sFRP2 Suppression of Bone Morphogenic Protein (BMP) and Wnt Signaling Mediates Mesenchymal Stem Cell (MSC) Self-renewal Promoting Engraftment and Myocardial Repair

Abstract

Transplantation of mesenchymal stem cells (MSCs) is a promising therapy for ischemic injury; however, inadequate survival of implanted cells in host tissue is a substantial impediment in the progress of cellular therapy. Secreted Frizzled-related protein 2 (sFRP2) has recently been highlighted as a key mediator of MSC-driven myocardial and wound repair. Notably, sFRP2 mediates significant enhancement of MSC engraftment in vivo. We hypothesized that sFRP2 improves MSC engraftment by modulating self-renewal through increasing stem cell survival and by inhibiting differentiation. In previous studies we demonstrated that sFRP2-expressing MSCs exhibited an increased proliferation rate. In the current study, we show that sFRP2 also decreased MSC apoptosis and inhibited both osteogenic and chondrogenic lineage commitment. sFRP2 activity occurred through the inhibition of both Wnt and bone morphogenic protein (BMP) signaling pathways. sFRP2-mediated inhibition of BMP signaling, as assessed by levels of pSMAD 1/5/8, was independent of its effects on the Wnt pathway. We further hypothesized that sFRP2 inhibition of MSC lineage commitment may reduce heterotopic osteogenic differentiation within the injured myocardium, a reported adverse side effect. Indeed, we found that sFRP2-MSC-treated hearts and wound tissue had less ectopic calcification. 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.Bone marrow-derived mesenchymal stem cells (MSCs) 2 are an attractive candidate for cell-mediated wound repair. Because of their plasticity, MSCs have been utilized in several preclinical and clinical trials of tissue regeneration (1).3 MSCs have been able to repair infarcted myocardium, bone, and soft tissue, albeit with varying degrees of success (3). These promising results are inconsistent, partly due to the low levels of engraftment of MSCs within the injured tissues (4). Hence, strategies to increase survival and engraftment within the wound may enhance MSC therapy.Self-renewal is an intrinsic property of stem cells that allows them to give rise to non-differentiated daughter cells by proliferating, preventing apoptosis, and avoid lineage commitment (5, 6). This process is important for the maintenance of a stem cell pool that, in the case of MSCs, can exert a more robust effect within the context of a wound. Although several cytokines, growth factors, adhesion molecules, and extracellular matrix components have been identified as cues that signal MSCs to differentiate, the molecular signals that modulate MSC self-renewal remain unknown (5). Data from the hematopoietic stem cell (HSC) field have documented the involvement of Wnt, Notch, and BMP signaling cascades in self-renewal; these pathways are implicated in the expansion of undifferentiated HSCs that upon transplantation into lethally irradiated mice successfully reconstitute the cleared bone marrow (7-9). Although no data are available to demonstrate the...

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