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.
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Acknowledgements
We thank A. Mosley for assisting with generating the transgenic M s l nCLN mice, and R. Kopito, M. Brandeis and K. Bersuker for usage and their assistance with the time-lapse video. We thank T. Violante for her assistance with sectioning, D. Hunter for his assistance with histochemical staining and G. Paz and D. Montoro for their assistance with figure preparation. The CreERT2IRES–lacZ–PGK–neo cassette was a gift from R. J. Gilbertson (St. Jude Children’s Research Hospital, USA). This work was supported in part by a grant from the California Institute of Regenerative Medicine (RC1 00354 to I.L.W.), the Smith Family Trust (to I.L.W.) and from the National Institutes of Health (RO1 DK064640 to P.X.X.). Y.R. is supported by the Human Frontier Science Program (HFSP) Long Term Fellowship, and the Machiah Foundation Fellowship.
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Y.R. designed and performed the experiments, with suggestions from I.L.W. Y.R. imaged and analysed the data from all experiments. T.M. created the MSLN–CreER construct, with help from Y.R. D.S. contributed the Boolean analysis. P-X.X. contributed the tetrachimaera mouse models. J.R.B. contributed the PoCre transgenic mice model. Y.R. and I.L.W. wrote the manuscript.
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Rinkevich, Y., Mori, T., Sahoo, D. et al. Identification and prospective isolation of a mesothelial precursor lineage giving rise to smooth muscle cells and fibroblasts for mammalian internal organs, and their vasculature. Nat Cell Biol 14, 1251–1260 (2012). https://doi.org/10.1038/ncb2610
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DOI: https://doi.org/10.1038/ncb2610
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