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