Resistance of bone marrow mesenchymal stem cells in a stressed environment - Comparison with osteocyte cells

Abstract

Introduction: Recently, the efficacy of mesenchymal stem cells (MSCs) mediated by their tissue repair and anti-inflammatory actions in the prevention and therapy of various disorders has been reported. In this research, our attention was focused specifically on the prevention and therapy of glucocorticoid-induced osteonecrosis. We investigated the stress resistance of MSC against glucocorticoid administration and hypoxic stress, which are factors known to induce osteocytic cell death. Materials and Methods: Mouse bone cells (MLO-Y4) and bone-marrow derived mouse MSCs were exposed to dexamethasone (Dex), hypoxia of 1% oxygen or both in vitro . Mitochondrial membrane potentials were estimated by mitochondria labeling with a cell-permeant probe (Mito tracker red); expression of these apoptosis-inducing molecules, oxidative stress marker (8-hydroxy-2'-deoxyguanosine), caspase-3, -9, and two apoptosis-inhibiting molecules, energy-producing ATP synthase (ATP5A) and X-linked inhibitor of apoptosis protein (XIAP), were analyzed by both immunofluorescence and western blot. Results: With exposure to either dexamethasone or hypoxia, MLO-Y4 showed reduced mitochondrial membrane potential, ATP5A and upregulation of 8-OHdG, cleaved caspases and XIAP. Those changes were significantly enhanced by treatment with dexamethasone plus hypoxia. In MSCs, however, mitochondrial membrane potentials were preserved, while no significant changes in the pro-apoptosis or anti-apoptosis molecules analyzed were found even with exposure to both dexamethasone and hypoxia. No such effects induced by treatment with dexamethasone, hypoxia, or both were demonstrated in MSCs at all. Discussion: In osteocyte cells subjected to the double stresses of glucocorticoid administration and a hypoxic environment osteocytic cell death was mediated via mitochondria. In contrast, MSC subjected to the same stressors showed preservation of mitochondrial function and reduced oxidative stress. Accordingly, even under conditions sufficiently stressful to cause the osteocytic cell death in vivo , it was thought that the function of MSC could be preserved, suggesting that in the case of osteonecrosis preventative and therapeutic strategies incorporating their intraosseous implantation may be promising.

Impact of High-Altitude Hypoxia on Bone Defect Repair: A Review of Molecular Mechanisms and Therapeutic Implications

“…Mitochondrial dysfunction can affect osteoblast, osteocyte, and vascular endothelial cell functions ( 69 , 70 ) as well as inflammatory reactions in chondrocytes. In turn, this leads to metabolic disorders in chondrocytes, affecting endochondral osteogenesis ( 71 ).…”

LncAABR07053481 inhibits bone marrow mesenchymal stem cell apoptosis and promotes repair following steroid-induced avascular necrosis

“…SANFH is a complex pathological process in which various factors lead to intramedullary microvascular lesions, affecting the blood and oxygen supply of the femoral head and ultimately causing hypoxia in the necrotic area [14][15][16][17] . The hypoxia apoptosis of transplanted BMSCs in the osteonecrotic area limits the transplantation efficacy of BMSCs 12,13 .…”

“…However, the transplanted BMSCs display high levels of apoptosis in the osteonecrotic area in vivo, which limits the transplantation efficacy 12,13 . The apoptosis of transplanted BMSCs is mainly related to the local hypoxic microenvironment in the necrotic area of the femoral head [14][15][16][17] . There is still a lack of effective intervention methods for hypoxia-induced apoptosis of transplanted BMSCs.…”

Mesenchymal Stem Cells Inhibit the Effects of Dexamethasone in Multiple Myeloma Cells

“…In recent years, the utilization of MSC-based strategies in the treatment of multiple myeloma has drawn much attention [ 17 , 28 – 30 ]. Shimasaki and colleagues found that the survival rate of MSCs is maintained after treatment with dexamethasone [ 31 ], indicating the resistance of MSCs to dexamethasone. However, it is still unclear whether MSCs had an impact on dexamethasone-mediated multiple myeloma therapy.…”