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Intercellular transfer to signalling endosomes regulates an ex vivo bone marrow niche

Nature Cell Biology volume 11, pages 303–311 (2009)Cite this article

Abstract

Haematopoietic stem-progenitor cells (HSPCs) reside in the bone marrow niche, where interactions with osteoblasts provide essential cues for their proliferation and survival. Here, we use live-cell imaging to characterize both the site of contact between osteoblasts and haematopoietic progenitor cells (HPCs) and events at this site that result in downstream signalling responses important for niche maintenance. HPCs made prolonged contact with the osteoblast surface through a specialized membrane domain enriched in prominin 1, CD63 and rhodamine PE. At the contact site, portions of the specialized domain containing these molecules were taken up by the osteoblast and internalized into SARA-positive signalling endosomes. This caused osteoblasts to downregulate Smad signalling and increase production of stromal-derived factor-1 (SDF-1), a chemokine responsible for HSPC homing to bone marrow. These findings identify a mechanism involving intercellular transfer to signalling endosomes for targeted regulation of signalling and remodelling events within an ex vivo osteoblastic niche.

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Figure 1: Organization and maintenance of the HPC plasma membrane.
Figure 2: HPC–osteoblast contact occurs through a specialized HPC membrane domain.
Figure 3: Intercellular transfer occurs between HPC and osteoblastic cells in a contact-dependent manner.
Figure 4: Transferred molecules are detected within various endocytic compartments of the osteoblasts.
Figure 5: Intercellular transfer correlates with decreased Smad 2/3 activation and an increased production of SDF-1 by the osteoblast.

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Acknowledgements

We are grateful to Victoria Cogger (University of Sydney, ANZAC Research Institute, Australia) for assistance with scanning electron microscopy. We would also like to thank Denis Corbeil (University of Dresden, Germany) for providing the prominin 1–GFP construct, and Suliana Manley and George Patterson (NIH) for critical reading of the manuscript. This project was supported by the Intramural Research Program of the US National Institute of Child Health and Human Development, National Institutes of Health.

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Authors and Affiliations

  1. Cell Biology and Metabolism Program, National Institute of Child Health and Human Development and National Institutes of Health, 9000 Rockville Pike, Bethesda, 20892, Maryland, USA

    Jennifer M. Gillette & Jennifer Lippincott-Schwartz

  2. Molecular Hematopoiesis Section, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, 20892, Maryland, USA

    Andre Larochelle & Cynthia E. Dunbar

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  1. Jennifer M. Gillette
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Contributions

J.G. was responsible for designing and completing the experimental work, analysing the data and writing the manuscript; A.L and C.D. isolated and provided primary HPCs and contributed to data and manuscript discussions; J.L-S. supervised the project and wrote the manuscript.

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Correspondence to Jennifer Lippincott-Schwartz.

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The authors declare no competing financial interests.

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Gillette, J., Larochelle, A., Dunbar, C. et al. Intercellular transfer to signalling endosomes regulates an ex vivo bone marrow niche. Nat Cell Biol 11, 303–311 (2009). https://doi.org/10.1038/ncb1838

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