mTOR inhibition and BMP signaling act synergistically to reduce muscle fibrosis and improve myofiber regeneration

Agarwal, Shailesh; Cholok, David; Loder, Shawn; Li, John; Breuler, Christopher; Chung, Michael T.; Sung, Hsiao Hsin; Ranganathan, Kavitha; Habbouche, Joe; Drake, James C.; Peterson, Joshua; Priest, Caitlin; Li, Shuli; Mishina, Yuji; Lévi, Benjamin

doi:10.1172/jci.insight.89805

Cited by 21 publications

(31 citation statements)

References 40 publications

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“…Following injury, FAPs rapidly proliferate, and failure to reduce their numbers to preinjury levels is associated with pathogenic accumulation of fatty and fibrotic tissues, which alter muscle architecture and impair function[64,76,118,119]. Whereas FAPs[76] were initially named for their fibrogenic and adipogenic potential[64,76], FAPs also exhibit osteogenic potential when stimulated by BMP ligands in culture[64,65] and, as noted above (Section 3.1), FAPs are a major contributor to BMP-induced HO in vivo[65]; Wosczyna et al[65] observed that Tie2-Cre[73] lineage-labeled FAPs accounted for ~50% of heterotopic cartilage and bone.…”

Section: Progenitors Of Heterotopic Ossificationmentioning

confidence: 99%

Stem cells and heterotopic ossification: Lessons from animal models

Lees-Shepard

Goldhamer

2018

Bone

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Put most simply, heterotopic ossification (HO) is the abnormal formation of bone at extraskeletal sites. HO can be classified into two main subtypes, genetic and acquired. Acquired HO is a common complication of major connective tissue injury, traumatic central nervous system injury, and surgical interventions, where it can cause significant pain and postoperative disability. A particularly devastating form of HO is manifested in the rare genetic disorder, fibrodysplasia ossificans progressiva (FOP), in which progressive heterotopic bone formation occurs throughout life, resulting in painful and disabling cumulative immobility. While the central role of stem/progenitor cell populations in HO is firmly established, the identity of the offending cell type(s) remains to be conclusively determined, and little is known of the mechanisms that direct these progenitor cells to initiate cartilage and bone formation. In this review, we summarize current knowledge of the cells responsible for acquired HO and FOP, highlighting the strengths and weaknesses of animal models used to interrogate the cellular origins of HO.

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Section: Progenitors Of Heterotopic Ossificationmentioning

confidence: 99%

Stem cells and heterotopic ossification: Lessons from animal models

Lees-Shepard

Goldhamer

2018

Bone

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“…The downstream effects of mTOR/AKT pathway are cell-specific, but control a vast array of cellular functions including autophagy, inflammatory polarization of T-cell populations, and proliferation of fibroblasts and chondrocytes [77]. In traumatic and genetic HO models, mTOR antagonism has been documented in a number of studies to mitigate HO formation using rapamycin [19,78]. Notably, rapamycin was able to reduce bone formation despite a preservation of BMP signaling as evidenced by levels of SMAD1/5 activity [78].…”

Section: Cell Signaling: Pathways Of Differentiation Growth and Promentioning

confidence: 99%

“…In traumatic and genetic HO models, mTOR antagonism has been documented in a number of studies to mitigate HO formation using rapamycin [19,78]. Notably, rapamycin was able to reduce bone formation despite a preservation of BMP signaling as evidenced by levels of SMAD1/5 activity [78]. Whether the effect of rapamycin can be completely attributed to the decrement in mTOR/AKT signaling, or whether the drug affects downstream pathways associated with hypoxia and subsequent chondrogenic signaling remain to be answered.…”

Section: Cell Signaling: Pathways Of Differentiation Growth and Promentioning

confidence: 99%

“…While specific BMP-Receptor inhibitors may remain ineffective in cases of genetic HO due to unfortunate consequences of chronic use, their use may prove preferable to standard treatments when used appropriately. As discussed previously, drugs targeting signaling pathways associated with growth/proliferation, retinoid signaling, and hypoxia have all been efficacious in preventing ectopic bone growth [19,78,80]. …”

