Irisin Pretreatment Reveals Enhanced Protective Response Upon Hematopoietic Reconstitution in the Acquired Aplastic Anemia Mouse Model

Acquired aplastic anemia (AA) is a prevalent nonmalignant hematologic disorder characterized by primary bone marrow failure (BMF), ineffective hematopoiesis, and consequent pancytopenia associated with abnormal immune responses and autoreactive T lymphocyte-mediated dysfunction of hematopoietic stem and progenitor cells (HSPCs). Recently, we observed a remarkable decrease in serum irisin levels in patients with AA, as well as beneficial effects of irisin administration on HSPC stemness and pancytopenia-related dysimmunity during BMF; however, the optimal protective effect of irisin on AA remains unknown. For this purpose, we further dissected the potential relationship between low irisin concentration and key T-cell subsets in patients and systematically compared the therapeutic effects of irisin pretreatment and irisin treatment in an AA mouse model using multifaceted analyses (e.g., body condition, peripheral blood cell counts, conventional staining, inflammatory cytokine detection, cell viability analysis of HSPCs, and T-cell subset analysis). Consistent with the decline in irisin concentration in AA, we further verified correlations with the indicated T-cell subsets. Using our well-established disease model, we found that AA mice with irisin pretreatment (Days -1 to 27) showed enhanced protective effects over those with irisin treatment (Days 7-27), including improved body condition and peripheral blood cell counts, reduced proinflammatory cytokines, rescue of HSPC stemness, and pancytopenia-related T-cell imbalance. Collectively, our data indicated the superiority of irisin pretreatment in alleviating AA-associated autoreactive T lymphocyte-mediated HSPC dysfunction and pancytopenia. Our findings provide new insights for the development of novel irisin-based regimens with enhanced protective effects against AA.