Identification and prospective isolation of a mesothelial precursor lineage giving rise to smooth muscle cells and fibroblasts for mammalian internal organs, and their vasculature
ABSTRACT 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.
- SourceAvailable from: Xinhong Lim
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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. "
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.
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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 · 2.20 Impact Factor
Article: Epicardial Lineages[Show abstract] [Hide abstract]
ABSTRACT: The epicardium is the mono-layered epithelium that covers the outer surface of the myocardium from early in cardiac development. Long thought to act merely passively to protect the myocardium from frictional forces in the pericardial cavity during the enduring contraction and expansion cycles of the heart, it is now considered to be a crucial source of cells and signals that direct myocardial growth and formation of the coronary vasculature during development and regeneration. Lineage tracing efforts in the chick, the mouse and the zebrafish unambiguously identified fibroblasts in interstitial and perivascular locations as well as coronary smooth muscle cells as the two major lineages that derive from epithelial-mesenchymal transition and subsequent differentiation from individual epicardial cells. However, controversies exist about an additional endothelial and myocardial fate of epicardial progenitor cells. Here, we review epicardial fate mapping efforts in three vertebrate model systems, describe their conceptual differences and discuss their methodological limitations to reach a consensus of the potential of (pro-)epicardial cells in vitro and in vivo.06/2013; 1(1):32-46. DOI:10.3390/jdb1010032