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Social Stress Mobilizes Hematopoietic Stem Cells to Establish Persistent Splenic Myelopoiesis.

ABSTRACT: Psychosocial stress accelerates myelopoietic production of monocytes and neutrophils that contributes to a variety of health complications ranging from atherosclerosis to anxiety. Here, we show that social stress in mice mobilizes hematopoietic stem progenitor cells (HSPCs) from the bone marrow that enter circulation, engraft into the spleen, and establish a persistent extramedullary hematopoietic depot. These splenic progenitors actively proliferate and differentiate into multiple cell types, including monocytes, neutrophils, and erythrocytes. Splenic erythropoiesis partially abrogates stress-induced anemia. Repeated injection with isoprenaline induces progenitor mobilization to the spleen, identifying a key role for ?-adrenergic signaling. Moreover, protracted splenic production of CD11b+ cells persists for at least 24 days after the cessation of social stress. Thus, chronic stress establishes a persistent extramedullary hematopoietic depot that can modify a wide range of chronic disease processes and alter homeostasis of the bi-directional regulatory axis between the nervous and immune systems.

SUBMITTER: McKim DB

PROVIDER: S-EPMC6342493 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Social Stress Mobilizes Hematopoietic Stem Cells to Establish Persistent Splenic Myelopoiesis.

McKim Daniel B DB Yin Wenyuan W Wang Yufen Y Cole Steve W SW Godbout Jonathan P JP Sheridan John F JF

Cell reports 20181101 9

Psychosocial stress accelerates myelopoietic production of monocytes and neutrophils that contributes to a variety of health complications ranging from atherosclerosis to anxiety. Here, we show that social stress in mice mobilizes hematopoietic stem progenitor cells (HSPCs) from the bone marrow that enter circulation, engraft into the spleen, and establish a persistent extramedullary hematopoietic depot. These splenic progenitors actively proliferate and differentiate into multiple cell types, i ...[more]

PMID: 30485819

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Project description:Elevated levels of the pro-inflammatory cytokine tumor necrosis factor-? (TNF?) inhibit erythropoiesis and cause anemia in patients with cancer and chronic inflammatory diseases. TNF? is also a potent activator of the sphingomyelinase (SMase)/ceramide pathway leading to ceramide synthesis and regulating cell differentiation, proliferation, apoptosis, senescence, and autophagy. Here we evaluated the implication of the TNF?/SMase/ceramide pathway on inhibition of erythropoiesis in human CD34+ hematopoietic stem/progenitor cells (CD34/HSPCs) from healthy donors. Exogenous synthetic C2- and C6-ceramide as well as bacterial SMase inhibited erythroid differentiation in erythropoietin-induced (Epo)CD34/HSPCs shown by the analysis of various erythroid markers. The neutral SMase inhibitor GW4869 as well as the genetic inhibition of nSMase with small interfering RNA (siRNA) against sphingomyelin phosphodiesterase 3 (SMPD3) prevented the inhibition by TNF?, but not the acid SMase inhibitor desipramine. Moreover, sphingosine-1-phosphate (S1P), a ceramide metabolite, restored erythroid differentiation, whereas TNF? inhibited sphingosine kinase-1, required for S1P synthesis. Analysis of cell morphology and colony formation demonstrated that erythropoiesis impairment was concomitant with a granulomonocytic differentiation in TNF?- and ceramide-treated EpoCD34/HSPCs. Inhibition of erythropoiesis and induction of granulomonocytic differentiation were correlated to modulation of hematopoietic transcription factors (TFs) GATA-1, GATA-2, and PU.1. Moreover, the expression of microRNAs (miR)-144/451, miR-146a, miR-155, and miR-223 was also modulated by TNF? and ceramide treatments, in line with cellular observations. Autophagy plays an essential role during erythropoiesis and our results demonstrate that the TNF?/neutral SMase/ceramide pathway inhibits autophagy in EpoCD34/HSPCs. TNF?- and ceramide-induced phosphorylation of mTORS2448 and ULK1S758, inhibited Atg13S355 phosphorylation, and blocked autophagosome formation as shown by transmission electron microscopy and GFP-LC3 punctae formation. Moreover, rapamycin prevented the inhibitory effect of TNF? and ceramides on erythropoiesis while inhibiting induction of myelopoiesis. In contrast, bafilomycin A1, but not siRNA against Atg5, induced myeloid differentiation, while both impaired erythropoiesis. We demonstrate here that the TNF?/neutral SMase/ceramide pathway inhibits erythropoiesis to induce myelopoiesis via modulation of a hematopoietic TF/miR network and inhibition of late steps of autophagy. Altogether, our results reveal an essential role of autophagy in erythroid vs. myeloid differentiation.

Dataset Information

Social Stress Mobilizes Hematopoietic Stem Cells to Establish Persistent Splenic Myelopoiesis.

Publications

Social Stress Mobilizes Hematopoietic Stem Cells to Establish Persistent Splenic Myelopoiesis.

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