A single-cell framework identifies functionally and molecularly distinct multipotent progenitors in adult human hematopoiesis

Affiliations

¹ Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA; Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA, USA; Cancer Biology Graduate Program, Stanford University, Stanford, CA, USA; Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
² Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA; Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA, USA; Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
³ Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA; Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA, USA; Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Immunology Graduate Program, Stanford University School of Medicine, Stanford, CA, USA.
⁴ Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA; Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA, USA.
⁵ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA.
⁶ Immunology Graduate Program, Stanford University School of Medicine, Stanford, CA, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
⁷ BD Biosciences, San Jose, CA 95131, USA.
⁸ Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA; Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA, USA; Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Japan Society for the Promotion of Science, Tokyo, Japan.
⁹ Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA.
¹⁰ Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA.
¹¹ Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA; Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA, USA; Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: rmajeti@stanford.edu.

PMID: 40911415
DOI: 10.1016/j.celrep.2025.116236

Free article

A single-cell framework identifies functionally and molecularly distinct multipotent progenitors in adult human hematopoiesis

Asiri Ediriwickrema et al. Cell Rep. 2025.

Free article

. 2025 Sep 23;44(9):116236.

doi: 10.1016/j.celrep.2025.116236. Epub 2025 Sep 3.

Authors

Affiliations

¹ Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA; Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA, USA; Cancer Biology Graduate Program, Stanford University, Stanford, CA, USA; Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
² Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA; Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA, USA; Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
³ Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA; Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA, USA; Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Immunology Graduate Program, Stanford University School of Medicine, Stanford, CA, USA.
⁴ Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA; Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA, USA.
⁵ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA.
⁶ Immunology Graduate Program, Stanford University School of Medicine, Stanford, CA, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
⁷ BD Biosciences, San Jose, CA 95131, USA.
⁸ Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA; Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA, USA; Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Japan Society for the Promotion of Science, Tokyo, Japan.
⁹ Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA.
¹⁰ Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA.
¹¹ Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA; Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA, USA; Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: rmajeti@stanford.edu.

PMID: 40911415
DOI: 10.1016/j.celrep.2025.116236

Abstract

Hematopoietic multipotent progenitors (MPPs) regulate blood cell production to meet the evolving demands of an organism. Adult human MPPs remain ill defined, whereas mouse MPPs are well characterized, with distinct immunophenotypes and lineage potencies. Using multi-omic single-cell analyses and functional assays, we identified distinct human MPPs within Lin-CD34+CD38dim/lo adult bone marrow with unique biomolecular and functional properties. These populations were prospectively isolated based on expression of CD69, CLL1, and CD2 in addition to classical markers like CD90 and CD45RA. We identified a CD69+ MPP with long-term engraftment and multilineage differentiation potential, a CLL1+ myeloid-biased MPP, and a CLL1-CD69- erythroid-biased MPP. We used this updated hematopoietic stem and progenitor cell (HSPC) profile to study human and mouse bone marrow cells and observe unique cell-type-specific homology between species and cell-type-specific changes associated with human aging. By identifying and functionally characterizing adult MPP sub-populations, we provide a framework for future studies in hematopoiesis.

Keywords: CP: Stem cell research; aging; bone marrow; differentiation; hematopoiesis; hematopoietic stem and progenitor cells; hematopoietic stem cells; multipotent progenitors; oligopotent progenitors; single-cell RNA sequencing and single-cell multi-omics.

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Conflict of interest statement

Declaration of interests R.M. is on the advisory boards of Kodikaz Therapeutic Solutions, Orbital Therapeutics, Pheast Therapeutics, 858 Therapeutics, Prelude Therapeutics, Mubadala Capital, and Aculeus Therapeutics. R.M. is a co-founder and equity holder of Pheast Therapeutics, MyeloGene, and Orbital Therapeutics. S.R. and M.N. previously worked at BD Biosciences.

Update of

A single cell framework identifies functionally and molecularly distinct multipotent progenitors in adult human hematopoiesis.
Ediriwickrema A, Nakauchi Y, Fan AC, Köhnke T, Hu X, Luca BA, Kim Y, Ramakrishnan S, Nakamoto M, Karigane D, Linde MH, Azizi A, Newman AM, Gentles AJ, Majeti R. Ediriwickrema A, et al. bioRxiv [Preprint]. 2024 May 10:2024.05.07.592983. doi: 10.1101/2024.05.07.592983. bioRxiv. 2024. Update in: Cell Rep. 2025 Sep 23;44(9):116236. doi: 10.1016/j.celrep.2025.116236. PMID: 38766031 Free PMC article. Updated. Preprint.

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A single-cell framework identifies functionally and molecularly distinct multipotent progenitors in adult human hematopoiesis

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A single-cell framework identifies functionally and molecularly distinct multipotent progenitors in adult human hematopoiesis

Authors

Affiliations

Abstract

Conflict of interest statement

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