Skeletal muscle-resident MSCs and bone formation

Lemos, Darío R.; Eisner, Christine; Hopkins, Claudia I.; Rossi, Fábio

doi:10.1016/j.bone.2015.06.013

Cited by 29 publications

(22 citation statements)

References 39 publications

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“…Recent studies have identified additional candidate HO including endothelial or nonendothelial Tie2+ cells and Glast‐Cre cells . Using markers such as PDGFRα, Sca1, and S100A4, others have shown that Tie2+ and Glast‐cre cells which contribute to HO are likely mesenchymal cells . Our findings confirm the coexpression of these mesenchymal cell markers in Scx‐creERT2 cells, in both trauma or BMP‐scaffold implantation.…”

Section: Discussionsupporting

confidence: 84%

“…These findings indicate that scleraxis‐lineage restricted cells have the capacity to form HO in the settings of trauma and with hyperactive BMP receptor activity. Recent studies have identified additional candidate HO including endothelial or nonendothelial Tie2+ cells and Glast‐Cre cells . Using markers such as PDGFRα, Sca1, and S100A4, others have shown that Tie2+ and Glast‐cre cells which contribute to HO are likely mesenchymal cells .…”

Section: Discussionmentioning

confidence: 99%

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Scleraxis-Lineage Cells Contribute to Ectopic Bone Formation in Muscle and Tendon

et al. 2016

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The pathologic development of heterotopic ossification (HO) is well described in patients with extensive trauma or with hyperactivating mutations of the bone morphogenetic protein (BMP) receptor ACVR1. However, identification of progenitor cells contributing to this process remains elusive. Here we show that connective tissue cells contribute to a substantial amount of HO anlagen caused by trauma using post-natal, tamoxifen-inducible, scleraxis-lineage restricted reporter mice (Scx-creERT2/tdTomatofl/fl). When the scleraxis-lineage is restricted specifically to adults prior to injury marked cells contribute to each stage of the developing HO anlagen and co-express markers of endochondral ossification (Osterix, SOX9). Furthermore, these adult pre-injury restricted cells co-expressed mesenchymal stem cell markers including PDGFRα, Sca1, and S100A4 in HO. When constitutively active ACVR1 (caACVR1) was expressed in scx-cre cells in the absence of injury (Scx-cre/caACVR1fl/fl), tendons and joints formed HO. Post-natal lineage-restricted, tamoxifen-inducible caACVR1 expression (Scx-creERT2/caACVR1fl/fl) was sufficient to form HO after directed cardiotoxin-induced muscle injury. These findings suggest that cells expressing scleraxis within muscle or tendon contribute to HO in the setting of both trauma or hyperactive bone morphogenetic protein receptor (e.g. caACVR1) activity.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Scleraxis-Lineage Cells Contribute to Ectopic Bone Formation in Muscle and Tendon

et al. 2016

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“…It could be speculated that, rather than BM-MSC, extraskeletal OS could be initiated by MSCs from soft tissues (muscle-derived MSC, ASC, etc.) presenting mutations that favor osteogenic differentiation and/or influenced by pathologically osteogenic signals from the microenvironment [ 79 ]. In this regard this type of tumors could be related to fibrodysplasia ossificans progressiva, a rare genetic disorder of connective tissue characterized by the presence of activating mutations in the ACVR1 gene, which encode a BMP type I receptor [ 80 ].…”

Section: Cell-of-origin For Osmentioning

confidence: 99%

Osteosarcoma: Cells‐of‐Origin, Cancer Stem Cells, and Targeted Therapies

Abarrategi

Tornín

Martinez-Cruzado

et al. 2016

Stem Cells International

177

168

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Osteosarcoma (OS) is the most common type of primary solid tumor that develops in bone. Although standard chemotherapy has significantly improved long-term survival over the past few decades, the outcome for those patients with metastatic or recurrent OS remains dismally poor and, therefore, novel agents and treatment regimens are urgently required. A hypothesis to explain the resistance of OS to chemotherapy is the existence of drug resistant CSCs with progenitor properties that are responsible of tumor relapses and metastasis. These subpopulations of CSCs commonly emerge during tumor evolution from the cell-of-origin, which are the normal cells that acquire the first cancer-promoting mutations to initiate tumor formation. In OS, several cell types along the osteogenic lineage have been proposed as cell-of-origin. Both the cell-of-origin and their derived CSC subpopulations are highly influenced by environmental and epigenetic factors and, therefore, targeting the OS-CSC environment and niche is the rationale for many recently postulated therapies. Likewise, some strategies for targeting CSC-associated signaling pathways have already been tested in both preclinical and clinical settings. This review recapitulates current OS cell-of-origin models, the properties of the OS-CSC and its niche, and potential new therapies able to target OS-CSCs.

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“…Because samples were examined by immunohistochemistry after 8 weeks, we do not know whether the initial representation of donor cells was higher, with progressive replacement by host cells as the newly formed woven bone was remodeled. It has been known for a long time that skeletal muscle contains osteoprogenitor cells, 14 but the identity of the progenitor cells within skeletal muscle that formed new tissue in the present experiment was not investigated here; candidates include satellite cells, 15 mesenchymal stem cells, 16 muscle-derived stem cells, 17 and endothelial lining cells from blood vessels within muscle. 18 Our data are also relevant to a discussion of the fate of chondrocytes during endochondral ossification, the mechanism through which the appendicular skeleton develops, 19 fractures heal, 20 heteropic ossification develops in FOP, 7 and genetically modified muscle forms bone in rat femora.…”

Section: Discussionmentioning

confidence: 99%

Contribution of Implanted, Genetically Modified Muscle Progenitor Cells Expressing BMP-2 to New Bone Formation in a Rat Osseous Defect

et al. 2018

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Because muscle contains osteoprogenitor cells and has a propensity to form bone, we have explored its utility in healing large osseous defects. Healing is achieved by the insertion of muscle fragments transduced with adenovirus encoding BMP-2 (Ad.BMP-2). However, it is not known whether the genetically modified muscle contributes osteoprogenitor cells to healing defects or merely serves as a local source of BMP-2. This question is part of the larger debate on the fate of progenitor cells introduced into sites of tissue damage to promote regeneration. To address this issue, we harvested fragments of muscle from rats constitutively expressing GFP, transduced them with Ad.BMP-2, and implanted them into femoral defects in wild-type rats under various conditions. GFP cells persisted within defects for the entire 8 weeks of the experiments. In the absence of bone formation, these cells presented as fibroblasts. When bone was formed, GFP cells were present as osteoblasts and osteocytes and also among the lining cells of new blood vessels. The genetically modified muscle thus contributed progenitor cells as well as BMP-2 to the healing defect, a property of great significance in light of the extensive damage to soft tissue and consequent loss of endogenous progenitors in problematic fractures.

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Skeletal muscle-resident MSCs and bone formation

Cited by 29 publications

References 39 publications

Scleraxis-Lineage Cells Contribute to Ectopic Bone Formation in Muscle and Tendon

Scleraxis-Lineage Cells Contribute to Ectopic Bone Formation in Muscle and Tendon

Osteosarcoma: Cells‐of‐Origin, Cancer Stem Cells, and Targeted Therapies

Contribution of Implanted, Genetically Modified Muscle Progenitor Cells Expressing BMP-2 to New Bone Formation in a Rat Osseous Defect

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