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Mesenchymal and haematopoietic stem cells form a unique bone marrow niche

Nature volume 466, pages 829–834 (2010)Cite this article

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Abstract

The cellular constituents forming the haematopoietic stem cell (HSC) niche in the bone marrow are unclear, with studies implicating osteoblasts, endothelial and perivascular cells. Here we demonstrate that mesenchymal stem cells (MSCs), identified using nestin expression, constitute an essential HSC niche component. Nestin+ MSCs contain all the bone-marrow colony-forming-unit fibroblastic activity and can be propagated as non-adherent ‘mesenspheres’ that can self-renew and expand in serial transplantations. Nestin+ MSCs are spatially associated with HSCs and adrenergic nerve fibres, and highly express HSC maintenance genes. These genes, and others triggering osteoblastic differentiation, are selectively downregulated during enforced HSC mobilization or β3 adrenoreceptor activation. Whereas parathormone administration doubles the number of bone marrow nestin+ cells and favours their osteoblastic differentiation, in vivo nestin+ cell depletion rapidly reduces HSC content in the bone marrow. Purified HSCs home near nestin+ MSCs in the bone marrow of lethally irradiated mice, whereas in vivo nestin+ cell depletion significantly reduces bone marrow homing of haematopoietic progenitors. These results uncover an unprecedented partnership between two distinct somatic stem-cell types and are indicative of a unique niche in the bone marrow made of heterotypic stem-cell pairs.

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Figure 1: Nes -GFP + cells are perivascular stromal cells targeted by the SNS, express high levels of Cxcl12 and are physically associated with HSCs.
Figure 2: Nes -GFP + cells are mesenchymal stem cells.
Figure 3: Adult nestin+ MSCs self-renew, differentiate and transfer haematopoietic activity in vivo.
Figure 4: Regulation of HSC maintenance by nestin + MSCs.

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Gene Expression Omnibus

Data deposits

The microarray data have been deposited in the Gene Expression Omnibus (GEO) databank (http://www.ncbi.nlm.nih.gov/geo) under the accession number GSE21941.

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Acknowledgements

We thank M. García-Fernández, Y. Kunisaki, C. Scheiermann, J. Isern, E. Nistal-Villan and D. Lucas for help with some experiments; M. Kiel and S. Morrison for advice about immunohistological analysis of HSCs; C. Lin for help with intravital microscopy imaging; G. Fishell for the gift of Nes-creERT2 and RCE:loxP transgenic mice; J. Ahmed, W. Kao and J. Godbold for help with immunofluorescence and statistical analyses; S. Lymperi for advice about LT-CIC; L. Silberstein, G. Khitrov and W. Zhang for help with microarray experiments; M. Grisotto for help with cell sorting; and L. Shang, A. J. Peired and C. Prophete for help with animals. This work was supported by the National Institutes of Health (R01 grants DK056638, HL69438, HL097819) and the Department of Defence (Idea Development Award PC060271) to P.S.F. and by the National Institute of Mental Health and Ira Hazan Fund to G.N.E. S.M.-F. is the recipient of a Scholar Award by the American Society of Hematology. P.S.F. is an Established Investigator of the American Heart Association.

Author information

Author notes

  1. Simón Méndez-Ferrer & Ben D. MacArthur

    Present address: Present address: Department of Cardiovascular Developmental Biology, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid 28029, Spain (S.M.-F.); Institute for Life Sciences, University of Southampton, Highfield, Southampton SO17 1BJ, UK (B.D.M.).,

Authors and Affiliations

  1. Department of Medicine, Mount Sinai School of Medicine, New York, 10029, New York, USA

    Simón Méndez-Ferrer, Sergio A. Lira & Paul S. Frenette

  2. Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, 10029, New York, USA

    Simón Méndez-Ferrer & Paul S. Frenette

  3. Cold Spring Harbor Laboratory, Cold Spring Harbor, 11724, New York, USA

    Tatyana V. Michurina & Grigori N. Enikolopov

  4. Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, 02114, Massachusetts, USA

    Francesca Ferraro & David T. Scadden

  5. Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, 10029, New York, USA

    Amin R. Mazloom, Ben D. MacArthur & Avi Ma’ayan

  6. Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, 10461, New York, USA

    Paul S. Frenette

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Contributions

All authors contributed to the design of experiments. S.M.-F. performed experiments, analysed data and wrote the manuscript. T.V.M. and S.M.-F. performed experiments involving depletion of nestin+ cells and lineage tracing studies. F.F. performed intravital homing experiments. A.M.’a., A.R.M. and B.D.M. designed and performed analyses of microarray experiments. G.N.E., D.T.S. and S.A.L. contributed reagents and provided advice on the manuscript. P.S.F. supervised experiments and the overall study, and wrote the manuscript.

Corresponding authors

Correspondence to Simón Méndez-Ferrer or Paul S. Frenette.

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The authors declare no competing financial interests.

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Méndez-Ferrer, S., Michurina, T., Ferraro, F. et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466, 829–834 (2010). https://doi.org/10.1038/nature09262

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