B-Lymphoid Tyrosine Kinase Crosslinks Redox and Apoptosis Signaling Networks to Promote the Survival of Transplanted Bone Marrow Mesenchymal Stem Cells

Stress-induced apoptosis presents an obstacle to bone marrow mesenchymal stem cell (BMSC) transplantation to repair steroid-induced osteonecrosis of the femoral head (SONFH). Thus, appropriate intervention strategies should be explored to mitigate this. In our previous study, we discovered a new subgroup of BMSCs-the oxidative stress-resistant BMSCs (OSR-BMSCs)-which can survive the oxidative stress microenvironment in the osteonecrotic area, through a mechanism that currently remains unclear. In this study, we found that B-lymphoid tyrosine kinase (BLK) may be the crucial factor regulating the oxidative stress resistance of OSR-BMSCs, as it is highly expressed in these cells. Knockdown of BLK eliminated oxidative stress resistance, aggravated oxidative stress-induced apoptosis, reduced the survival of OSR-BMSCs in the oxidative stress microenvironment of the osteonecrotic area, and greatly weakened the transplantation efficacy of OSR-BMSCs for SONFH. By contrast, BLK was weakly expressed in oxidative stress-sensitive BMSCs (OSS-BMSCs). Overexpression of BLK in susceptible OSS-BMSCs allowed them to acquire oxidative stress resistance, inhibited oxidative stress-induced apoptosis, promoted their survival in the osteonecrotic area, and improved the transplantation efficacy of OSS-BMSCs for SONFH. Mechanistically, BLK concurrently activates redox and apoptotic signaling networks through its tyrosine kinase activity, which confers oxidative stress resistance to BMSCs and inhibits their stress-induced apoptosis of BMSCs. Herein, we report that OSR-BMSCs have intrinsic oxidative stress resistance that is conferred and mediated by BLK. This finding provides a potential new intervention strategy for improving the survival of transplanted BMSCs and the therapeutic efficacy of BMSC transplantation for SONFH.