Lineage tracking of mesenchymal and endothelial progenitors in BMP-induced bone formation

Kolind, Mille; Bobyn, Justin D.; Matthews, Brya G.; Mikulec, Kathy; Aiken, Alastair; Little, David; Kalajzić, Ivo

doi:10.1016/j.bone.2015.06.023

Cited by 14 publications

(11 citation statements)

References 34 publications

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“…This may be due to contribution of muscle-derived cells to chondrocytes (51,52). Notably, αSMA expression is present in some muscle cells, both myogenic satellite cells, and a separate population of stromal cells that can contribute to heterotopic bone formation (27,53). It is also possible that there is a periosteal population that is restricted to chondrogenic and perhaps fibroblastic lineages, although we are not aware of any cell populations that have shown these properties in vivo.…”

Section: Discussionmentioning

confidence: 99%

Heterogeneity of murine periosteum progenitors involved in fracture healing

Matthews

Novak

Sbrana

et al. 2021

eLife

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The periosteum is the major source of cells involved in fracture healing. We sought to characterize progenitor cells and their contribution to bone fracture healing. The periosteum is highly enriched for progenitor cells, including Sca1+ cells, CFU-F and label-retaining cells compared to the endosteum and bone marrow. Using lineage tracing, we demonstrate that αSMA identifies long-term, slow-cycling, self-renewing osteochondroprogenitors in the adult periosteum that are functionally important for bone formation during fracture healing. In addition, Col2.3CreER-labeled osteoblast cells contribute around 10% of osteoblasts, but no chondrocytes in fracture calluses. Most periosteal osteochondroprogenitors following fracture, can be targeted by αSMACreER. Previously identified skeletal stem cell populations were common in periosteum, but contained high proportions of mature osteoblasts. We have demonstrated that the periosteum is highly enriched for skeletal progenitor cells and there is heterogeneity in the populations of cells that contribute to mature lineages during periosteal fracture healing.

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Section: Discussionmentioning

confidence: 99%

Heterogeneity of murine periosteum progenitors involved in fracture healing

Matthews

Novak

Sbrana

et al. 2021

eLife

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“…Recently, Kolind et al . have studied the endothelial and mesenchymal contributions to BMP2-induced bone formation using Tie2-cre and αSMA-CreERT labeled mice 21 . They found that Tie2 primarily marked endothelial cells in this model; closer evaluation of their immunostaining shows some expression of SOX9 in Tie2-labeled cells.…”

Section: Discussionmentioning

confidence: 99%

Local and Circulating Endothelial Cells Undergo Endothelial to Mesenchymal Transition (EndMT) in Response to Musculoskeletal Injury

Agarwal

Loder

Cholok

et al. 2016

Sci Rep

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Endothelial-to-mesenchymal transition (EndMT) has been implicated in a variety of aberrant wound healing conditions. However, unambiguous evidence of EndMT has been elusive due to limitations of in vitro experimental designs and animal models. In vitro experiments cannot account for the myriad ligands and cells which regulate differentiation, and in vivo tissue injury models may induce lineage-independent endothelial marker expression in mesenchymal cells. By using an inducible Cre model to mark mesenchymal cells (Scx-creERT/tdTomato + ) prior to injury, we demonstrate that musculoskeletal injury induces expression of CD31, VeCadherin, or Tie2 in mesenchymal cells. VeCadherin and Tie2 were expressed in non-endothelial cells (CD31−) present in marrow from uninjured adult mice, thereby limiting the specificity of these markers in inducible models (e.g. VeCadherin- or Tie2-creERT). However, cell transplantation assays confirmed that endothelial cells (ΔVeCadherin/CD31+/CD45−) isolated from uninjured hindlimb muscle tissue undergo in vivo EndMT when transplanted directly into the wound without intervening cell culture using PDGFRα, Osterix (OSX), SOX9, and Aggrecan (ACAN) as mesenchymal markers. These in vivo findings support EndMT in the presence of myriad ligands and cell types, using cell transplantation assays which can be applied for other pathologies implicated in EndMT including tissue fibrosis and atherosclerosis. Additionally, endothelial cell recruitment and trafficking are potential therapeutic targets to prevent EndMT.

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“…Studies from FOP patients have suggested that both circulating cells and endothelial cells contribute to osteogenesis[16, 17]. However, studies using Cre-directed lineage tracing in murine models have indicated that hematopoietic, endothelial, and smooth muscle lineages do not contribute to bony elements within lesions formed in BMP-induced HO[18–21]. In addition, myogenic lineages make little or no contribution to osteoblasts or chondrocytes in HO based on studies using Myf5-Cre and MyoD-Cre[18, 19].…”

Section: Introductionmentioning

confidence: 99%

“…In addition, myogenic lineages make little or no contribution to osteoblasts or chondrocytes in HO based on studies using Myf5-Cre and MyoD-Cre[18, 19]. Studies with Tie2-Cre, which labels both endothelial, hematopoietic, and, in some Tie2-Cre lines, mesenchymal lineages, indicated that only the CD45 − CD31 − Sca1 + PDGFRα + population significantly contributed to bone formation[20, 21]. However, Tie2-Cre only labeled 40–50% of osteoblasts and chondrocytes in BMP-induced HO suggesting that other cell populations may be involved[19, 20].…”

Section: Introductionmentioning

confidence: 99%

Osteogenic potential of alpha smooth muscle actin expressing muscle resident progenitor cells

Matthews

Torreggiani

Roeder

et al. 2016

Bone

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Heterotopic ossification (HO) is a pathological process where bone forms in connective tissues such as skeletal muscle. Previous studies have suggested that muscle-resident non-myogenic mesenchymal progenitors are the likely source of osteoblasts and chondrocytes in HO. However, the previously identified markers of muscle-resident osteoprogenitors label up to half the osteoblasts within heterotopic lesions, suggesting other cell populations are involved. We have identified alpha smooth muscle actin (αSMA) as a marker of osteoprogenitor cells in bone and periodontium, and of osteo-chondro progenitors in the periosteum during fracture healing. We therefore utilized a lineage tracing approach to evaluate whether αSMACreERT2 identifies osteoprogenitors in the muscle. We show that in the muscle, αSMACreERT2 labels both perivascular cells, and satellite cells. αSMACre-labeled cells undergo osteogenic differentiation in vitro and form osteoblasts and chondrocytes in BMP2-induced HO in vivo. In contrast, Pax7CreERT2-labeled muscle satellite cells were restricted to myogenic differentiation in vitro, and rarely contributed to HO in vivo. Our data indicate that αSMACreERT2 labels a large proportion of osteoprogenitors in skeletal muscle, and therefore represents another marker of muscle-resident cells with osteogenic potential under HO-inducing stimulus. In contrast, muscle satellite cells make minimal contribution to bone formation in vivo.

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Lineage tracking of mesenchymal and endothelial progenitors in BMP-induced bone formation

Cited by 14 publications

References 34 publications

Heterogeneity of murine periosteum progenitors involved in fracture healing

Heterogeneity of murine periosteum progenitors involved in fracture healing

Local and Circulating Endothelial Cells Undergo Endothelial to Mesenchymal Transition (EndMT) in Response to Musculoskeletal Injury

Osteogenic potential of alpha smooth muscle actin expressing muscle resident progenitor cells

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