A reference model of circulating hematopoietic stem cells across the lifespan with applications to diagnostics

N. Furer; N. Rappoport; O. Milman; S. Tavor; A. Lifshitz; A. Bercovich; O. Ben-Kiki; A. Danin; M. Kedmi; Z. Shipony; D. Lipson; E. Meiri; G. Yanai; S. Shapira; N. Arber; S. Berdichevsky; J. Tyner; S. Joshi; D. Landau; S. Ganesan; N. Dusaj; P. Chamely; N. Kaushansky; N. Chapal-Ilani; R. Shamir; A. Tanay; L. Shlush

doi:10.1038/s41591-025-03716-5

A reference model of circulating hematopoietic stem cells across the lifespan with applications to diagnostics

N. Furer, N. Rappoport, O. Milman, S. Tavor, A. Lifshitz, A. Bercovich, O. Ben-Kiki, A. Danin, M. Kedmi, Z. Shipony, D. Lipson, E. Meiri, G. Yanai, S. Shapira, N. Arber, S. Berdichevsky, J. Tyner, S. Joshi, D. Landau, S. GanesanN. Dusaj, P. Chamely, N. Kaushansky, N. Chapal-Ilani, R. Shamir, A. Tanay^*, L. Shlush^*

^*Corresponding author for this work

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Abstract

With aging, deviation of human blood counts from their normal range accompanies the transition from health to disease. Hematopoietic stem and progenitor cells (HSPCs) deliver life-long multi-lineage output, but their variation across healthy humans with aging, and their diagnostic utility, haven’t been characterized in depth thus far. To address this, we introduced an HSPC reference model using single-cell RNA profiling of circulating CD34+ HSPCs from 148 healthy age- and sex-diverse individuals. We characterized physiological circulating HSPC composition, showed that age-related myeloid bias is predominant in older men and defined age-related transcriptional signatures in lymphoid progenitors. We further demonstrated the potential of this resource to facilitate the diagnosis of myelodysplastic syndrome (MDS) from peripheral blood without bone marrow sampling, defining classes of patients with MDS and abnormal lymphocyte, basophil or granulocyte progenitor frequencies. Our resource provides insights into HSPC reference ranges across the lifespan and has the potential to facilitate the clinical applications of single-cell genomics in hematology.

Original language	English
Pages (from-to)	2442-2451
Number of pages	10
Journal	Nature Medicine
Volume	31
Issue number	7
DOIs	https://doi.org/10.1038/s41591-025-03716-5
Publication status	Published - 27 Jun 2025

Funding

The present study was generously supported by the Adelis Foundation. Research was also supported by the ISF-IPMP-Israel Precision Medicine Program no. 3165/19. Additional grant support includes LLS and Rising Tide Foundation (grant nos. RTF6005-19, ISF-NSFC 2427/18 and ISF 1123/21), the Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine, ERC Advanced grant (Cells2Tissues) and ISF-MAPATZ (grant no. 714459). This research was also supported by the Sagol Institute for Longevity Research, the Barry and Eleanore Reznik Family Cancer Research Fund, the Steven B. Rubenstein Research Fund for Leukemia and Other Blood Disorders, the Applebaum Foundation, the Bolton Hope foundation, the Anthony Beck foundation, the estate of Hartz de Rooij, ICRF-USA-PG, IMOS German Program no. 0004070, and the EU Horizon 2020 funding project MAMLE ID 714731. L.S. is an incumbent of the Ruth and Louis Leland career development chair. The contribution of N.R. is part of a PhD thesis research conducted at Tel Aviv University. N.R. was supported in part by a fellowship from the Edmond J. Safra Center for Bioinformatics, Tel Aviv University and the Planning and Budgeting Committee fellowship for excellent PhD students in Data Sciences. N.R. was also supported by awards from the Herczeg Institute on Aging and the Tel Aviv University Healthy Longevity Research Center. We thank all members of the L.S. and A.T. laboratories for their constructive comments. We thank all the individuals who participated in the present study.

All Science Journal Classification (ASJC) codes

General Biochemistry,Genetics and Molecular Biology

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Furer, N., Rappoport, N., Milman, O., Tavor, S., Lifshitz, A., Bercovich, A., Ben-Kiki, O., Danin, A., Kedmi, M., Shipony, Z., Lipson, D., Meiri, E., Yanai, G., Shapira, S., Arber, N., Berdichevsky, S., Tyner, J., Joshi, S., Landau, D., ... Shlush, L. (2025). A reference model of circulating hematopoietic stem cells across the lifespan with applications to diagnostics. Nature Medicine, 31(7), 2442-2451. https://doi.org/10.1038/s41591-025-03716-5

