Activin-dependent signaling in fibro/adipogenic progenitors causes fibrodysplasia ossificans progressiva

Lees-Shepard, John B; Yamamoto, Masakazu; Biswas, Arpita; Stoessel, Sean J.; Nicholas, Sarah Anne E.; Cogswell, Cathy A.; Devarakonda, Parvathi Madhavi; Schneider, Michael J.; Cummins, Samantha M.; Legendre, Nicholas P.; Yamamoto, Shoko; Kaartinen, Vesa; Hunter, Jeff; Goldhamer, David J.

doi:10.1038/s41467-018-02872-2

Cited by 174 publications

(387 citation statements)

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“…Similarities in marker expression, developmental potential, and anatomical location of lineage-labeled and unlabeled PDGFRα+SCA1+ cells are consistent with the suggestion that Cre inefficiency accounted for at least some, if not all, of the unlabeled cells in skeletal lesions[65]. Importantly, FAP-like cells exist in humans[64,65,120,121], and recent findings[38,70] strongly support a major role for FAPs in FOP (see Section 3.7).…”

Section: Progenitors Of Heterotopic Ossificationsupporting

confidence: 82%

“…Our recent lineage tracing and cell transplantation studies using a new genetic mouse model of FOP strongly support a prominent role for FAPs in FOP[70]. Indeed, mice in which Acvr1 R206H expression is targeted to FAPs recapitulate all major aspects of HO pathogenesis in FOP, including both injury-induced and spontaneous disease, and the occurrence of HO in appendicular and back musculature, tendons/ligaments, major joints, and the jaw.…”

Section: Progenitors Of Heterotopic Ossificationmentioning

confidence: 82%

“…Although initial studies with Acvr1 [R206H]FlEx mice were not designed to identify activin-responsive cell populations responsible for skeletal lesions, the capacity for cell type-specific activation of ACVR1(R206H) using Cre/loxP methodologies provides a powerful means of identifying offending cell types with the intrinsic capacity to initiate and contribute to HO in FOP (see Section 3.7). In this regard, we have developed a new FOP allele of Acvr1 ( Acvr1 tnR206H ) that, in addition to allowing cell-specific targeting of Acvr1 R206H expression, incorporates a fluorescent read-out of recombination status of the FOP allele so that issues of cell-autonomy can be directly addressed[70] (Section 3.7).…”

Section: Animal Models Of Heterotopic Ossificationmentioning

confidence: 99%

“…Further, no contribution of lineage-labeled cells to BMP-induced HO was detected using a VE-Cadherin-Cre driver[77], which primarily labels endothelium and a subset of hematopoietic cells[65]. The absence of HO when endothelial cells were targeted in vivo for expression of caACVR1[38] or ACVR1(R206H)[70] also argues against an endothelial origin of skeletal lesional cells. Notably, however, transfection of human endothelial cells with an ACVR1(R206H) expression construct or treatment with BMP4 or TGFβ2 converted endothelial cells to a mesenchymal, multipotent, cell that exhibited osteogenic differentiation capacity[74].…”

Section: Progenitors Of Heterotopic Ossificationmentioning

confidence: 99%

“…However, lineage tracing[41,42,65,93] and transplantation[65] studies clearly demonstrated that satellite cells do not contribute to BMP-induced HO in vivo. Further, targeted expression of caACVR1[38,94] or ACVR1(R206H)[70] in satellite cells is not sufficient to induce HO. Collectively, these studies strongly argue against a direct role for satellite cells in acquired or genetic forms of HO, and illustrate the need for caution when interpreting results from cell culture systems, which may represent relatively permissive environments that are not necessarily reflective of in vivo settings.…”

Section: Progenitors Of Heterotopic Ossificationmentioning

confidence: 99%

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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 Ossificationsupporting

confidence: 82%

Section: Progenitors Of Heterotopic Ossificationmentioning

confidence: 82%

Section: Animal Models Of Heterotopic Ossificationmentioning

confidence: 99%

Section: Progenitors Of Heterotopic Ossificationmentioning

confidence: 99%

Section: Progenitors Of Heterotopic Ossificationmentioning

confidence: 99%

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Stem cells and heterotopic ossification: Lessons from animal models

