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 mesothelium a mouse cell lineage that is committed to FSMCs. 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 examination of multiple aspects of smooth muscle and fibroblast biology as well as the prospective isolation of these precursors for potential regenerative medicine purposes.

Neural crest cell-autonomous roles of fibronectin in cardiovascular development

“…Known embryonic sources of VSMCs include the lateral and paraxial mesoderm, mesothelia and the NC (Jiang et al, 2000;Le Lievre and Le Douarin, 1975;Que et al, 2008;Rinkevich et al, 2012;Wasteson et al, 2008;Wilm et al, 2005). Studies by others and our lab indicated that integrin α5 is not required for the differentiation of mesodermal cells into VSMCs Turner et al, 2014Turner et al, , 2015.…”

Heterogeneity of adipose tissue in development and metabolic function

“…Wt1 expression is restricted to the intermediate and lateral plate mesoderm during development, structures that give rise to the omentum, mesentery and the mesothelium lining the organs of the visceral cavity. Consequently, these studies showed that the mesothelium provides a source of adipocyte progenitors for VAT but not SAT (Asahina et al, 2011;Cano et al, 2013;Chau et al, 2014;Rinkevich et al, 2012). These studies also showed that Wt1 positive progenitors are not the sole source of adipocytes because, depending on the individual VAT depot, only 30-80% of adipocytes in adult mice derive from cells that express Wt1 during embryonic development (Chau et al, 2014) (Fig.…”

Developmental origin and lineage plasticity of endogenous cardiac stem cells

“…Developmental fate cCFU-F and the cardiac PDGFRα + stromal cell fraction may share properties with the epicardium and other mesothelia that give rise to stromal and smooth muscle lineages during development (Asli et al, 2014;Rinkevich et al, 2012). In the adult heart, cCFU-F have been proposed to give rise to the diverse variety of stromal cells as well as perivascular cells, adipocytes, myofibroblasts, coronary endothelial cells and (controversially) cardiomyocytes in homeostasis and disease (Asli et al, 2014).…”