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abstract = "With aging, deviation of human blood counts from their normal range accompanies the transition from health to disease. Hematopoietic stem and progenitor cells (HSPCs) deliver life-long multi-lineage output, but their variation across healthy humans with aging, and their diagnostic utility, haven{\textquoteright}t been characterized in depth thus far. To address this, we introduced an HSPC reference model using single-cell RNA profiling of circulating CD34+ HSPCs from 148 healthy age- and sex-diverse individuals. We characterized physiological circulating HSPC composition, showed that age-related myeloid bias is predominant in older men and defined age-related transcriptional signatures in lymphoid progenitors. We further demonstrated the potential of this resource to facilitate the diagnosis of myelodysplastic syndrome (MDS) from peripheral blood without bone marrow sampling, defining classes of patients with MDS and abnormal lymphocyte, basophil or granulocyte progenitor frequencies. Our resource provides insights into HSPC reference ranges across the lifespan and has the potential to facilitate the clinical applications of single-cell genomics in hematology.",

author = "N. Furer and N. Rappoport and O. Milman and S. Tavor and A. Lifshitz and A. Bercovich and O. Ben-Kiki and A. Danin and M. Kedmi and Z. Shipony and D. Lipson and E. Meiri and G. Yanai and S. Shapira and N. Arber and S. Berdichevsky and J. Tyner and S. Joshi and D. Landau and S. Ganesan and N. Dusaj and P. Chamely and N. Kaushansky and N. Chapal-Ilani and R. Shamir and A. Tanay and L. Shlush",

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Furer, N, Rappoport, N, Milman, O, Tavor, S, Lifshitz, A , Bercovich, A , Ben-Kiki, O, Danin, A, Kedmi, M, Shipony, Z, Lipson, D, Meiri, E, Yanai, G, Shapira, S, Arber, N, Berdichevsky, S, Tyner, J, Joshi, S, Landau, D, Ganesan, S, Dusaj, N, Chamely, P, Kaushansky, N, Chapal-Ilani, N, Shamir, R, Tanay, A & Shlush, L 2025, 'A reference model of circulating hematopoietic stem cells across the lifespan with applications to diagnostics', Nature Medicine, vol. 31, no. 7, pp. 2442-2451. https://doi.org/10.1038/s41591-025-03716-5

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AU - Furer, N.

AU - Rappoport, N.

AU - Milman, O.

AU - Tavor, S.

AU - Lifshitz, A.

AU - Bercovich, A.

AU - Ben-Kiki, O.

AU - Danin, A.

AU - Kedmi, M.

AU - Shipony, Z.

AU - Lipson, D.

AU - Meiri, E.

AU - Yanai, G.

AU - Shapira, S.

AU - Arber, N.

AU - Berdichevsky, S.

AU - Tyner, J.

AU - Joshi, S.

AU - Landau, D.

AU - Ganesan, S.

AU - Dusaj, N.

AU - Chamely, P.

AU - Kaushansky, N.

AU - Chapal-Ilani, N.

AU - Shamir, R.

AU - Tanay, A.

AU - Shlush, L.

PY - 2025/6/27

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N2 - With aging, deviation of human blood counts from their normal range accompanies the transition from health to disease. Hematopoietic stem and progenitor cells (HSPCs) deliver life-long multi-lineage output, but their variation across healthy humans with aging, and their diagnostic utility, haven’t been characterized in depth thus far. To address this, we introduced an HSPC reference model using single-cell RNA profiling of circulating CD34+ HSPCs from 148 healthy age- and sex-diverse individuals. We characterized physiological circulating HSPC composition, showed that age-related myeloid bias is predominant in older men and defined age-related transcriptional signatures in lymphoid progenitors. We further demonstrated the potential of this resource to facilitate the diagnosis of myelodysplastic syndrome (MDS) from peripheral blood without bone marrow sampling, defining classes of patients with MDS and abnormal lymphocyte, basophil or granulocyte progenitor frequencies. Our resource provides insights into HSPC reference ranges across the lifespan and has the potential to facilitate the clinical applications of single-cell genomics in hematology.

AB - With aging, deviation of human blood counts from their normal range accompanies the transition from health to disease. Hematopoietic stem and progenitor cells (HSPCs) deliver life-long multi-lineage output, but their variation across healthy humans with aging, and their diagnostic utility, haven’t been characterized in depth thus far. To address this, we introduced an HSPC reference model using single-cell RNA profiling of circulating CD34+ HSPCs from 148 healthy age- and sex-diverse individuals. We characterized physiological circulating HSPC composition, showed that age-related myeloid bias is predominant in older men and defined age-related transcriptional signatures in lymphoid progenitors. We further demonstrated the potential of this resource to facilitate the diagnosis of myelodysplastic syndrome (MDS) from peripheral blood without bone marrow sampling, defining classes of patients with MDS and abnormal lymphocyte, basophil or granulocyte progenitor frequencies. Our resource provides insights into HSPC reference ranges across the lifespan and has the potential to facilitate the clinical applications of single-cell genomics in hematology.

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U2 - 10.1038/s41591-025-03716-5

DO - 10.1038/s41591-025-03716-5

M3 - Article

SN - 1546-170X

VL - 31

SP - 2442

EP - 2451

JO - Nature Medicine

JF - Nature Medicine

IS - 7

ER -

A reference model of circulating hematopoietic stem cells across the lifespan with applications to diagnostics

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