite Cells ◽  
Muscle Regeneration ◽  
Intracellular Signaling ◽  
Skeletal Muscles ◽  
Early Stage ◽  
Skeletal Muscle Regeneration ◽  
Stat3 Signaling

Although growth factors and cytokines play critical roles in skeletal muscle regeneration, intracellular signaling molecules that are activated by these factors in regenerating muscles have been not elucidated. Several lines of evidence suggest that leukemia inhibitory factor (LIF) is an important cytokine for the proliferation and survival of myoblasts in vitro and acceleration of skeletal muscle regeneration. To elucidate the role of LIF signaling in regenerative responses of skeletal muscles, we examined the spatial and temporal activation patterns of an LIF-associated signaling molecule, the signal transducer and activator transcription 3 (STAT3) proteins in regenerating rat skeletal muscles induced by crush injury. At the early stage of regeneration, activated STAT3 proteins were first detected in the nuclei of activated satellite cells and then continued to be activated in proliferating myoblasts expressing both PCNA and MyoD proteins. When muscle regeneration progressed, STAT3 signaling was no longer activated in differentiated myoblasts and myotubes. In addition, activation of STAT3 was also detected in myonuclei within intact sarcolemmas of surviving myofibers that did not show signs of necrosis. These findings suggest that activation of STAT3 signaling is an important molecular event that induces the successful regeneration of injured skeletal muscles.

scholarly journals Modulation of HOXA9 after skeletal muscle denervation and reinnervation

2020 ◽  
Vol 318 (6) ◽  
pp. C1154-C1165
Author(s):  
Xiaomei Lu ◽  
Bingsheng Liang ◽  
Shuaijie Li ◽  
Zhi Chen ◽  
Wenkai Chang
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Satellite Cells ◽  
Myogenic Differentiation ◽  
Cell Activity ◽  
Skeletal Muscle Regeneration ◽  
Sham Operation ◽  
Denervated Muscle ◽  
Differentiation Potential

Homeobox A9 (HOXA9), the expression of which is promoted by mixed lineage leukemia 1 (MLL1) and WD-40 repeat protein 5 (WDR5), is a homeodomain-containing transcription factor that plays an essential role in regulating stem cell activity. HOXA9 has been found to inhibit skeletal muscle regeneration and delay recovery after muscle wounding in aged mice, but little is known about its role in denervated/reinnervated muscles. We performed detailed time-dependent expression analyses of HOXA9 and its promoters, MLL1 and WDR5, in rat gastrocnemius muscles after the following three types of sciatic nerve surgeries: nerve transection (denervation), end-to-end repair (repair), and sham operation (sham). Then, the specific mechanisms of HOXA9 were detected in vitro by transfecting primary satellite cells with empty pIRES2-DsRed2, pIRES2-DsRed2-HOXA9, empty pPLK/GFP-Puro, and pPLK/GFP-Puro-HOXA9 small hairpin RNA (shRNA) plasmids. We found, for the first time, that HOXA9 protein expression simultaneously increased with increasing denervated muscle atrophy severity and that upregulated MLL1 and WDR5 expression was partly associated with denervation. Indeed, in vitro experiments revealed that HOXA9 inhibited myogenic differentiation, affected the best known atrophic signaling pathways, and promoted apoptosis but did not eliminate the differentiation potential of primary satellite cells. HOXA9 may promote denervated muscle atrophy by regulating the activity of satellite cells.

The unique activity of bone morphogenetic proteins in bone: a critical role of the Smad signaling pathway

2013 ◽  
Vol 394 (6) ◽  
pp. 703-714 ◽  
Author(s):  
Takenobu Katagiri ◽  
Sho Tsukamoto
Keyword(s):  
Skeletal Muscle ◽  
Transcription Factors ◽  
Bone Formation ◽  
Bone Morphogenetic Proteins ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Type I ◽  
Heterotopic Bone ◽  
Heterotopic Bone Formation ◽  
Smad Signaling ◽  
Smad Signaling Pathway

Abstract Bone morphogenetic proteins (BMPs) are multifunctional cytokines that belong to the transforming growth factor-β family. BMPs were originally identified based on their unique activity, inducing heterotopic bone formation in skeletal muscle. This unique BMP activity is transduced by specific type I and type II transmembrane kinase receptors. Among the downstream pathways activated by these receptors, the Smad1/5/8 transcription factors appear to play critical roles in BMP activity. Smad1/5/8 transcription factors are phosphorylated at the C-terminal SVS motif by BMP type I receptors and then induce the transcription of early BMP-responsive genes by binding to conserved sequences in their enhancer regions. The linker regions of Smad1/5/8 contain multiple kinase phosphorylation sites, and phosphorylation and dephosphorylation of these sites regulate the transcriptional activity of Smad proteins. Gain-of-function mutations in one BMP type I receptor have been identified in patients with fibrodysplasia ossificans progressiva, a rare genetic disorder that is characterized by progressive heterotopic bone formation in the skeletal muscle. The mutant receptors activate the Smad signaling pathway even in the absence of BMPs, therefore novel inhibitors for the BMP receptor – Smad axis are being developed to prevent heterotopic bone formation in fibrodysplasia ossificans progressiva. Taken together, the data in the literature show that the BMP type I receptor – Smad signaling axis is the critical pathway for the unique activity of BMPs and is a potential therapeutic target for pathological conditions caused by inappropriate BMP activity.

