ReviewFibrosis

Tissue-resident mesenchymal stromal cells: Implications for tissue-specific antifibrotic therapies

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Science Translational Medicine  31 Jan 2018:
Vol. 10, Issue 426, eaan5174
DOI: 10.1126/scitranslmed.aan5174

Figures

  • Fig. 1 Perivascular MPCs with varying lineage capacities generate distinct connective tissues and specialized mesenchymal cells, depending on the tissue of residence.

    Mesenchymal progenitor cells (MPCs), neural/NG2+ (glial antigen 2) pericytes, and fibroblasts participate in tissue-specific fibrosis processes through the generation of αSMA+ (α–smooth muscle actin) myofibroblasts that drive excessive production of extracellular matrix (ECM). The arrows indicate cell fate.

    CREDIT: A. KITTERMAN/SCIENCE TRANSLATIONAL MEDICINE
  • Fig. 2 Tissue-specific mechanisms of fibrosis driven by mesenchymal stromal cells with unique anatomical identities.

    A combination of perivascular MPCs, pericytes, and fibroblasts residing in the alveolar niche participate in idiopathic pulmonary fibrosis. Dlk1+ (delta-like notch ligand 1) lineage–derived dermal MPCs and ADAM12+ (disintegrin and metallopeptidase domain 12) perivascular MPCs drive cutaneous fibrosis. In the liver, hepatic stellate cells (HSCs) and, to a lesser extent, portal fibroblasts drive hepatic fibrosis. Peritubular fibroblasts, perivascular Gli1+ (glioma-associated oncogene homolog 1) MPCs and NG2+ pericytes contribute to renal fibrosis in tubulointerstitial disease. Perivascular FAPs (fibro/adipogenic progenitors) are the main fibrogenic cell population driving skeletal muscle fibrosis in muscular dystrophy. LepR+ (leptin receptor) and Gli1+ MPCs generate myofibroblasts in bone marrow myelofibrosis. The latest therapeutically relevant molecular pathways are indicated in red. Progenitor cells and their fibrogenic derivatives are color-coded. IF, interstitial fibroblast; RTKs, receptor tyrosine kinases; PDGFRα, platelet-derived growth factor receptor α; LPAR1, lysophosphatidic acid receptor 1; αvβ6, alpha v beta 6; PPAR, peroxisome proliferator–activated receptor; IRAK, interleukin-1 receptor–associated kinase; TGFR, transforming growth factor receptor; HDAC, histone deacetylase; JAK, janus activate kinase; STAT, signal transducer and activator of transcription; OSM, oncostatin M; 5-HT, 5-hydroxytryptamine; LOXL2, lysyl oxidase-like 2; CASP, caspases; FoxD1, forkhead box D1.

    CREDIT: A. KITTERMAN/SCIENCE TRANSLATIONAL MEDICINE

Tables

  • Table 1 In vivo lineage-traced fibrogenic MSC populations shown to participate in tissue fibrosis.

    MSC, mesenchymal stromal cell; Lrat, lecithin-retinol acyltransferase; EN-1, engrailed 1.

    Organ/tissueLineage tracing markerMSC populations labeledAdult mesenchymal tissue
    contribution in vivo
    References
    LungFoxD1Pericyte-like MPCMyofibroblast(59)
    NG2PericytePericyte(60)
    AdrpLipofibroblastMyofibroblast(61)
    PDGFRαFibroblastFibroblast(60)
    Skeletal musclePDGFRαPericyte-like MPCMyofibroblast, adipocyte(20, 25)
    ADAM12Pericyte-like MPCMyofibroblast(23)
    LiverLratPericyte-like MPCMyofibroblast(45)
    KidneyFoxD1Pericyte-like MPC, pericytes, pertibular fibroblastsMyofibroblast, pericyte(33)
    Gli1Pericyte-like MPCMyofibroblast, pericyte(34)
    Bone marrowLepRPericyte-like MPCMyofibroblast, osteocyte,
    chondrocyte, adipocyte
    (1012)
    Gli1Pericyte-like MPC, endosteal
    MPCs
    Myofibroblast(18)
    SkinADAM12Pericyte-like MPCMyofibroblast(23)
    EN-1FibroblastMyofibroblast(68)
    Dlk1Fibroblast/MPCMyofibroblast, adipocyte(69)

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