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The role of the haematopoietic stem cell niche in development and ageing

Nature Reviews Molecular Cell Biology volume 26, pages 32–50 (2025)Cite this article

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An Author Correction to this article was published on 26 September 2024

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Abstract

Blood production depends on rare haematopoietic stem cells (HSCs) and haematopoietic stem and progenitor cells (HSPCs) that ultimately take up residence in the bone marrow during development. HSPCs and HSCs are subject to extrinsic regulation by the bone marrow microenvironment, or niche. Studying the interactions between HSCs and their niche is critical for improving ex vivo culturing conditions and genetic manipulation of HSCs, which is pivotal for improving autologous HSC therapies and transplantations. Additionally, understanding how the complex molecular network in the bone marrow is altered during ageing is paramount for developing novel therapeutics for ageing-related haematopoietic disorders. HSCs are unique amongst stem and progenitor cell pools in that they engage with multiple physically distinct niches during their ontogeny. HSCs are specified from haemogenic endothelium in the aorta, migrate to the fetal liver and, ultimately, colonize their final niche in the bone marrow. Recent studies employing single-cell transcriptomics and microscopy have identified novel cellular interactions that govern HSC specification and engagement with their niches throughout ontogeny. New lineage-tracing models and microscopy tools have raised questions about the numbers of HSCs specified, as well as the functional consequences of HSCs interacting with each developmental niche. Advances have also been made in understanding how these niches are modified and perturbed during ageing, and the role of these altered interactions in haematopoietic diseases. In this Review, we discuss these new findings and highlight the questions that remain to be explored.

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Fig. 1: Comparison of HSC niches across species and through development.
Fig. 2: The mouse specifying niche.
Fig. 3: HSC niche transitions from mouse fetal liver to perinatal bone marrow niches.
Fig. 4: Ageing bone marrow niche.

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Acknowledgements

This work was supported by the National Institute of Diabetes and Digestive and Kidney Disease (R01DK116835 and R01DK104028, to S.M.-F.), National Heart, Lung, and Blood Institute (F31HL170678, to T.L.C.), American Lebanese Syrian Associated Charities (to S.M.-F. and M.D.), Leukaemia Research Foundation (to M.D.) and WES Foundation (to M.D.). S.M.-F. is a Scholar of The Leukaemia & Lymphoma Society. The content is solely the responsibility of the authors and does not necessarily represent the official views of the US National Institutes of Health.

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  1. Department of Haematology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Terri L. Cain, Marta Derecka & Shannon McKinney-Freeman

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  1. Terri L. Cain
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  2. Marta Derecka
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Correspondence to Shannon McKinney-Freeman.

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Nature Reviews Molecular Cell Biology thanks Sandra Pinho; Maria Carolina Florian, who co-reviewed with Francesca Matteini; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

β-Catenin

A key adhesion protein and transcription factor in the Wnt signalling pathway.

Aorta–gonad–mesonephros

(AGM). An embryonic mesodermal region from which haematopoietic stem cells (HSCs) emerge in mammals.

Adipokines

Cytokines produced by adipose tissue that have roles in inflammatory and metabolic signalling.

A-ZIP/F1 lipoatrophic mice

A mouse model that has significantly reduced white and brown adipose tissue.

Carnegie stage

(CS). A classification system of 23 stages developed as a standard timeline of human embryonic development.

Catecholamine

An aromatic amine that serves as a neurotransmitter, such as dopamine and adrenaline.

CellComm

A bioinformatics algorithm that predicts cell-to-cell communications via ligand–receptor interactions based on single-cell RNA sequencing (scRNA-seq) or spatial transcriptomics data.

CellPhoneDB

A bioinformatic algorithm that can predict ligand–receptor cellular interactions based on single-cell RNA sequencing (scRNA-seq) expression of the ligands, receptors and associated signalling pathway genes across annotated cellular populations.

Endosteal niche

A microenvironment on the outer edge of the bone marrow comprising many cell types, including haematopoietic stem cells (HSCs).

In cis interactions

Interactions between ligand and receptor pairs occurring on the same cell.

Intermediate cell mass

A narrow section of the embryonic mesoderm from which haematopoietic stem cells (HSCs) emerge in zebrafish, and ultimately gives rise to the urogenital systems.

Lycorine

A toxic alkaloid found in some plant species.

Lymphopenia

A haematological disorder in which there is a clinical decrease in the number of lymphocytes present in the blood.

Metalloproteases

Enzymes found in the intercellular space that break down extracellular proteins.

Myeloid lineage bias

Occurs when an individual haematopoietic stem cell (HSC) has an increased relative contribution of myeloid lineage progeny compared with lymphoid lineage progeny.

Neural crest

A group of multipotent stem cells that migrate during development and give rise to large groups of tissues, such as connective tissue, skin pigmentation cells and craniofacial bones.

Platelet-derived growth factor receptor (PDGFR) signalling

A regulator of many developmentally relevant processes in a tissue-dependent manner, including cell proliferation and growth.

Xenotransplantation

The transplantation of organs or tissues, such as blood, between two different species.

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Cain, T.L., Derecka, M. & McKinney-Freeman, S. The role of the haematopoietic stem cell niche in development and ageing. Nat Rev Mol Cell Biol 26, 32–50 (2025). https://doi.org/10.1038/s41580-024-00770-8

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