Sca-1-Expressing Nonmyogenic Cells Contribute to Fibrosis in Aged Skeletal Muscle

Peripheral artery disease (PAD) currently affects approximately 27 million patients in Europe and North America, and if untreated, may progress to the stage of critical limb ischemia (CLI), which has implications for amputation and potential mortality. Unfortunately, few therapies exist for treating the ischemic skeletal muscle in these conditions. Biomaterials have been used to increase cell transplant survival as well as deliver growth factors to treat limb ischemia; however, existing materials do not mimic the native skeletal muscle microenvironment they are intended to treat. Furthermore, no therapies involving biomaterials alone have been examined. The goal of this study was to develop a clinically relevant injectable hydrogel derived from decellularized skeletal muscle extracellular matrix and examine its potential for treating PAD as a stand-alone therapy by studying the material in a rat hindlimb ischemia model. We tested the mitogenic activity of the scaffold's degradation products using an in vitro assay and measured increased proliferation rates of smooth muscle cells and skeletal myoblasts compared to collagen. In a rat hindlimb ischemia model, the femoral artery was ligated and resected, followed by injection of 150 µL of skeletal muscle matrix or collagen 1 week postinjury. We demonstrate that the skeletal muscle matrix increased arteriole and capillary density, as well as recruited more desmin-positive and MyoD-positive cells compared to collagen. Our results indicate that this tissue-specific injectable hydrogel may be a potential therapy for treating ischemia related to PAD, as well as have potential beneficial effects on restoring muscle mass that is typically lost in CLI.

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“…9). The MyoD staining was prevalently perinuclear, which has been shown in other studies (Hidestrand et al, 2008;Yamamoto et al, 2008).…”

Section: Ja Dequach Et Al Hydrogel For Treating Ischemic Skeletal Musupporting

confidence: 85%

Injectable skeletal muscle matrix hydrogel promotes neovascularization and muscle cell infiltration in a hindlimb ischemia model

DeQuach

Lin²,

Cam³

et al. 2012

eCM

141

159

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“…Other downstream target genes of Wnt2, such as fibronectin and ctgf, were also overexpressed, which may contribute to the stroma-rich appearance of some ERMS. 59 Expression of Wnt2 and other markers of fibrosis increases in aging normal myoblasts, which show impaired myogenic differentiation 33 potentially mediated through a noncanonical pathway.…”

Section: Discussionmentioning

confidence: 99%

“…Sequences of the primers are listed in Table 1. Two-step real-time RT-PCR was performed on the ABI PRISM 7700 Sequence Detection System by using random hexamers and the TaqMan Reverse Transcription Reagents, and the SYBR Green PCR Master Mix for the PCR step (Applied Biosystems) as described in Hidestrand et al 33 …”

Section: Sybr Green Real-time Rt-pcrmentioning

confidence: 99%

Impaired Wnt Signaling in Embryonal Rhabdomyosarcoma Cells from p53/c-fos Double Mutant Mice

Singh¹,

Vinson²,

Gurley³

et al. 2010

The American Journal of Pathology

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Rhabdomyosarcoma is a primitive neoplasm with a poorly understood etiology that exhibits features of fetal skeletal muscle. It represents the most frequent malignant soft tissue sarcoma affecting the pediatric population and is often treated very aggressively. Embryonal rhabdomyosarcoma (ERMS) and alveolar rhabdomyosarcoma constitute the two major subtypes and exhibit different molecular features. We investigated one potential molecular basis for ERMS by using cells derived from tumors produced in p53 Efforts to unravel the molecular events underlying the origin of different types of cancer have contributed to finding treatments for these diseases. However, largely left behind in this effort are tumors with poorly understood etiologies like rhabdomyosarcoma (RMS). RMS describes a heterogeneous group of poorly differentiated pediatric sarcomas that display features of developing muscle.1 Representing 60% of all pediatric sarcomas and accounting for 5% to 10% of all childhood malignancies, treatment is often very aggressive, involving local irradiation, lengthy rounds of combination chemotherapy, and tumor resection.2 RMS is broadly categorized into two subtypes, embryonal (ERMS) and alveolar (ARMS), that possess distinctive clinical, pathological, and biological properties. 3ARMS portends a poor prognosis and predominantly occurs in the extremities.1 Cytogenetically, most ARMS harbor one or both of two distinct chromosomal translocations: t(2;13)(q35;q14) or t(1;13)(p36;q14), resulting in the formation of the fusion genes PAX3-FOXO1 or PAX7-FOXO1 that contribute to pathogenesis. 4 Conversely, ERMS represents 75% of all cases of RMS, most frequently occurs in the orbit, head and neck, and genitourinary tract, 3 and lacks any of the signature chromosomal rearrangements identified in ARMS.

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“…Cells were isolated by enzymatic digestion of individual gastrocnemius muscles and resuspended in PBS with 0.5% fetal bovine serum (PF buffer) as described by Hidestrand et al (Hidestrand et al, 2008). Cells were counted, re-pelleted and resuspended in viral supernatant 2.4G2 (HB197, ATCC) at a concentration of 5ϫ10 6 cells/ml for 15 minutes to block nonspecific antibody binding.…”

Section: Fluorescence-activated Cell Sorting (Facs)mentioning

confidence: 99%

Effective fiber hypertrophy in satellite cell-depleted skeletal muscle

et al. 2011

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SUMMARYAn important unresolved question in skeletal muscle plasticity is whether satellite cells are necessary for muscle fiber hypertrophy. To address this issue, a novel mouse strain (Pax7-DTA) was created which enabled the conditional ablation of >90% of satellite cells in mature skeletal muscle following tamoxifen administration. To test the hypothesis that satellite cells are necessary for skeletal muscle hypertrophy, the plantaris muscle of adult Pax7-DTA mice was subjected to mechanical overload by surgical removal of the synergist muscle. Following two weeks of overload, satellite cell-depleted muscle showed the same increases in muscle mass (approximately twofold) and fiber cross-sectional area with hypertrophy as observed in the vehicle-treated group. The typical increase in myonuclei with hypertrophy was absent in satellite cell-depleted fibers, resulting in expansion of the myonuclear domain. Consistent with lack of nuclear addition to enlarged fibers, long-term BrdU labeling showed a significant reduction in the number of BrdU-positive myonuclei in satellite cell-depleted muscle compared with vehicle-treated muscle. Single fiber functional analyses showed no difference in specific force, Ca 2+ sensitivity, rate of cross-bridge cycling and cooperativity between hypertrophied fibers from vehicle and tamoxifen-treated groups. Although a small component of the hypertrophic response, both fiber hyperplasia and regeneration were significantly blunted following satellite cell depletion, indicating a distinct requirement for satellite cells during these processes. These results provide convincing evidence that skeletal muscle fibers are capable of mounting a robust hypertrophic response to mechanical overload that is not dependent on satellite cells.

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Sca-1-Expressing Nonmyogenic Cells Contribute to Fibrosis in Aged Skeletal Muscle

Cited by 42 publications

References 50 publications

Injectable skeletal muscle matrix hydrogel promotes neovascularization and muscle cell infiltration in a hindlimb ischemia model

Injectable skeletal muscle matrix hydrogel promotes neovascularization and muscle cell infiltration in a hindlimb ischemia model

Impaired Wnt Signaling in Embryonal Rhabdomyosarcoma Cells from p53/c-fos Double Mutant Mice

Effective fiber hypertrophy in satellite cell-depleted skeletal muscle

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