SMAD Signaling Regulates CXCL12 Expression in the Bone Marrow Niche, Affecting Homing and Mobilization of Hematopoietic Progenitors

Khurana, Satish; Melacarne, Alessia; Yadak, Rana; Schouteden, Sarah; Notelaers, Tineke; Pistoni, Mariaelena; Maes, Christa; Verfaillie, Catherine M.

doi:10.1002/stem.1794

Cited by 35 publications

(29 citation statements)

References 59 publications

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“…1g). As published before31, we sorted osteoblasts (lin − CD45 − Ter119 − CD51 + Sca-1 − ), mesenchymal stem cells (lin − CD45 − Ter119 − CD51 + Sca-1 + ) and endothelial progenitor cells (lin − CD45 − Ter119 − CD31 + Sca-1 + ) to analyse expression of Postn . We observed the highest expression of Postn in the endothelial progenitors.…”

Section: Resultsmentioning

confidence: 99%

Outside-in integrin signalling regulates haematopoietic stem cell function via Periostin-Itgav axis

et al. 2016

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Integrins play an important role in haematopoietic stem cell (HSC) maintenance in the bone marrow niche. Here, we demonstrate that Periostin (Postn) via interaction with Integrin-αv (Itgav) regulates HSC proliferation. Systemic deletion of Postn results in peripheral blood (PB) anaemia, myelomonocytosis and lymphopenia, while the number of phenotypic HSCs increases in the bone marrow. Postn−/− mice recover faster from radiation injury with concomitant loss of primitive HSCs. HSCs from Postn−/− mice show accumulation of DNA damage generally associated with aged HSCs. Itgav deletion in the haematopoietic system leads to a similar PB phenotype and HSC-intrinsic repopulation defects. Unaffected by Postn, Vav-Itgav−/− HSCs proliferate faster in vitro, illustrating the importance of Postn-Itgav interaction. Finally, the Postn-Itgav interaction inhibits the FAK/PI3K/AKT pathway in HSCs, leading to increase in p27Kip1 expression resulting in improved maintenance of quiescent HSCs. Together, we demonstrate a role for Itgav-mediated outside-in signalling in regulation of HSC proliferation and stemness.

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Section: Resultsmentioning

confidence: 99%

Outside-in integrin signalling regulates haematopoietic stem cell function via Periostin-Itgav axis

et al. 2016

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“…Adrenergic signaling reduces CXCL12 expression in the BM. affecting maintenance of HSC and the differential lineage commitment [7,95]. …”

Section: Correlations With Other Systems and Functionsmentioning

confidence: 99%

Osteoimmunology and Beyond

Ginaldi

Martinis²

2016

CMC

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ObjectiveOsteoimmunology investigates interactions between skeleton and immune system. In the light of recent discoveries in this field, a new reading register of osteoporosis is actually emerging, in which bone and immune cells are strictly interconnected. Osteoporosis could therefore be considered a chronic immune mediated disease which shares with other age related disorders a common inflammatory background. Here, we highlight these recent discoveries and the new landscape that is emerging.MethodExtensive literature search in PubMed central.ResultsWhile the inflammatory nature of osteoporosis has been clearly recognized, other interesting aspects of osteoimmunology are currently emerging. In addition, mounting evidence indicates that the immunoskeletal interface is involved in the regulation of important body functions beyond bone remodeling. Bone cells take part with cells of the immune system in various immunological functions, configuring a real expanded immune system, and are therefore variously involved not only as target but also as main actors in various pathological conditions affecting primarily the immune system, such as autoimmunity and immune deficiencies, as well as in aging, menopause and other diseases sharing an inflammatory background.ConclusionThe review highlights the complexity of interwoven pathways and shared mechanisms of the crosstalk between the immune and bone systems. More interestingly, the interdisciplinary field of osteoimmunology is now expanding beyond bone and immune cells, defining new homeostatic networks in which other organs and systems are functionally interconnected. Therefore, the correct skeletal integrity maintenance may be also relevant to other functions outside its involvement in bone mineral homeostasis, hemopoiesis and immunity.

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“…Tzeng and colleagues demonstrated that the stroma‐secreted CXCL12 (stromal cell‐derived factor‐1) keeps the HSCs in a quiescent state and maintains them in the osteoblastic niche . CXCL12 has been shown to be involved in hematopoietic progenitor cell homing and mobilization . A recent experimental study documented that under conditions of chronic variable stress in mice, sympathetic nerve fibers released surplus noradrenaline, which signaled bone‐marrow (BM) niche cells to suppress CXCL12 expression through the Adrβ3 …”

Section: Introductionmentioning

confidence: 99%

Dipeptidyl Peptidase‐4 Regulates Hematopoietic Stem Cell Activation in Response to Chronic Stress

Zhu

Hu²,

et al. 2017

JAHA

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BackgroundDPP4 (Dipeptidyl peptidase‐4)‐GLP‐1 (glucagon‐like peptide‐1) and its receptor (GLP‐1R) axis has been involved in several intracellular signaling pathways. The Adrβ3 (β3‐adrenergic receptor)/CXCL12 (C‐X‐C motif chemokine 12) signal was required for the hematopoiesis. We investigated the novel molecular requirements between DPP4‐GLP‐1/GLP‐1 and Adrβ3/CXCL12 signals in bone marrow (BM) hematopoietic stem cell (HSC) activation in response to chronic stress.Methods and ResultsMale 8‐week‐old mice were subjected to 4‐week intermittent restrain stress and orally treated with vehicle or the DPP4 inhibitor anagliptin (30 mg/kg per day). Control mice were left undisturbed. The stress increased the blood and brain DPP4 levels, the plasma epinephrine and norepinephrine levels, and the BM niche cell Adrβ3 expression, and it decreased the plasma GLP‐1 levels and the brain GLP‐1R and BM CXCL12 expressions. These changes were reversed by DPP4 inhibition. The stress activated BM sca‐1highc‐Kithigh CD48low CD150high HSC proliferation, giving rise to high levels of blood leukocytes and monocytes. The stress‐activated HSC proliferation was reversed by DPP4 depletion and by GLP‐1R activation. Finally, the selective pharmacological blocking of Adrβ3 mitigated HSC activation, accompanied by an improvement of CXCL12 gene expression in BM niche cells in response to chronic stress.ConclusionsThese findings suggest that DPP4 can regulate chronic stress‐induced BM HSC activation and inflammatory cell production via an Adrβ3/CXCL12‐dependent mechanism that is mediated by the GLP‐1/GLP‐1R axis, suggesting that the DPP4 inhibition or the GLP‐1R stimulation may have applications for treating inflammatory diseases.

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SMAD Signaling Regulates CXCL12 Expression in the Bone Marrow Niche, Affecting Homing and Mobilization of Hematopoietic Progenitors

Cited by 35 publications

References 59 publications

Outside-in integrin signalling regulates haematopoietic stem cell function via Periostin-Itgav axis

Outside-in integrin signalling regulates haematopoietic stem cell function via Periostin-Itgav axis

Osteoimmunology and Beyond

Dipeptidyl Peptidase‐4 Regulates Hematopoietic Stem Cell Activation in Response to Chronic Stress

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