Multipotential stromal cells / mesenchymal stem cells (MSCs) are ideal candidates for regenerative therapy as these cells differentiate into multiple lineages and positively influence neighboring cells. However on implantation, these cells are faced with nutrient deprivation and non-specific inflammation, resulting in cell loss. We have shown that surface-restricted epidermal growth factor receptor (EGFR) signaling by a tethered form of EGF enhances MSC MSC in the presence of death cytokines, serum deprivation and low oxygen in vitro. This was proposed due to plasma-membrane restriction of EGFR signaling. Interestingly, during wound repair an ECM component Tenascin C (TNC) containing EGF-like repeats (EGFL) and fibronectin like repeats (FNL) is upregulated. The EGFL bind wtih low affinity / high avidity causing sustained surface-restricted EGFR signaling. We queried whether signaling by this physiologically-relevant EGFR matrikine also protects MSC; TNC was selected as a naturally occurring molecule that would not be immunogenic. MSCs grown on TNC and Collagen I (as TNC by itself is anti-adhesive) displayed a survival advantage in the presence of FasL. TNC neither sequestered nor neutralized FasL; rather the effects were via cell signaling of TNC activating EGFR and downstream pathways of Erk and Akt through EGFL; to a much lesser extent the FNL of TNC also contributed to survival. Finally MSCs were found to deposit TNC in proliferative media in culture. Importantly, TNC, like tethered EGF, neither impelled or impeded MSC differentiation into osteoblasts or adipocytes, enabling this molecule to be used in cell replacement therapies. Taken together these results suggested that providing MSC with a non-immunogenic naturally occurring ECM moiety like TNC enhances their survival in the presence of death factors via signaling of EGFR, primarily, and integrins, secondarily. This matrix is being used to supplement MSC delivery on scaffolds to provide a survival advantage against non-specific inflammation in vivo.