The Wnt modulator sFRP2 enhances mesenchymal stem cell engraftment, granulation tissue formation and myocardial repair
| Autor: | Maria P. Alfaro, Matthew Pagni, James B. Atkinson, Pampee P. Young, Justin M M Cates, Jeffrey M. Davidson, Ethan Lee, Alicia Vincent, Jeffrey N. Rottman, Michael F. Hill |
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| Rok vydání: | 2008 |
| Předmět: |
Cell
Enzyme-Linked Immunosorbent Assay Biology Cell Line Mice Downregulation and upregulation In vivo medicine Animals Humans Regeneration Wound Healing Gene knockdown Multidisciplinary Regeneration (biology) Mesenchymal stem cell Wnt signaling pathway Membrane Proteins Granulation tissue Heart Mesenchymal Stem Cells Biological Sciences Cell biology Mice Inbred C57BL medicine.anatomical_structure Immunology |
| Zdroj: | Proceedings of the National Academy of Sciences. 105:18366-18371 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.0803437105 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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