Abstract
Hematopoietic stem cell (HSC) transplantation offers a cure for a variety of blood disorders, predominantly affecting the elderly; however, its application, especially in this demographic, is limited by treatment toxicity. In response, we developed a murine transplantation model based on low-intensity conditioning protocols using antibody-mediated HSC depletion. Initially, we identified significant age-related impediments to effective HSC engraftment. By optimizing HSC doses and non-toxic targeting methods, we could significantly enhance the long-term multilineage activity of the transplanted cells. We demonstrate that young HSCs, once transplanted, not only survive but thrive in aged hosts, dramatically improving hematopoietic output and ameliorating age-compromised lymphopoiesis. This culminated in a strategy that robustly mitigated disease progression in a genetic model of myelodysplastic syndrome. These results suggest that non-invasive HSC transplantation could fundamentally change the clinical management of age-associated hematological disorders, offering a novel, prophylactic tool to delay or even prevent their onset in elderly patients.