Section: The Evolving Practice Of Diagnosis and Treatmentmentioning

confidence: 99%

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Heterotopic ossification and the elucidation of pathologic differentiation

Cholok

Chung

Ranganathan

et al. 2018

Bone

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Tissue regeneration following acute or persistent inflammation can manifest a spectrum of phenotypes ranging from the adaptive to the pathologic. Heterotopic Ossification (HO), the endochondral formation of bone within soft-tissue structures following severe injury serves as a prominent example of pathologic differentiation; and remains a persistent clinical issue incurring significant patient morbidity and expense to adequately diagnose and treat. The pathogenesis of HO provides an intriguing opportunity to better characterize the cellular and cell-signaling contributors to aberrant differentiation. Indeed, recent work has continued to resolve the unique cellular lineages, and causative pathways responsible for ectopic bone development yielding promising avenues for the development of novel therapeutic strategies shown to be successful in analogous animal models of HO development. This review details advances in the understanding of HO in the context of inciting inflammation, and explains how these advances inform the current standards of diagnosis and treatment.

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“…In animal models of severe traumas there has been limited success in manipulating the regenerative process to promote muscle regeneration and reduce non-regenerative defects. Although, where clear biochemical rationale exists, for example limiting the expansion of specific cell populations with small molecules, progress has been made (Fiore et al, 2016;Lemos et al, 2015;Agarwal et al, 2016). This limited success may be attributed to the lack of easily manipulated, high-throughput models of injury and regeneration, thus limiting understanding of the fundamental biology of muscle injury and regeneration/repair.…”

Section: Introductionmentioning

confidence: 99%

Bioengineered human skeletal muscle with a Pax7+ satellite cell niche capable of functional regeneration

Fleming

Capel

Rimington

et al. 2020

Preprint

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Skeletal muscle (SkM) regenerates following injury, replacing damaged tissue with high fidelity.However, in serious injuries non-regenerative defects leave patients with loss of function, increased reinjury risk and often chronic pain. Progress in treating these non-regenerative defects has been slow, with advances only occurring where a comprehensive understanding of regeneration has been gained.Tissue engineering has allowed the development of bioengineered models of SkM which regenerate following injury to support research in regenerative physiology. To date however, no studies have utilised human myogenic precursor cells (hMPCs) to closely mimic human physiology due to difficulties generating sufficient cell numbers and the relatively low myogenic potential of hMPCs.Here we address problems associated with cell number and hMPC mitogenicity using magnetic association cell sorting (MACS), for the marker CD56, and media supplementation with fibroblast growth factor 2 (FGF-2) and B-27 supplement. Cell sorting allowed extended expansion of myogenic cells and supplementation was shown to improve myogenesis within engineered tissues and force generation at maturity. In addition, these engineered human SkM contained a Pax7+ niche and regenerated following Barium Chloride (BaCl2) injury. Following injury, reductions in function (87.5%) and myotube number (33.3%) were observed, followed by a proliferative phase with increased MyoD+ cells and a subsequent recovery of function and myotube number. An expansion of the Pax7+ cell population was observed across recovery suggesting an ability to generate Pax7+ cells within the tissue, similar to the self-renewal of satellite cells seen in vivo. This work outlines an engineered human SkM capable of functional regeneration following injury, built upon an open source system adding to the pre-clinical testing toolbox to improve the understanding of basic regenerative physiology.

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mTOR inhibition and BMP signaling act synergistically to reduce muscle fibrosis and improve myofiber regeneration

Cited by 21 publications

References 40 publications

Stem cells and heterotopic ossification: Lessons from animal models

Stem cells and heterotopic ossification: Lessons from animal models

Heterotopic ossification and the elucidation of pathologic differentiation

Bioengineered human skeletal muscle with a Pax7+ satellite cell niche capable of functional regeneration

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