Dataset Information

Tissue-Resident PDGFRα⁺ Progenitor Cells Contribute to Fibrosis versus Healing in a Context- and Spatiotemporally Dependent Manner.

ABSTRACT: PDGFRα⁺ mesenchymal progenitor cells are associated with pathological fibro-adipogenic processes. Conversely, a beneficial role for these cells during homeostasis or in response to revascularization and regeneration stimuli is suggested, but remains to be defined. We studied the molecular profile and function of PDGFRα⁺ cells in order to understand the mechanisms underlying their role in fibrosis versus regeneration. We show that PDGFRα⁺ cells are essential for tissue revascularization and restructuring through injury-stimulated remodeling of stromal and vascular components, context-dependent clonal expansion, and ultimate removal of pro-fibrotic PDGFRα⁺-derived cells. Tissue ischemia modulates the PDGFRα⁺ phenotype toward cells capable of remodeling the extracellular matrix and inducing cell-cell and cell-matrix adhesion, likely favoring tissue repair. Conversely, pathological healing occurs if PDGFRα⁺-derived cells persist as terminally differentiated mesenchymal cells. These studies support a context-dependent "yin-yang" biology of tissue-resident mesenchymal progenitor cells, which possess an innate ability to limit injury expansion while also promoting fibrosis in an unfavorable environment.

SUBMITTER: Santini MP

PROVIDER: S-EPMC7030884 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Publications

Tissue-Resident PDGFRα+ Progenitor Cells Contribute to Fibrosis versus Healing in a Context- and Spatiotemporally Dependent Manner.

Santini Maria Paola MP Malide Daniela D Hoffman Gabriel G Pandey Gaurav G D'Escamard Valentina V Nomura-Kitabayashi Aya A Rovira Ilsa I Kataoka Hiroshi H Ochando Jordi J Harvey Richard P RP Finkel Toren T Kovacic Jason C JC

Cell reports 20200101 2

PDGFRα+ mesenchymal progenitor cells are associated with pathological fibro-adipogenic processes. Conversely, a beneficial role for these cells during homeostasis or in response to revascularization and regeneration stimuli is suggested, but remains to be defined. We studied the molecular profile and function of PDGFRα+ cells in order to understand the mechanisms underlying their role in fibrosis versus regeneration. We show that PDGFRα+ cells are essential for t ...[more]

PMID: 31940496

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Project description:Unlike during embryogenesis, the identity of tissue resident progenitor cells that contribute to postnatal tendon growth and natural healing is poorly characterized. Therefore, we utilized 1) an inducible Cre driven by alpha smooth muscle actin (SMACreERT2), that identifies mesenchymal progenitors, 2) a constitutively active Cre driven by growth and differentiation factor 5 (GDF5Cre), a critical regulator of joint condensation, in combination with 3) an Ai9 Cre reporter to permanently label SMA9 and GDF5-9 populations and their progeny. In growing mice, SMA9+ cells were found in peritendinous structures and scleraxis-positive (ScxGFP+) cells within the tendon midsubstance and myotendinous junction. The progenitors within the tendon midsubstance were transiently labeled as they displayed a 4-fold expansion from day 2 to day 21 but reduced to baseline levels by day 70. SMA9+ cells were not found within tendon entheses or ligaments in the knee, suggesting a different origin. In contrast to the SMA9 population, GDF5-9+ cells extended from the bone through the enthesis and into a portion of the tendon midsubstance. GDF5-9+ cells were also found throughout the length of the ligaments, indicating a significant variation in the progenitors that contribute to tendons and ligaments. Following tendon injury, SMA9+ paratenon cells were the main contributors to the healing response. SMA9+ cells extended over the defect space at 1 week and differentiated into ScxGFP+ cells at 2 weeks, which coincided with increased collagen signal in the paratenon bridge. Thus, SMA9-labeled cells represent a unique progenitor source that contributes to the tendon midsubstance, paratenon, and myotendinous junction during growth and natural healing, while GDF5 progenitors contribute to tendon enthesis and ligament development. Understanding the mechanisms that regulate the expansion and differentiation of these progenitors may prove crucial to improving future repair strategies.

Dataset Information

Tissue-Resident PDGFRα⁺ Progenitor Cells Contribute to Fibrosis versus Healing in a Context- and Spatiotemporally Dependent Manner.

Publications

Tissue-Resident PDGFRα<sup>+</sup> Progenitor Cells Contribute to Fibrosis versus Healing in a Context- and Spatiotemporally Dependent Manner.

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