title: Very late antigen-5 facilitates stromal progenitor cell differentiation into myofibroblast.
abstract: Fibrotic disease is associated with abrogated stromal cell proliferation and activity. The precise identity of the cells that drive fibrosis remains obscure, in part because of a lack of information on their lineage development. To investigate the role of an early stromal progenitor cell (SPC) on the fibrotic process, we selected for, and monitored the stages of, fibroblast development from a previously reported free-floating anchorage-independent cell (AIC) progenitor population. Our findings demonstrate that organotypic pulmonary, cardiac, and renal fibroblast commitment follows a two-step process of attachment and remodeling in culture. Cell differentiation was confirmed by the inability of SPCs to revert to the free-floating state and functional mesenchymal stem/stromal cell (MSC) differentiation into osteoblast, adipocyte, chondrocyte, and fibroblastic lineages. The myofibroblastic phenotype was reflected by actin stress-fiber formation, α-smooth muscle production, and a greater than threefold increase in proliferative activity compared with that of the progenitors. SPC-derived pulmonary myofibroblasts demonstrated a more than 300-fold increase in fibronectin-1 (Fn1), collagen, type 1, α1, integrin α-5 (Itga5), and integrin β-1 (Itgb1) transcript levels. Very late antigen-5 (ITGA5/ITGB1) protein cluster formations were also prevalent on the differentiated cells. Normalized SPC-derived myofibroblast expression patterns reflected those of primary cultured lung myofibroblasts. Intratracheal implantation of pulmonary AICs into recipient mouse lungs resulted in donor cell FN1 production and evidence of epithelial derivation. SPC derivation into stromal tissue in vitro and in vivo and the observation that MSC and fibroblast lineages share a common ancestor could potentially lead to personalized antifibrotic therapies.
authors.affiliation: Department of Biology, Yeshiva University, New York, New York, USA; Department of Pulmonary Medicine, Albert Einstein College of Medicine, Yeshiva University, Bronx, New York, USA.
authors.forename: Namita
authors.initials: N
authors.lastname: Sen
authors.affiliation: Department of Biology, Yeshiva University, New York, New York, USA; Department of Pulmonary Medicine, Albert Einstein College of Medicine, Yeshiva University, Bronx, New York, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Weingarten
authors.affiliation: Department of Biology, Yeshiva University, New York, New York, USA; Department of Pulmonary Medicine, Albert Einstein College of Medicine, Yeshiva University, Bronx, New York, USA peter@yu.edu.
authors.forename: Yakov
authors.initials: Y
authors.lastname: Peter
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis; D002454:Cell Differentiation; D005260:Female; D005786:Gene Expression Regulation; D039081:Integrin alpha5beta1 / Q000096:biosynthesis*; D008168:Lung / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D058628:Myofibroblasts / Q000166:cytology / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism
chemical_list: D000943:Antigens, Differentiation; D039081:Integrin alpha5beta1
keywords: Anchorage-independent cells; Cell transplantation; Mesenchymal stromal cells; Myofibroblast development; Stromal progenitor cells; Very late antigen-5