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A single-cell transcriptomic atlas of rhesus macaque hematopoiesis reveals age-related myeloid bias and differentiation changes

ABSTRACT: Aging is accompanied by profound functional declines in the hematopoietic system, including diminished regenerative capacity and a skewing toward the myeloid lineage. While murine models have provided critical insights into hematopoietic stem cell (HSC) aging, the evolutionary distance to humans limits their translational applicability. Non-human primates, such as rhesus macaques, offer a highly relevant model, yet a comprehensive single-cell transcriptomic map of their aging hematopoietic system has been lacking. Here, we present a high-resolution single-cell RNA sequencing atlas of rhesus macaque hematopoiesis, profiling whole bone marrow, peripheral blood, and CD34-enriched progenitor cells from young and late-middle-aged cohorts. Our analysis delineates the transcriptional landscape of macaque hematopoiesis and identifies robust surface markers for prospective isolation of progenitor subpopulations. We uncover distinct, lineage-specific aging signatures, with the most profound transcriptional alterations occurring in multipotent progenitors and classical monocytes. Pseudotime and RNA velocity analyses reveal that aged HSCs reside in a more advanced state of differentiation with altered kinetics, providing a molecular basis for the observed age-related myeloid bias. Furthermore, cross-species integration with healthy human bone marrow data demonstrates profound transcriptional conservation of the stem and progenitor compartments between R. macaques and humans, with minimal species-specific divergence. These findings establish the rhesus macaque as a highly faithful surrogate for human hematopoietic aging and provide a critical resource for developing targeted interventions to rejuvenate the aging blood system.

ORGANISM(S): Macaca mulatta

PROVIDER: GSE329536 | GEO | 2026/09/16

REPOSITORIES: GEO

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Project description:The occurrence of clonal perturbations and leukemia in patients transplanted with retrovirally-transduced autologous hematopoietic stem and progenitor cells (HSPCs) has stimulated extensive investigation, demonstrating that proviral insertions perturb adjacent proto-oncogene expression. Although enhancer-deleted lentiviruses are less likely to result in insertional oncogenesis, there is evidence that they may perturb transcript splicing, and one patient with a benign clonal expansion of lentivirally-transduced HPSC has been reported. The rhesus macaque model provides an opportunity for informative long-term analysis to ask whether transduction impacts on long-term HSPC properties. We utilized two techniques to examine whether lentivirally-transduced HSPCs from eight rhesus macaques transplanted 1-13.5 years previously are perturbed at a population level, comparing telomere length as a measure of replicative history and gene expression profile of vector positive versus vector negative cells. There were no differences in telomere lengths between sorted GFP+ and GFP- blood cells, suggesting that lentiviral transduction did not globally disrupt replicative patterns. Bone marrow GFP+ and GFP- CD34+ cells showed no differences in gene expression using unsupervised and principal component analysis. These studies did not uncover any global long-term perturbation of proliferation, differentiation, or other important functional parameters of transduced HSPCs in the rhesus macaque model. CD34+ hematopoietic stem and progenitor cells were purified from bone marrow aspirates obtained from 4 rhesus macaques 3-9 years following transplantation with lentivirally-transduced autologous hematopoietic stem and progenitor cells. All lentiviral vectors contained the GFP marker gene. The CD34+ cells from each animal were sorted via flow cytometry into GFP+ and GFP- fractions, and RNA from these cells was used for Affymetrix gene expression analysis as detailed below. There were two samples, GFP+ and GFP-, from each of 4 animals.

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A single-cell transcriptomic atlas of rhesus macaque hematopoiesis reveals age-related myeloid bias and differentiation changes

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