Low Oxidative Stress-Mediated ProliferationViaJNK-FOXO3a-Catalase Signaling in Transplanted Adult Stem Cells Promotes Wound Tissue Regeneration

Abstract

Aims: Stem cells exposed to pathological levels of reactive oxygen species (ROS) at wound sites fail to regenerate tissue. The molecular mechanism underlying differential levels of ROS-mediated regulation of stem cells remains elusive. This study elucidates the mechanistic role of catalase at 10 μM H2O2-induced proliferation of mouse bone marrow stromal (BMSC) and hematopoietic (HSPC) stem/progenitor cells. Results: BMSCs and HSPCs depicted an increased growth rate and colony formation, in the presence of 10 μM but not 100 μM concentration of H2O2, an effect that was perturbed by Vit. C. Mechanistically, JNK activation-FOXO3a nuclear translocation and binding of FOXO3a to catalase promoter at 10 μM H2O2 led to an increased expression and activity of anti-oxidant gene, catalase. This was followed by an increased proliferative phenotype via the AKT-dependent pathway that was perturbed in the presence of catalase-inhibitor, 3-aminotriazole due to an increased ROS-mediated inactivation of AKT. Preclinically, 10 μM H2O2-mediated preconditioning of BMSCs/HSPCs transplantation accelerated wound closure, enhanced catalase expression, and decreased ROS levels at the wound site. Transplantation of male donor cells into female recipient mice or GFP-labeled BMSCs or HSPCs depicted an increased engraftment and proliferation in preconditioned cell transplanted groups as compared with the wound control. Wound healing occurred via keratinocyte generation and vascularization in preconditioned BMSCs, whereas only neo-vascularization occurred in the preconditioned HSPCs transplanted groups. Innovation and Conclusion: Our study suggests a distinct role of catalase that protects BMSCs and HSPCs from low ROS and promotes proliferation. Transplantation of preconditioned stem cells enhanced wound tissue regeneration with a better antioxidant defense mechanism-as a therapeutic approach in stem cell transplantation-mediated tissue regeneration. Antioxid. Redox Signal. 28, 1047-1065.