title: Lung-derived mesenchymal stromal cell post-transplantation survival, persistence, paracrine expression, and repair of elastase-injured lung.
abstract: While multipotent mesenchymal stromal cells have been recently isolated from adult lung (L-MSCs), there is very limited data on their biological properties and therapeutic potential in vivo. How L-MSCs compare with bone marrow-derived MSCs (BM-MSCs) is also unclear. In this study, we characterized L-MSC phenotype, clonogenicity, and differentiation potential, and compared L-MSCs to BM-MSCs in vivo survival, retention, paracrine gene expression, and repair or elastase injury after transplantation. L-MSCs were highly clonogenic, frequently expressed aldehyde dehydrogenase activity, and differentiated into osteocytes, chondrocytes, adipocytes, myofibroblasts, and smooth muscle cells. After intravenous injection (2 h), L-MSCs showed greater survival than BM-MSCs; similarly, L-MSCs were significantly more resistant than BM-MSCs to anchorage independent culture (4 h) in vitro. Long after transplantation (4 or 32 days), a significantly higher number of CD45(neg) L-MSCs were retained than BM-MSCs. By flow cytometry, L-MSCs expressed more intercellular adhesion molecule-1 (ICAM-1), platelet derived growth factor receptor alpha (PDGFRα), and integrin α2 than BM-MSCs; these proteins were found to modulate endothelial adherence, directional migration, and migration across Matrigel in L-MSCs. Further, L-MSCs with low ICAM-1 showed poorer lung retention and higher phagocytosis in vivo. Compared with BM-MSCs, L-MSCs expressed higher levels of several transcripts (e.g., Ccl2, Cxcl2, Cxcl10, IL-6, IL-11, Hgf, and Igf2) in vitro, although gene expression in vivo was increased by L-MSCs and BM-MSCs equivalently. Accordingly, both L-MSCs and BM-MSCs reduced elastase injury to the same extent. This study demonstrates that tissue-specific L-MSCs possess mechanisms that enhance their lung retention after intravenous transplantation, and produce substantial healing of elastase injury comparable to BM-MSCs.
authors.affiliation: Tufts University Cummings School of Veterinary Medicine, North Grafton, Massachusetts 01536, USA. andrew.hoffman@tufts.edu
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Hoffman
authors.forename: Julia A
authors.initials: JA
authors.lastname: Paxson
authors.forename: Melissa R
authors.initials: MR
authors.lastname: Mazan
authors.forename: Airiel M
authors.initials: AM
authors.lastname: Davis
authors.forename: Shivraj
authors.initials: S
authors.lastname: Tyagi
authors.forename: Shankar
authors.initials: S
authors.lastname: Murthy
authors.forename: Edward P
authors.initials: EP
authors.lastname: Ingenito
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002448:Cell Adhesion; D002454:Cell Differentiation / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D055370:Lung Injury / Q000235:genetics / Q000473:pathology* / Q000628:therapy*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D039902:Multipotent Stem Cells / Q000166:cytology; D010196:Pancreatic Elastase; D019899:Paracrine Communication / Q000235:genetics; D016019:Survival Analysis; D014945:Wound Healing / Q000235:genetics
chemical_list: D008565:Membrane Proteins; D010196:Pancreatic Elastase