Osteoblastic expansion induced by parathyroid hormone receptor signaling in murine osteocytes is not sufficient to increase hematopoietic stem cells
ABSTRACT Microenvironmental expansion of hematopoietic stem cells (HSCs) is induced by treatment with parathyroid hormone (PTH) or activation of the PTH receptor (PTH1R) in osteoblastic cells; however, the osteoblastic subset mediating this action of PTH is unknown. Osteocytes are terminally differentiated osteoblasts embedded in mineralized bone matrix but are connected with the BM. Activation of PTH1R in osteocytes increases osteoblastic number and bone mass. To establish whether osteocyte-mediated PTH1R signaling expands HSCs, we studied mice expressing a constitutively active PTH1R in osteocytes (TG mice). Osteoblasts, osteoclasts, and trabecular bone were increased in TG mice without changes in BM phenotypic HSCs or HSC function. TG mice had progressively increased trabecular bone but decreased HSC function. In severely affected TG mice, phenotypic HSCs were decreased in the BM but increased in the spleen. TG osteocytes had no increase in signals associated with microenvironmental HSC support, and the spindle-shaped osteoblastic cells that increased with PTH treatment were not present in TG bones. These findings demonstrate that activation of PTH1R signaling in osteocytes does not expand BM HSCs, which are instead decreased in TG mice. Therefore, osteocytes do not mediate the HSC expansion induced by PTH1R signaling. Further, osteoblastic expansion is not sufficient to increase HSCs.
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ABSTRACT: Hematopoietic stem cells (HSCs) reside in regulatory niches in the bone marrow (BM). Although HSC niches have been extensively characterized, the role of endosteal osteoblasts (OBs) in HSC regulation requires further clarification, and the role of OBs in regulating leukemic stem cells (LSC) is not well studied. We used an OB visualization and ablation mouse model to study the role of OBs in regulating normal HSC and chronic myelogenous leukemia (CML) LSC. OB ablation resulted in increase in cells with a LSK Flt3-CD150+CD48- long-term HSC (LTHSC) phenotype, but reduction of a more highly selected LSK Flt3-CD34-CD49b-CD229- LTHSC subpopulation. LTHSCs from OB-ablated mice demonstrated loss of quiescence, and reduced long-term engraftment and self-renewal capacity. Ablation of OB in a transgenic CML mouse model resulted in accelerated leukemia development with reduced survival compared to control mice. The notch ligand Jagged-1 was overexpressed on CML OB. Normal and CML LTHSC cultured with Jagged-1 demonstrated reduced cell cycling, consistent with a possible role for loss of Jagged-1 signals in altered HSC and LSC function after OB ablation. These studies support an important role for OBs in regulating quiescence and self-renewal of LTHSCs, and a previously unrecognized role in modulating leukemia development in CML. Copyright © 2015 American Society of Hematology.Blood 03/2015; 125(17). DOI:10.1182/blood-2014-06-582924 · 9.78 Impact Factor
09/2014; 3:572. DOI:10.1038/bonekey.2014.67
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ABSTRACT: Hematopoiesis in vertebrates is sustained over the duration of an organism's lifetime due to strict regulation of the highly hierarchical hematopoietic system, where a few immature hematopoietic stem cells continuously regenerate the entire blood supply, which is constantly being replaced. While HSCs self-regulate through cell-autonomous processes, they also receive a variety of signals from their microenvironment or niche. Within the microenvironment, HSCs are regulated through both cell-cell interactions and secreted signals, including hormones. HSCs at the apex of the blood supply integrate these signals in order produce progeny to support hematopoiesis, while simultaneously maintaining a stem cell pool. In the past 10 years advances in genetic models and flow cytometry have provided the tools to test how the microenvironment regulates HSCs. This review is organized in three main parts and will focus on cellular components of the HSC niche which are potential targets for hormonal signals, then review critical regulatory signals in the HSC niche and finally highlight the emerging role of hormonal and paracrine signals in the bone marrow.Molecular Endocrinology 08/2014; DOI:10.1210/me.2014-1079 · 4.20 Impact Factor