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Title page for ETD etd-03142011-094951


Type of Document Dissertation
Author Alfaro, Maria Paula
Author's Email Address maria.p.alfaro@vanderbilt.edu
URN etd-03142011-094951
Title Mesenchymal stem cells and secreted frizzled related protein 2; enhancing the healing potential
Degree PhD
Department Pathology
Advisory Committee
Advisor Name Title
Larry Swift Committee Chair
Andries Zijlstra Committee Member
Antonis Hatzopoulos Committee Member
Ethan Lee Committee Member
Jeffrey M. Davidson Committee Member
Keywords
  • self-renewal
  • secretome
  • engraftment
  • MSCs
  • sFRP2
  • Wnt
  • BMP
  • myocardial repair
Date of Defense 2011-02-17
Availability unrestricted
Abstract
Bone marrow-derived mesenchymal stem cells (MSCs) are an attractive candidate for cell-mediated wound repair. Due to their plasticity, MSCs have been utilized in several preclinical and clinical trials of tissue regeneration. MSCs have been able to repair infarcted myocardium, bone, and soft tissue, albeit with varying degrees of success. These promising results are inconsistent partly due to the low levels of engraftment of MSCs within the injured tissues. Hence, strategies to increase survival and engraftment within the wound may enhance MSC therapy. We compared MSCs isolated from MRL/MpJ mice, known to demonstrate enhanced regenerative capacity, to those from C57BL/6 wild-type (WT) mice. Genomic and functional analysis indicated a down regulation of the canonical Wnt pathway in MRL-MSCs characterized by significant up-regulation of secreted frizzled-related protein 2 (sFRP2). These results led us to generate WT-MSCs overexpressing sFRP2 (sFRP2-MSCs) by retroviral transduction. sFRP2-MSCs, when implanted in vivo, resulted in enhanced engraftment, vascular density, reduced infarct size, and increased cardiac function after myocardial injury in mice. Besides increasing the proliferative index of MSCs, sFRP2 also decreased MSC apoptosis and inhibited both osteogenic and chondrogenic lineage commitment. sFRP2 activity occurred through the inhibition of both Wnt and BMP signaling pathways. We found that sFRP2-MSC-treated hearts and wound tissue had less ectopic calcification. We hypothesized that sFRP2 also increased MSC-directed wound repair by regulating their secretome and proteomic analysis of the conditioned media identified Connective Tissue Growth Factor (CTGF) to play physiological role in early wound repair. This work provides important new insight into the mechanisms by which sFRP2 increases MSC self-renewal leading to superior tissue engraftment and enhanced wound healing. These findings implicate sFRP2 as a key molecule for the biogenesis of a superior regenerative phenotype in MSCs.
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