scholarly journals DLL4 and PDGF-BB regulate migration of human iPSC-derived skeletal myogenic progenitors

2021 ◽  
Author(s):  
Giulia Ferrari ◽  
SungWoo Choi ◽  
Louise Anne Moyle ◽  
Kirsty Mackinlay ◽  
Naira Naouar ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Stem Cells ◽  
Cell Migration ◽  
Negative Impact ◽  
Muscle Growth ◽  
Differentiation Potential ◽  
Cell Therapies ◽  
Muscle Gene

Muscle satellite stem cells (MuSCs) are responsible for skeletal muscle growth and regeneration. Despite their differentiation potential, human MuSCs have limited in vitro amplification and in vivo migration capacity, limiting their use in cell therapies for diseases affecting multiple skeletal muscle groups such as muscular dystrophies. Several protocols have been established to derive progenitor cells similar to MuSCs from human induced pluripotent stem cells (hiPSCs), in order to establish a source of myogenic cells with controllable proliferation and differentiation capacity. However, currently available hiPSC myogenic derivatives also suffer from limitations of cell migration, ultimately delaying their clinical translation. Here we provide evidence that activation of NOTCH and PDGF pathways with DLL4 and PDGF-BB improves migration of hiPSC-derived myogenic progenitors in vitro. Transcriptomic and functional analyses demonstrate that this property is conserved across species and multiple hiPSC lines, including genetically-corrected hiPSC derivatives from a patient with Duchenne muscular dystrophy. DLL4 and PDGF-BB treatment had no negative impact on cell proliferation; cells maintained their myogenic memory, with differentiation fully rescued by NOTCH inhibition. RNAseq analysis indicate that pathways involved in cell migration are modulated in treated myogenic progenitors, consistent with results from functional profiling of cell motility at single cell resolution. Notably, treated cells also showed enhanced trans-endothelial migration in transwell assays. Enhancing extravasation is a key translational milestone for intravascular delivery of hiPSC myogenic derivatives: our study establishes the foundations of a transgene-free, developmentally inspired strategy to achieve this goal, moving hiPSCs one step closer to future muscle gene and cell therapies.

scholarly journals Myogenic specification of side population cells in skeletal muscle

2002 ◽  
Vol 159 (1) ◽  
pp. 123-134 ◽  
Author(s):  
Atsushi Asakura ◽  
Patrick Seale ◽  
Adele Girgis-Gabardo ◽  
Michael A. Rudnicki
Keyword(s):  
Skeletal Muscle ◽  
Stem Cells ◽  
Satellite Cell ◽  
Satellite Cells ◽  
Essential Gene ◽  
Side Population ◽  
Stem Cell Marker ◽  
Differentiation Potential ◽  
Hematopoietic Stem

Skeletal muscle contains myogenic progenitors called satellite cells and muscle-derived stem cells that have been suggested to be pluripotent. We further investigated the differentiation potential of muscle-derived stem cells and satellite cells to elucidate relationships between these two populations of cells. FACS® analysis of muscle side population (SP) cells, a fraction of muscle-derived stem cells, revealed expression of hematopoietic stem cell marker Sca-1 but did not reveal expression of any satellite cell markers. Muscle SP cells were greatly enriched for cells competent to form hematopoietic colonies. Moreover, muscle SP cells with hematopoietic potential were CD45 positive. However, muscle SP cells did not differentiate into myocytes in vitro. By contrast, satellite cells gave rise to myocytes but did not express Sca-1 or CD45 and never formed hematopoietic colonies. Importantly, muscle SP cells exhibited the potential to give rise to both myocytes and satellite cells after intramuscular transplantation. In addition, muscle SP cells underwent myogenic specification after co-culture with myoblasts. Co-culture with myoblasts or forced expression of MyoD also induced muscle differentiation of muscle SP cells prepared from mice lacking Pax7 gene, an essential gene for satellite cell development. Therefore, these data document that satellite cells and muscle-derived stem cells represent distinct populations and demonstrate that muscle-derived stem cells have the potential to give rise to myogenic cells via a myocyte-mediated inductive interaction.

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