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

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.

SUBMITTER: Gillette JM

PROVIDER: S-EPMC2748410 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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

Gillette Jennifer M JM Larochelle Andre A Dunbar Cynthia E CE Lippincott-Schwartz Jennifer J

Nature cell biology 20090208 3

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 ...[more]

PMID: 19198600

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Project description:IntroductionThere is a clinical need for developing systemic transplantation protocols for use of human skeletal stem cells (also known bone marrow stromal stem cells) (hBMSC) in tissue regeneration. In systemic transplantation studies, only a limited number of hBMSC home to injured tissues suggesting that only a subpopulation of hBMSC possesses "homing" capacity. Thus, we tested the hypothesis that a subpopulation of hBMSC defined by ability to form heterotopic bone in vivo, is capable of homing to injured bone.MethodsWe tested ex vivo and in vivo homing capacity of a number of clonal cell populations derived from telomerized hBMSC (hBMSC-TERT) with variable ability to form heterotopic bone when implanted subcutaneously in immune deficient mice. In vitro transwell migration assay was used and the in vivo homing ability of transplanted hBMSC to bone fractures in mice was visualized by bioluminescence imaging (BLI). In order to identify the molecular phenotype associated with enhanced migration, we carried out comparative DNA microarray analysis of gene expression of hBMSC-derived high bone forming (HBF) clones versus low bone forming (LBF) clones.ResultsHBF clones were exhibited higher ex vivo transwell migration and following intravenous injection, better in vivo homing ability to bone fracture when compared to LBF clones. Comparative microarray analysis of HBF versus LBF clones identified enrichment of gene categories of chemo-attraction, adhesion and migration associated genes. Among these, platelet-derived growth factor receptor (PDGFR) α and β were highly expressed in HBF clones. Follow up studies showed that the chemoattractant effects of PDGF in vitro was more enhanced in HBF compared to LBF clones and this effect was reduced in presence of a PDGFRβ-specific inhibitor: SU-16 f. Also, PDGF exerted greater chemoattractant effect on PDGFRβ(+) cells sorted from LBF clones compared to PDGFRβ(-) cells.ConclusionOur data demonstrate phenotypic and molecular association between in vivo bone forming ability and migratory capacity of hBMSC. PDGFRβ can be used as a potential marker for the prospective selection of hBMSC populations with high migration and bone formation capacities suitable for clinical trials for enhancing bone regeneration.

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

Publications

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

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