Temporal multimodal single-cell profiling of native hematopoiesis illuminates altered differentiation trajectories with age

TLDR

Aging impairs hematopoiesis, leading to immune dysfunction and blood disorders, yet the in‑vivo dynamics of HSC decline remain poorly understood. The study combines longitudinal HSC lineage tracing with single‑cell transcriptomic and epitope profiling to map native hematopoietic trajectories over time. Native aging causes a marked loss of lymphoid output through early lymphoid‑primed progenitors, and although in‑vitro activation cannot rescue most aged HSCs, expanding candidate HSCs restores lymphopoiesis, highlighting rare aged HSC clones as targets to improve lymphopoiesis in the elderly.

Abstract

Aging negatively affects hematopoiesis, with consequences for immunity and acquired blood cell disorders. Although impairments in hematopoietic stem cell (HSC) function contribute to this, the in vivo dynamics of such changes remain obscure. Here, we integrate extensive longitudinal functional assessments of HSC-specific lineage tracing with single-cell transcriptome and epitope profiling. In contrast to recent suggestions from single-cell RNA sequencing alone, our data favor a defined structure of HSC/progenitor differentiation that deviates substantially from HSC-derived hematopoiesis following transplantation. Native age-dependent attrition in HSC differentiation manifests as drastically reduced lymphoid output through an early lymphoid-primed progenitor (MPP Ly-I). While in vitro activation fails to rescue lymphoid differentiation from most aged HSCs, robust lymphopoiesis can be achieved by culturing elevated numbers of candidate HSCs. Therefore, our data position rare chronologically aged HSC clones, fully competent at producing lymphoid offspring, as a prime target for approaches aimed to improve lymphopoiesis in the elderly.