title: Enrichment for STRO-1 expression enhances the cardiovascular paracrine activity of human bone marrow-derived mesenchymal cell populations.
abstract: The cardiovascular therapeutic potential of bone marrow mesenchymal stromal/stem cells (MSC) is largely mediated by paracrine effects. Traditional preparation of MSC has involved plastic adherence-isolation. In contrast, prospective immunoselection aims to improve cell isolation by enriching for mesenchymal precursor cells (MPC) at higher purity. This study compared the biological characteristics and cardiovascular trophic activity of plastic adherence-isolated MSC (PA-MSC) and MPC prepared from the same human donors by immunoselection for stromal precursor antigen-1 (STRO-1). Compared to PA-MSC, STRO-1-MPC displayed greater (1) clonogenicity, (2) proliferative capacity, (3) multilineage differentiation potential, and (4) mRNA expression of mesenchymal stem cell-related transcripts. In vitro assays demonstrated that conditioned medium from STRO-1-MPC had greater paracrine activity than PA-MSC, with respect to cardiac cell proliferation and migration and endothelial cell migration and tube formation. In keeping with this, STRO-1-MPC exhibited higher gene and protein expression of CXCL12 and HGF. Inhibition of these cytokines attenuated endothelial tube formation and cardiac cell proliferation, respectively. Paracrine responses were enhanced by using supernatant from STRO-1(Bright) MPC and diminished with STRO-1(Dim) conditioned medium. Together, these findings indicate that prospective isolation gives rise to mesenchymal progeny that maintain a higher proportion of immature precursor cells compared to traditional plastic adherence-isolation. Enrichment for STRO-1 is also accompanied by increased expression of cardiovascular-relevant cytokines and enhanced trophic activity. Immunoselection thus provides a strategy for improving the cardiovascular reparative potential of mesenchymal cells.
authors.affiliation: Centre for Stem Cell Research, Robinson Institute and Department of Medicine, University of Adelaide, South Australia, Australia.
authors.forename: P J
authors.initials: PJ
authors.lastname: Psaltis
authors.forename: S
authors.initials: S
authors.lastname: Paton
authors.forename: F
authors.initials: F
authors.lastname: See
authors.forename: A
authors.initials: A
authors.lastname: Arthur
authors.forename: S
authors.initials: S
authors.lastname: Martin
authors.forename: S
authors.initials: S
authors.lastname: Itescu
authors.forename: S G
authors.initials: SG
authors.lastname: Worthley
authors.forename: S
authors.initials: S
authors.lastname: Gronthos
authors.forename: A C W
authors.initials: AC
authors.lastname: Zannettino
mesh_terms: D000954:Antigens, Surface / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D002318:Cardiovascular Diseases / Q000628:therapy*; D002448:Cell Adhesion / Q000276:immunology; D018929:Cell Culture Techniques / Q000295:instrumentation / Q000379:methods; D002454:Cell Differentiation / Q000502:physiology*; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D017077:Culture Media, Conditioned / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects; D006801:Humans; D018189:Immunomagnetic Separation / Q000379:methods; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D039902:Multipotent Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects; D019899:Paracrine Communication / Q000187:drug effects / Q000502:physiology*; D010969:Plastics / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism; D012038:Regeneration / Q000502:physiology
chemical_list: D000954:Antigens, Surface; D015415:Biomarkers; D017077:Culture Media, Conditioned; D010969:Plastics; D012333:RNA, Messenger; C525591:STRO-1 antigen, human