A Non-Genotoxic Stem Cell Therapy Boosts Lymphopoiesis and Averts Age-Related Blood Diseases in Mice

Hematopoietic stem cell (HSC) transplantation can potentially cure various blood disorders, which are especially prevalent among the elderly. However, the high toxicity of conventional conditioning often makes elderly patients ineligible for this treatment. In response, we developed and tested low-intensity conditioning protocols based on antibody-mediated HSC depletion in a murine transplantation model. Initially, we identified significant age-related impediments to effective HSC engraftment. By optimizing HSC doses and a combination of non-toxic targeting methods, we significantly enhanced the long-term multilineage activity of the transplanted cells. We demonstrated that young donor HSCs, once transplanted, not only survive but thrive in aged hosts, dramatically improving hematopoietic output and correcting defective 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 strategies 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. Overall design: This study examined how aging bone marrow (BM) environment affects the molecular profiles of lymphoid associated multipotent progenitor (MPP Ly) cells. To this end, we established chimeric animals by transplanting young ex vivo expanded HSCs into young (3 months) and aged (16 months) recipients conditioned with G-CSF/AMD3100. After 20 weeks, mice were additionally treated with CD45.2-saporin to deplete host BM cells. Each experimental group comprised four biological replicates. After 16 weeks of treatment with CD45.2-saporin, 200 donor (young) and host (young or aged) MPP Ly cells were isolated by FACS from each recipient and subjected to bulk transcriptome profiling. Cell isolation was performed in two batches, with each batch containing samples from both young and aged recipients.