Reduced irradiation pulmonary fibrosis and stromal cell migration in Smad3-/- marrow chimeric mice
Epperly, M.W.; Franicola, D.; Zhang, X.; Nie, S.; Wang, H.; Bahnson, A.B.; Shields, D.S.; Goff, J.P.; Shen, H.; Greenberger, J.S.
In Vivo 20(5): 573-582
2006
ISSN/ISBN: 0258-851X PMID: 17091762 Document Number: 602982
Pulmonary irradiation fibrosis involves migration to the lungs of bone marrow origin myofibroblast progenitor cells (marrow stromal cells (MSCs)). Smad3-/- mice display decreased ionizing irradiation-induced skin fibrosis, defective osteo-chondrogenesis and other abnormalities thought to be associated with a defective stromal cell response (s) to transforming growth factor-beta (TGF beta). Clonal bone marrow stromal cell lines were derived from the adherent layer of continuous bone marrow cultures of homozygous deletion recombinant negative Smad3-/- mice and Smad3+/+ littermates. Quantitation in an Automated Cell Tracking System of the in vitro single cell migratory capacity over five days demonstrated a significant decrease in locomotion in microns per 24 h of Smad3-/- compared to Smad3+/+ clonal MSC lines. Reexpression by retroviral vector transfection of the Smad3 but not control ds-red transgene restored in vitro migratory capacity. Intravenously injected GFP transgene product labeled Smad3-/- (MSCs) seeded 10-fold less effectively than ds-red transgene product labeled Smad3+/+ cells to the 80 dayspost 20 Gy irradiated lungs of C57BL16J mice and Proliferated less significantly for 60 days after cell injection. Female mice chimeric for male Smad3-/- compared to Smad3+/+ marrow showed decreased irradiation pulmonary fibrosis, Y+ stromal cell migration to the lungs, and improved survival. The data show that the reduced in vitro and in vivo migratory capacity of Smad3-/- bone marrow stromal cells correlates with decreased radiation pulmonary fibrosis observed in mice chimeric for Smad3-/- marrow.