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Haematopoietic stem cell activity and interactions with the niche


The haematopoietic stem cell (HSC) microenvironment in the bone marrow, termed the niche, ensures haematopoietic homeostasis by controlling the proliferation, self-renewal, differentiation and migration of HSCs and progenitor cells at steady state and in response to emergencies and injury. Improved methods for HSC isolation, driven by advances in single-cell and molecular technologies, have led to a better understanding of their behaviour, heterogeneity and lineage fate and of the niche cells and signals that regulate their function. Niche regulatory signals can be in the form of cell-bound or secreted factors and other local physical cues. A combination of technological advances in bone marrow imaging and genetic manipulation of crucial regulatory factors has enabled the identification of several candidate cell types regulating the niche, including both non-haematopoietic (for example, perivascular mesenchymal stem and endothelial cells) and HSC-derived (for example, megakaryocytes, macrophages and regulatory T cells), with better topographical understanding of HSC localization in the bone marrow. Here, we review advances in our understanding of HSC regulation by niches during homeostasis, ageing and cancer, and we discuss their implications for the development of therapies to rejuvenate aged HSCs or niches or to disrupt self-reinforcing malignant niches.

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The authors apologize to investigators whose work could not be cited owing to space limitations. The authors thank the members of the Frenette laboratory for helpful discussions and recognize funding support for their laboratory from the US National Institutes of Health (R01DK056638, R01HL069438, U01DK116312 and R01DK112976), the Leukemia and Lymphoma Society (LLS-TRP 6475-15) and the New York State Department of Health (NYSTEM IIRP C029570 and C029154).

Reviewer information

Nature Reviews Molecular Cell Biology thanks H. Nakauchi and other anonymous reviewers for their contribution to the peer review of this work.

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The authors contributed equally to all aspects of the article.

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The authors declare no competing interests.

Correspondence to Paul S. Frenette.



An in vivo procedure to replace the haematopoietic system of a recipient by delivering a sufficient total number of bone marrow cells from a donor or enriched populations of haematopoietic stem and progenitor cells.


The capacity of a cell to divide and give rise to identical cells with equivalent developmental potential resulting either from an asymmetrical cell division that yields a daughter cell and a cell committed to differentiation or from a symmetrical cell division that yields two identical daughter cells.

Genotoxic insults

Radiation or chemical agents that induce damage to the genetic material in cells.


The capacity of a single cell to give rise to progeny of multiple lineages.


The return of haematopoietic stem cells to the bone marrow by trans-endothelial migration.


The process by which, following homing, haematopoietic stem cells anchor in a specific region.


Tissue that covers the outer surface of the bone and consists of two layers: an outer fibrous layer that contains fibroblasts and collagen fibres and an inner cambium layer that consists of osteoblasts and skeletal stem cells with bone regeneration capacity.


Specialized thin-walled capillaries with a wide lumen. Sinusoids distribute evenly throughout the bone marrow and form a web of fenestrated vessels that facilitate trafficking of haematopoietic cells and factors in and out of the circulation.

Cortical bone

A type of bone tissue, also known as compact bone, that has a mechanical function, forming a hard shell for long-bone diaphysis and accounting for the majority of total bone mass in the human skeleton.


Inner surface of bone cavities and the outer surface of trabeculae bone spicules within the cavities covered by bone-forming osteoblasts and bone-resorbing osteoclasts.

Trabecular bone

A type of bone tissue, also known as cancellous or spongy bone, that actively remodels and is mostly present in flat and irregular bones as well as in the epiphysis and metaphysis of long bones.

Bone marrow stromal cells

Cells of non-haematopoietic origin (classically defined as CD45TER119) in the bone marrow. Stromal cells may or may not include endothelial cells, depending on whether cells that express CD31 or tyrosine kinase with immunoglobulin and EGF homology domains 2 (TIE2) are included in the definition.

Mesenchymal stem cells

(MSCs). Self-renewing precursor cells that can differentiate into bone, fat or cartilage and form stromal cells of the bone marrow.


The state of being inactive or dormant in the G0 phase of the cell cycle, which is important for long-term function.

Mesenchymal stem and progenitor cells

(MSPCs). A population of stromal cells that remains undefined but is expected to contain self-renewing mesenchymal stem cells and colony-forming mesenchymal progenitor cells.

Sympathetic nervous system

(SNS). A branch of the autonomic nervous system that emerges from the thoracolumbar spinal cord and prepares the body for situations requiring alertness by releasing noradrenaline, which binds to adrenergic receptors.

Perivascular niches

Specialized microenvironments located adjacent to the bone marrow vasculature that regulate the maintenance of haematopoietic stem cells and/or progenitor cells.


The process by which donor haematopoietic stem cells persist in the host, generate mature progeny and repopulate the haematopoietic stem cell pool.


A state in which the numbers and/or function of HSPCs are compromised owing to high turnover as a consequence of high demand for reconstitution in stress or serial transplantation.


In the context of transplantation, cells or tissue that are from the same species but are genetically different from the recipient.

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Fig. 1: Microarchitecture of the adult mouse femur and sternum bone marrow.
Fig. 2: Cellular and molecular constituents of the HSC niche.
Fig. 3: The adult bone marrow HSC niche in homeostasis.
Fig. 4: The adult bone marrow HSC niche in ageing and malignancy.