Identification and prospective isolation of a mesothelial precursor lineage giving rise to smooth muscle cells and fibroblasts for mammalian internal organs, and their vasculature

Institute for Stem Cell Biology and Regenerative Medicine, Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA.
Nature Cell Biology (Impact Factor: 19.68). 11/2012; 14(12). DOI: 10.1038/ncb2610
Source: PubMed


Fibroblasts and smooth muscle cells (FSMCs) are principal cell types of connective and adventitial tissues that participate in the development, physiology and pathology of internal organs, with incompletely defined cellular origins. Here, we identify and prospectively isolate from the mesothelium a mouse cell lineage that is committed to FSMCs. The mesothelium is an epithelial monolayer covering the vertebrate thoracic and abdominal cavities and internal organs. Time-lapse imaging and transplantation experiments reveal robust generation of FSMCs from the mesothelium. By targeting mesothelin (MSLN), a surface marker expressed on mesothelial cells, we identify and isolate precursors capable of clonally generating FSMCs. Using a genetic lineage tracing approach, we show that embryonic and adult mesothelium represents a common lineage to trunk FSMCs, and trunk vasculature, with minimal contributions from neural crest, or circulating cells. The isolation of FSMC precursors enables the examination of multiple aspects of smooth muscle and fibroblast biology as well as the prospective isolation of these precursors for potential regenerative medicine purposes.

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    • "These results of renal tubule-restricted clonal segment-specific epithelial cells are complemented by our previous studies that demonstrated generation of nonepithelial fibroblasts and smooth muscle cells from a mesothelial precursor lineage (Rinkevich et al., 2012) and collectively demonstrate a mechanism of organ renewal by tissue-and lineage-restricted precursors for both renal tubule and nontubule (endothelial, smooth muscle , mesothelium, and fibroblast) components. Like our studies on digit-tip regeneration in mice, wherein lineage-restricted local tissue-type-specific stem/progenitor cells (Rinkevich et al., 2012) rather than dedifferentiated pluripotent blastema cells are responsible for regeneration, and our previous studies that blood-forming stem cells can only make blood (Wagers et al., 2002), and not other tissues such as heart cells (Balsam et al., 2004), brain cells (Massengale et al., 2005), or any endoderm-derived epithelial cells (Wagers and Weissman, 2004) by transdifferentiation, it appears that the mouse and human body plans for tissue maintenance occurs via tissue-restricted and tissue subregion-specific cells with stem/progenitor characteristics. "
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    ABSTRACT: The mechanism and magnitude by which the mammalian kidney generates and maintains its proximal tubules, distal tubules, and collecting ducts remain controversial. Here, we use long-term in vivo genetic lineage tracing and clonal analysis of individual cells from kidneys undergoing development, maintenance, and regeneration. We show that the adult mammalian kidney undergoes continuous tubulogenesis via expansions of fate-restricted clones. Kidneys recovering from damage undergo tubulogenesis through expansions of clones with segment-specific borders, and renal spheres developing in vitro from individual cells maintain distinct, segment-specific fates. Analysis of mice derived by transfer of color-marked embryonic stem cells (ESCs) into uncolored blastocysts demonstrates that nephrons are polyclonal, developing from expansions of singly fated clones. Finally, we show that adult renal clones are derived from Wnt-responsive precursors, and their tracing in vivo generates tubules that are segment specific. Collectively, these analyses demonstrate that fate-restricted precursors functioning as unipotent progenitors continuously maintain and self-preserve the mouse kidney throughout life.
    Cell Reports 05/2014; 7(4). DOI:10.1016/j.celrep.2014.04.018 · 8.36 Impact Factor
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    • "Given the diversity of function in these various settings, it is interesting to note that nothing is known about potential heterogeneity within this cellular phenotype. As exemplified by a recent report [13], mesothelia are considered a singular cell type. In fact, the assumption has been made that all mesothelia are “the same cell” [14], “hardly varying from site to site” [15]. "
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    ABSTRACT: Mesothelia, which cover all coelomic organs and body cavities in vertebrates, perform diverse functions in embryonic and adult life. Yet, mesothelia are traditionally viewed as simple, uniform epithelia. Here we demonstrate distinct differences between visceral and parietal mesothelia, the most basic subdivision of this tissue type, in terms of gene expression, adhesion, migration, and invasion. Gene profiling determined that autotaxin, a secreted lysophospholipase D originally discovered as a tumor cell-motility-stimulating factor, was expressed exclusively in the more motile and invasive visceral mesothelia and at abnormally high levels in mesotheliomas. Gain and loss of function studies demonstrate that autotaxin signaling is indeed a critical factor responsible for phenotypic differences within mesothelia. Furthermore, we demonstrate that known and novel small molecule inhibitors of the autotaxin signaling pathway dramatically blunt migratory and invasive behaviors of aggressive mesotheliomas. Taken together, this study reveals distinct phenotypes within the mesothelial cell lineage, demonstrates that differential autotaxin expression is the molecular underpinning for these differences, and provides a novel target and lead compounds to intervene in invasive mesotheliomas.
    PLoS ONE 07/2013; 8(7):e69712. DOI:10.1371/journal.pone.0069712 · 3.23 Impact Factor
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    ABSTRACT: Long-term peritoneal dialysis (PD) can lead to fibrotic changes in the peritoneum, characterized by loss of mesothelial cells (MCs) and thickening of the submesothelial area with an accumulation of collagen and myofibroblasts. The origin of myofibroblasts is a central question in peritoneal fibrosis that remains unanswered at present. Numerous clinical and experimental studies have suggested that MCs, through epithelial-mesenchymal transition (EMT), contribute to the pool of peritoneal myofibroblasts. However, recent work has placed significant doubts on the paradigm of EMT in organ fibrogenesis (in the kidney particularly), highlighting the need to reconsider the role of EMT in the generation of myofibroblasts in peritoneal fibrosis. In particular, selective cell isolation and lineage-tracing experiments have suggested the existence of progenitor cells in the peritoneum, which are able to switch to fibroblast-like cells when stimulated by the local environment. These findings highlight the plastic nature of MCs and its contribution to peritoneal fibrogenesis. In this review, we summarize the key findings and caveats of EMT in organ fibrogenesis, with a focus on PD-related peritoneal fibrosis, and discuss the potential of peritoneal MCs as a source of myofibroblasts. Copyright © 2015 International Society for Peritoneal Dialysis.
    Peritoneal dialysis international: journal of the International Society for Peritoneal Dialysis 02/2015; 35(1):14-25. DOI:10.3747/pdi.2014.00188 · 1.53 Impact Factor
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