Integrated analysis of hematopoietic changes following heterochronic bone marrow transplantation between young and aged mice.

BACKGROUND: aging is a multifactorial process characterized by progressive loss of tissue homeostasis and regenerative capacity, with haematopoiesis being profoundly affected. Age-associated changes in hematopoietic stem cells (HSCs) include increased frequency but reduced function, impaired self-renewal, and myeloid bias, driven by both intrinsic defects and extrinsic cues from the bone marrow (BM) niche. While heterochronic BM transplantation (hBMT) has been used to distinguish donor- versus niche-driven mechanisms, most studies have focused on isolated readouts under simplified conditions. OBJECTIVE: to perform a systematic and descriptive analysis of hematopoietic reconstitution following hBMT in mice. STUDY DESIGN: young and aged CD45.1 mouse BM cells were transplanted into lethally irradiated young or aged CD45.2 recipients mice, and hematopoietic output was evaluated six months later. Age-matched non-transplanted controls were included to contextualize aging trajectories. RESULTS: the study confirm canonical features of hematopoietic aging, such as HSC accumulation, impaired lymphopoiesis, T cell memory skewing, and erythroid decline, but reveal that their expression after transplantation depends on the interplay of donor age, recipient environment, and procedural stress. Donor-intrinsic programs dominated the T cell compartment, driving naïve-to-memory conversion, PD1 upregulation, and Helios expression in regulatory T cells. By contrast, myeloid skewing and erythroid decline were dictated by recipient age, underscoring environmental influence. Importantly, the transplantation process itself imposed selective lineage stress, disproportionately affecting B cell development and conventional T cells, while sparing regulatory T cells and most myeloid compartment. CONCLUSIONS: together, this study provides a descriptive phenotypic atlas of post-transplant haematopoiesis, highlighting detrimental effects of the transplantation process itself and lineage- and tissue-specific vulnerabilities.