Matrix tethered EGF promotes survival of MSC secondary to preferential activation of surface‐restricted signaling pathways

Abstract

Multipotential stromal cells (MSC) are being tested to replace traditional tissue transplantations. However, the major loss of MSC seen after implantation may be due to non‐specific inflammation killing these cells. Epidermal Growth Factor (EGF) promotes MSC expansion but does not cause MSC differentiation and when covalently tethered on an engineered biomaterial surface (tEGF) offers a survival advantage to MSC in the presence of FasL, while soluble EGF (sEGF) increases death. Thus, we hypothesize that tEGF by restricting signaling of EGF receptor to the plasma membrane changes the persistence and balance of intracellular signaling pathways towards survival in MSC. Our results show caspase8 and caspase3 activation upon treatment with FasL. Addition of sEGF to these cells shows enhanced apoptosis in line with earlier findings. However a key question is what occurs as MSC differentiate into the desired tissue. We now propose that as MSC differentiate their susceptibility to death signals diminish. Preliminary studies show reduced apoptosis in response to FasL as MSC are driven down the osteogenic lineage. Studies with tEGF are underway. Still, the early findings of relative resistance to death of the differentiating cells suggest that the tEGF survival signal need not persist which allows for a degradative scaffold to be used to repair wounds including non‐healing bone lesions.Funding: NIGMS (AW), NIDCR (LG)