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The young circulatory milieu capable of delaying aging in individual tissues is of interest as rejuvenation strategies, but how it achieves cellular- and systemic-level effects has remained unclear. Here, we constructed a single-cell transcriptomic atlas across aged tissues/organs and their rejuvenation in heterochronic parabiosis (HP), a classical model to study systemic aging. In general, HP rejuvenated adult stem cells and their niches across tissues. In particular, we identified hematopoietic stem and progenitor cells (HSPCs) as one of the most responsive cell types to young blood exposure, from which a continuum of cell state changes across the hematopoietic and immune system emanated, through the restoration of a youthful transcriptional regulatory program and cytokine-mediated cell-cell communications in HSPCs. Moreover, the reintroduction of the identified rejuvenating factors alleviated age-associated lymphopoiesis decline. Overall, we provide comprehensive frameworks to explore aging and rejuvenating trajectories at single-cell resolution and revealed cellular and molecular programs that instruct systemic revitalization by blood-borne factors.
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•A single-cell transcriptomic atlas across aged tissues and their rejuvenation in HP•HP systemically rejuvenated senile adult stem cells and their niches across tissues•Youthful transcriptomes were restored in resident HSPCs upon young blood exposure•Reintroduction of rejuvenating factors in aged HSCs mitigated lymphopoiesis decline
Ma and colleagues report a multi-tissue single-cell transcriptomic atlas of HP. They reveal that adult stem cells, especially bone marrow HSPCs, are responsive to the changing milieu. Focusing on HSPCs, they uncover HP-induced rejuvenating programs with underlying key mediators, overexpression of which recharges the lymphopoiesis potential of aged HSCs.