Low Oxidative Stress-Mediated Proliferation <i>Via</i> JNK-FOXO3a-Catalase Signaling in Transplanted Adult Stem Cells Promotes Wound Tissue Regeneration

Abstract

<b><i>Aims:</i></b> 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 μ<i>M</i> H₂O₂-induced proliferation of mouse bone marrow stromal (BMSC) and hematopoietic (HSPC) stem/progenitor cells. <b><i>Results:</i></b> BMSCs and HSPCs depicted an increased growth rate and colony formation, in the presence of 10 μ<i>M</i> but not 100 μ<i>M</i> 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 μ<i>M</i> H₂O₂ led to an increased expression and activity of anti-oxidant gene, catalase. This was followed by an increased proliferative phenotype <i>via</i> 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 μ<i>M</i> 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 <i>via</i> keratinocyte generation and vascularization in preconditioned BMSCs, whereas only neo-vascularization occurred in the preconditioned HSPCs transplanted groups. <b><i>Innovation and Conclusion:</i></b> 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. <i>Antioxid. Redox Signal</i>. 28, 1047-1065.