The dynamics of hematopoiesis over the human lifespan

Hojun Li^{1

2

3

4

5

6}, Parker Côté^#^{7

8}, Michael Kuoch^#⁷, Jideofor Ezike^{9

10}, Katie Frenis¹¹, Anton Afanassiev¹², Laura Greenstreet¹², Mayuri Tanaka-Yano^{11

13}, Giuseppe Tarantino¹⁴, Stephen Zhang¹², Jennifer Whangbo^{15

11

13

16}, Vincent L Butty¹⁷, Enrico Moiso⁷, Marcelo Falchetti¹⁸, Kate Lu⁷, Guinevere G Connelly⁷, Vivian Morris¹¹, Dahai Wang¹¹, Antonia F Chen^{13

19}, Giada Bianchi^{13

14}, George Q Daley^{11

13}, Salil Garg^{7

20}, David Liu^{13

14}, Stella T Chou^{21

22}, Aviv Regev^{23

24}, Edroaldo Lummertz da Rocha¹⁸, Geoffrey Schiebinger¹², R Grant Rowe^{25

26

27}

Affiliations

¹ Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. hojun@health.ucsd.edu.
² Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. hojun@health.ucsd.edu.
³ Harvard Medical School, Boston, MA, USA. hojun@health.ucsd.edu.
⁴ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. hojun@health.ucsd.edu.
⁵ Department of Pediatrics, University of California, San Diego, CA, USA. hojun@health.ucsd.edu.
⁶ Division of Hematology/Oncology, Rady Children's Hospital, San Diego, CA, USA. hojun@health.ucsd.edu.
⁷ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁸ Department of Pediatrics, University of California, San Diego, CA, USA.
⁹ Computational and Systems Biology Program, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹⁰ Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹¹ Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
¹² Department of Mathematics, University of British Columbia, Vancouver, British Columbia, Canada.
¹³ Harvard Medical School, Boston, MA, USA.
¹⁴ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹⁵ Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹⁶ Vor Biopharma, Cambridge, MA, USA.
¹⁷ Barbara K. Ostrom Bioinformatics Facility, Integrated Genomics and Bioinformatics Core of the Koch Institute, Cambridge, MA, USA.
¹⁸ Departments of Microbiology, Immunology and Parasitology, Federal University of Santa Catarina, Florianopolis, Brazil.
¹⁹ Department of Orthopedic Surgery, Brigham and Women's Hospital, Boston, MA, USA.
²⁰ Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
²¹ Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
²² Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
²³ Division of Hematology/Oncology, Rady Children's Hospital, San Diego, CA, USA.
²⁴ Genentech, South San Francisco, CA, USA.
²⁵ Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. grant_rowe@dfci.harvard.edu.
²⁶ Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. grant_rowe@dfci.harvard.edu.
²⁷ Harvard Medical School, Boston, MA, USA. grant_rowe@dfci.harvard.edu.

^# Contributed equally.

PMID: 39639169
PMCID: PMC11908799 (available on 2026-02-01)
DOI: 10.1038/s41592-024-02495-0

The dynamics of hematopoiesis over the human lifespan

Hojun Li et al. Nat Methods. 2025 Feb.

. 2025 Feb;22(2):422-434.

doi: 10.1038/s41592-024-02495-0. Epub 2024 Dec 5.

Authors

Affiliations

¹ Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. hojun@health.ucsd.edu.
² Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. hojun@health.ucsd.edu.
³ Harvard Medical School, Boston, MA, USA. hojun@health.ucsd.edu.
⁴ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. hojun@health.ucsd.edu.
⁵ Department of Pediatrics, University of California, San Diego, CA, USA. hojun@health.ucsd.edu.
⁶ Division of Hematology/Oncology, Rady Children's Hospital, San Diego, CA, USA. hojun@health.ucsd.edu.
⁷ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁸ Department of Pediatrics, University of California, San Diego, CA, USA.
⁹ Computational and Systems Biology Program, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹⁰ Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹¹ Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
¹² Department of Mathematics, University of British Columbia, Vancouver, British Columbia, Canada.
¹³ Harvard Medical School, Boston, MA, USA.
¹⁴ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹⁵ Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹⁶ Vor Biopharma, Cambridge, MA, USA.
¹⁷ Barbara K. Ostrom Bioinformatics Facility, Integrated Genomics and Bioinformatics Core of the Koch Institute, Cambridge, MA, USA.
¹⁸ Departments of Microbiology, Immunology and Parasitology, Federal University of Santa Catarina, Florianopolis, Brazil.
¹⁹ Department of Orthopedic Surgery, Brigham and Women's Hospital, Boston, MA, USA.
²⁰ Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
²¹ Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
²² Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
²³ Division of Hematology/Oncology, Rady Children's Hospital, San Diego, CA, USA.
²⁴ Genentech, South San Francisco, CA, USA.
²⁵ Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. grant_rowe@dfci.harvard.edu.
²⁶ Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. grant_rowe@dfci.harvard.edu.
²⁷ Harvard Medical School, Boston, MA, USA. grant_rowe@dfci.harvard.edu.

^# Contributed equally.

PMID: 39639169
PMCID: PMC11908799 (available on 2026-02-01)
DOI: 10.1038/s41592-024-02495-0

Abstract

Over a lifetime, hematopoietic stem cells (HSCs) adjust their lineage output to support age-aligned physiology. In model organisms, stereotypic waves of hematopoiesis have been observed corresponding to defined age-biased HSC hallmarks. However, how the properties of hematopoietic stem and progenitor cells change over the human lifespan remains unclear. To address this gap, we profiled individual transcriptome states of human hematopoietic stem and progenitor cells spanning gestation, maturation and aging. Here we define the gene expression networks dictating age-specific differentiation of HSCs and the dynamics of fate decisions and lineage priming throughout life. We additionally identifiy and functionally validate a fetal-specific HSC state with robust engraftment and multilineage capacity. Furthermore, we observe that classification of acute myeloid leukemia against defined transcriptional age states demonstrates that utilization of early life transcriptional programs associates with poor prognosis. Overall, we provide a disease-relevant framework for heterochronic orientation of stem cell ontogeny along the real time axis of the human lifespan.

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Conflict of interest statement

Competing interests: A.R. is a cofounder and equity holder of Celsius Therapeutics, an equity holder in Immunitas and was an SAB member of ThermoFisher Scientific, Syros Pharmaceuticals, Neogene Therapeutics and Asimov. From 1 August 2020, A.R. is an employee of Genentech. From 13 December 2021, J.W. is an employee of Vor Biopharma. The other authors declare no competing interests.

References

1. Li Y et al. Single-cell analysis of neonatal HSC ontogeny reveals gradual and uncoordinated transcriptional reprogramming that begins before birth. Cell Stem Cell 27, 732–747 e737 (2020). - PMC - PubMed
1. Bian Z et al. Deciphering human macrophage development at single-cell resolution. Nature 582, 571–576 (2020). - PubMed
1. Buenrostro JD et al. Integrated single-cell analysis maps the continuous regulatory landscape of human hematopoietic differentiation. Cell 173, 1535–1548 e1516 (2018). - PMC - PubMed
1. Cao J et al. A human cell atlas of fetal gene expression. Science 370, eaba7721 (2020). - PMC - PubMed
1. Han X et al. Construction of a human cell landscape at single-cell level. Nature 581, 303–309 (2020). - PubMed

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The dynamics of hematopoiesis over the human lifespan

Affiliations

The dynamics of hematopoiesis over the human lifespan

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases

Miscellaneous