Vitronectin Mediates Survival of Human WJ-MSCs Under Inflammatory Temperature Stress Via Cell Cycle Arrest

Abstract

BACKGROUND: Due to their anti-inflammatory and immunomodulatory capabilities, mesenchymal stem cells (MSCs) are being widely used in cell-based therapies for the treatment of a wide spectrum of inflammatory disorders. Despite their promises, substantial cell loss post transplantation leads to compromised therapeutic benefits in clinical trials, which remains a challenge to overcome. Inflammatory microenvironment comprises the presence of pro-inflammatory cytokines, elevated temperature, etc., which could hamper MSC viability following transplantation. Thus, identifying the underlying molecular factors controlling survival mechanism under such stress conditions becomes important. Also, since MSCs from different origins have significantly varied biology, choosing the appropriate MSC source could be critical in determining the fate of transplanted MSCs in a stressful milieu. OBJECTIVE: As extracellular matrix (ECM) components can mediate cell survival signals, in the present study, we have evaluated the role of ECM matricellular protein, vitronectin (VTN), in the survival of human umbilical cord-derived Wharton’s Jelly MSCs (WJ-MSCs) under the condition of inflammatory temperature stress. METHODS AND RESULTS: On exposure to 40°C, WJ-MSCs underwent cell cycle arrest with no significant change in viability status, along with an induction in VTN expression both at mRNA and protein levels. Interestingly, inhibition of pro-survival signalling pathways, ERK or PI3K, at 40°C led to further upregulation in VTN expression without any significant impact on viability or cell cycle arrest status. Interestingly, esiRNA mediated knockdown of VTN in WJ-MSCs at 40°C, with or without pro-survival pathway inhibitors, resulted in reduced cellular viability accompanied by a reversal in G0/G1 cell cycle arrest. CONCLUSIONS: These results established VTN as a protective factor that maintained the viability of WJ-MSCs at 40°C temperature stress. Finally, autophagy was indicated as a mechanism adopted by VTN in executing its pro-survival role.