Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects.
Previously we described a reliable method based on immunodepletion for isolating mesenchymal stem cells (MSCs) from murine bone marrow and showed that, after intracranial transplantation, the cells migrated throughout forebrain and cerebellum and adopted neural cell fates. Here we systemically administered MSCs purified by immunodepletion from male bleomycin (BLM)-resistant BALB/c mice into female BLM-sensitive C57BL/6 recipients and quantified engraftment levels in lung by real-time PCR. Male DNA accounted for 2.21 x 10(-5)% of the total lung DNA in control-treated mice but was increased 23-fold (P = 0.05) in animals exposed to BLM before MSC transplantation. Fluorescence in situ hybridization revealed that engrafted male cells were localized to areas of BLM-induced injury and exhibited an epithelium-like morphology. Moreover, purification of type II epithelial cells from the lungs of transplant recipients resulted in a 3-fold enrichment of male, donor-derived cells as compared with whole lung tissue. MSC administration immediately after exposure to BLM also significantly reduced the degree of BLM-induced inflammation and collagen deposition within lung tissue. Collectively, these studies demonstrate that murine MSCs home to lung in response to injury, adopt an epithelium-like phenotype, and reduce inflammation and collagen deposition in lung tissue of mice challenged with BLM.
Ortiz
Luis A
LA
Division of Occupational Medicine, Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15261, USA. lao1@pitt.edu
Gambelli
Frederica
F
McBride
Christine
C
Gaupp
Dina
D
Baddoo
Melody
M
Kaminski
Naftali
N
Phinney
Donald G
DG
D000818:Animals; D001761:Bleomycin / Q000633:toxicity*; D016026:Bone Marrow Transplantation; D003094:Collagen / Q000096:biosynthesis / Q000235:genetics; D004351:Drug Resistance; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D006085:Graft Survival; D006909:Hydroxyproline / Q000032:analysis; D017404:In Situ Hybridization, Fluorescence; D008168:Lung / Q000737:chemistry / Q000187:drug effects; D008297:Male; D020782:Matrix Metalloproteinases / Q000096:biosynthesis / Q000235:genetics; D008648:Mesoderm / Q000166:cytology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053495:Osteopontin; D016133:Polymerase Chain Reaction; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000517:prevention & control / Q000628:therapy*; D012333:RNA, Messenger / Q000096:biosynthesis; D012795:Sialoglycoproteins / Q000096:biosynthesis / Q000235:genetics; D033581:Stem Cell Transplantation; D016042:Transplantation, Heterotopic
D012333:RNA, Messenger; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; D053495:Osteopontin; D001761:Bleomycin; D003094:Collagen; D020782:Matrix Metalloproteinases; D006909:Hydroxyproline