Altered Adhesion and Migration of Human Mesenchymal Stromal Cells under Febrile Temperature Stress Involves NF-κβ Pathway

Abstract

Mesenchymal stromal cells (MSCs) are clinically beneficial for regenerative treatment of chronic inflammation and autoimmune disorders. However, to attain maximum efficacy from the transplanted MSCs, evaluation of its interaction with the microenvironment, becomes critical. Fever being an important hallmark of inflammation, we investigated the effect of febrile temperature stress on adhesion and migration of umbilical cord-derived MSCs. 40 °C-exposure altered cellular morphology with significant cell flattening, delayed cell-matrix de-adhesion response and slower migration of MSCs, accompanied by suppressed directionality ratio and cell trajectory. Corresponding to the observed changes, mRNA expression of extracellular matrix genes like COLs and VTN were upregulated, while matrix metalloproteinase MMP-1, showed a significant downregulation. NF-κβ pathway inhibition at 40 °C, led to reversal of gene expression pattern, cell spreading, de-adhesion dynamics and migration rate. Independent knockdown of p65 and p53 at 40 °C indicated inhibitory role of p65/p53/p21 axis in regulation of MMP-1 expression. P21 inhibits JNK activity, and JNK pathway inhibition at 40 °C resulted in further downregulation of MMP-1. Hence, our study provides the first evidence of cell migration getting adversely affected in MSCs under elevated temperature stress due to an inverse relationship between p65/p53/p21 and MMP1 with a possible involvement of the JNK pathway.