Lees-Shepard

Goldhamer

2018

Bone

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Molecular Genetics of Fibrodysplasia Ossificans Progressiva

Brewer¹,

Allen²,

Mullins³

et al. 2021

Encyclopedia of Life Sciences

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Fibrodysplasia ossificans progressiva (FOP, MIM# 135100) is an autosomal‐dominant genetic disorder, caused by heterozygous mutations in the ACVR1 gene. While most with FOP have the same single‐nucleotide substitution (c.617G>A; R206H), occasional variant mutations in ACVR1 have also been identified. The defining clinical features of FOP are malformations of the great toes and progressive heterotopic (extraskeletal) ossification (HO). However, the clinical presentations among FOP patients vary and, at least in some cases, there appear to be genotype–phenotype correlations with specific ACVR1 mutations, even among the small number of patients. FOP‐associated ACVR1 mutations are activating mutations that enhance signalling through the BMP‐pSmad1/5 signalling pathway and direct the induction of cartilage and bone cell differentiation to form ectopic bone in postnatal soft connective tissues. Recent studies examining the molecular mechanisms, reveal that the mutant ACVR1 receptors have lost the normal constraints that regulate the activation of the ACVR1 receptor signalling complex. Key Concepts Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder of heterotopic ossification. FOP is caused by heterozygous activating mutations in the ACVR1 gene. Most FOP patients share the identical ACVR1 c.617G>A mutation that causes a single amino acid substitution (R206H). Additional variant mutations have been identified in ACVR1 and are associated with distinct clinical manifestations in some cases. ACVR1 is a type I receptor in the BMP signalling pathway, an important pathway in regulating bone formation. FOP mutant ACVR1 receptors have lost regulatory constraints that control how downstream signalling is activated.

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Spatiotemporal Analysis of Mesenchymal Stem Cells Fate Determination by Inflammatory Niche Following Soft Tissue Injury at a Single‐Cell Level

Kan,

Tan,

Wang

et al. 2024

Advanced Science

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Heterotopic ossification (HO), often arising in response to traumatic challenges, results from the aberrant osteochondral differentiation of mesenchymal stem cells (MSCs). Nevertheless, the impact of trauma‐induced inflammatory exposure on MSC fate determination remains ambiguous. In this study, the cellular diversity within inflammatory lesions is elucidated, comprising MSCs and several innate and adaptive immune cells. It is observed that quiescent MSCs transition into cycling MSCs, subsequently giving rise to chondrogenic (cMSC) and/or osteogenic (oMSC) lineages within the inflammatory microenvironment following muscle or tendon injuries, as revealed through single‐cell RNA sequencing (scRNA‐seq), spatial transcriptome and lineage tracing analysis. Moreover, these investigations demonstrate that neutrophils and natural killer (NK) cells enhance transition of quiescent MSCs into cycling MSCs, which is also controlled by M1 macrophages, a subpopulation of macrophages can also stimulate cMSC and oMSC production from cycling MSCs. Additionally, M2 macrophages, CD4+ and CD8+ T lymphocytes are found to promote chondrogenesis. Further analysis demonstrates that immune cells promotes the activation of signaling transducers and activators of transcription (STAT) pathway and phosphoinositide 3 (PI3K)/protein kinase B (AKT) pathway in MSC proliferation and osteochondral progenitors’ production, respectively. These findings highlight the dynamics of MSC fate within the inflammatory lesion and unveil the molecular landscape of osteoimmunological interactions, which holds promise for advancing HO treatment.

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Activin-dependent signaling in fibro/adipogenic progenitors causes fibrodysplasia ossificans progressiva

Cited by 174 publications

References 50 publications

Stem cells and heterotopic ossification: Lessons from animal models

Stem cells and heterotopic ossification: Lessons from animal models

Molecular Genetics of Fibrodysplasia Ossificans Progressiva

Spatiotemporal Analysis of Mesenchymal Stem Cells Fate Determination by Inflammatory Niche Following Soft Tissue Injury at a Single‐Cell Level

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