title: The Wnt modulator sFRP2 enhances mesenchymal stem cell engraftment, granulation tissue formation and myocardial repair.
abstract: Cell-based therapies, using multipotent mesenchymal stem cells (MSCs) for organ regeneration, are being pursued for cardiac disease, orthopedic injuries and biomaterial fabrication. The molecular pathways that regulate MSC-mediated regeneration or enhance their therapeutic efficacy are, however, poorly understood. We compared MSCs isolated from MRL/MpJ mice, known to demonstrate enhanced regenerative capacity, to those from C57BL/6 (WT) mice. Compared with WT-MSCs, MRL-MSCs demonstrated increased proliferation, in vivo engraftment, experimental granulation tissue reconstitution, and tissue vascularity in a murine model of repair stimulation. The MRL-MSCs also reduced infarct size and improved function in a murine myocardial infarct model compared with WT-MSCs. Genomic and functional analysis indicated a downregulation of the canonical Wnt pathway in MRL-MSCs characterized by significant up-regulation of specific secreted frizzled-related proteins (sFRPs). Specific knockdown of sFRP2 by shRNA in MRL-MSCs decreased their proliferation and their engraftment in and the vascular density of MRL-MSC-generated experimental granulation tissue. These results led us to generate WT-MSCs overexpressing sFRP2 (sFRP2-MSCs) by retroviral transduction. sFRP2-MSCs maintained their ability for multilineage differentiation in vitro and, when implanted in vivo, recapitulated the MRL phenotype. Peri-infarct intramyocardial injection of sFRP2-MSCs resulted in enhanced engraftment, vascular density, reduced infarct size, and increased cardiac function after myocardial injury in mice. These findings implicate sFRP2 as a key molecule for the biogenesis of a superior regenerative phenotype in MSCs.
authors.affiliation: Department of Pathology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Maria P
authors.initials: MP
authors.lastname: Alfaro
authors.forename: Matthew
authors.initials: M
authors.lastname: Pagni
authors.forename: Alicia
authors.initials: A
authors.lastname: Vincent
authors.forename: James
authors.initials: J
authors.lastname: Atkinson
authors.forename: Michael F
authors.initials: MF
authors.lastname: Hill
authors.forename: Justin
authors.initials: J
authors.lastname: Cates
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Davidson
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Rottman
authors.forename: Ethan
authors.initials: E
authors.lastname: Lee
authors.forename: Pampee P
authors.initials: PP
authors.lastname: Young
mesh_terms: D000818:Animals; D002460:Cell Line; D004797:Enzyme-Linked Immunosorbent Assay; D006321:Heart / Q000503:physiopathology*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D012038:Regeneration / Q000502:physiology*; D014945:Wound Healing; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D008565:Membrane Proteins; C491628:Sfrp2 protein, mouse; D000094742:Secreted Frizzled-Related Proteins