The dynamics of hematopoiesis over the human lifespan

Hojun Li; Parker Côté; Michael Kuoch; Jideofor Ezike; Katie Frenis; Anton Afanassiev; Laura Greenstreet; Mayuri Tanaka-Yano; Giuseppe Tarantino; Stephen Zhang; Jennifer Whangbo; Vincent L Butty; Enrico Moiso; Marcelo Falchetti; Kate Lu; Guinevere G Connelly; Vivian Morris; Dahai Wang; Antonia F Chen; Giada Bianchi; George Q Daley; Salil Garg; David Liu; Stella T Chou; Aviv Regev; Edroaldo Lummertz da Rocha; Geoffrey Schiebinger; R Grant Rowe

doi:10.1038/s41592-024-02495-0

The dynamics of hematopoiesis over the human lifespan

Nat Methods. 2024 Dec 5. doi: 10.1038/s41592-024-02495-0. Online ahead of print.

Authors

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. [email protected].
² Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. [email protected].
³ Harvard Medical School, Boston, MA, USA. [email protected].
⁴ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. [email protected].
⁵ Department of Pediatrics, University of California, San Diego, CA, USA. [email protected].
⁶ Division of Hematology/Oncology, Rady Children's Hospital, San Diego, CA, USA. [email protected].
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. [email protected].
²⁶ Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. [email protected].
²⁷ Harvard Medical School, Boston, MA, USA. [email protected].

^# Contributed equally.

PMID: 39639169
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.

Abstract

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