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• W2126804912 abstract "HomeCirculation ResearchVol. 116, No. 3Waking Up the Stem Cell Niche Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBWaking Up the Stem Cell NicheHow Hematopoietic Stem Cells Generate Inflammatory Monocytes After Stroke Dennis Wolf and Klaus Ley Dennis WolfDennis Wolf From the Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA. Search for more papers by this author and Klaus LeyKlaus Ley From the Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA. Search for more papers by this author Originally published30 Jan 2015https://doi.org/10.1161/CIRCRESAHA.114.305678Circulation Research. 2015;116:389–392A substantial proportion of cardiovascular mortality is caused by atherosclerosis of large and midsized arteries that supply the brain. Stroke is the main complication of cerebral atherosclerosis and ranks second as cause of death worldwide.1 Recruitment of some myeloid cell subpopulations to atherosclerotic lesions can drive plaque inflammation and predispose to stroke. After a stroke, myeloid cells may also be harmful by directly aggravating the reperfusion injury to the brain. The latter possibility is of significant clinical relevance because epidemiological data have suggested that increased numbers of circulating leukocytes, particularly monocytes and neutrophils, after stroke correlate with poor outcomes.2 However, the functional mechanistic links between monocytosis and neutrophilia and stroke were unknown.Article, see p 407In the current issue of Circulation Research, Courties, Nahrendorf et al addressed this intriguing question and elucidate how stroke speeds up the turnover of hematopoietic stem cells (HSCs) to specifically generate myeloid cell populations and release them into the blood circulation.3 In their study, the authors have chosen an established mouse stroke model, in which the middle cerebral artery was transiently occluded. After this procedure, the numbers of monocytes and neutrophils resident in the bone marrow increased within 3 days, an effect caused by enhanced proliferation of myeloid progenitors, such as granulocyte-macrophage progenitors and monocyte/dendritic cell progenitors. Interestingly, this effect seems to be specific for myeloid cells because neither noninflammatory Ly6Clow monocytes, nor B cells or lymphoid progenitors showed increased turnover. In fact, the numbers of nonmyeloid cells, as well as expression of their lineage-characterizing factors, such as IL-7 receptor, decreased, whereas the myeloid transcription factor PU-1 increased, suggesting a specific effect on the myeloid lineage. In seeking the most upstream cause of this myeloid bias—a state defined by an increased myeloid-to-lymphoid cell ratio in the bone marrow—the authors found that HSC proliferation and cell cycle turnover was significantly promoted after stroke. So what activated these HSCs to cycle? The authors hypothesized that the tone of the autonomous nervous system could provide this link. Indeed, sympathetic nerves branching out into the bone marrow can directly activate the bone marrow niche, a part of the bone marrow microenvironment comprising all nonhematopoietic cells involved in HSC maintenance, quiescence, proliferation, and mobilization. Sympathetic nerve terminals secrete noradrenaline (also known as norepinephrine), which binds and activates adrenergic receptors expressed on cells of the bone marrow niche. In the current study, the authors show that mice deficient for the β3-adrenergic receptor do not show enhanced HSC cycling after transient middle cerebral artery occlude, concluding that sympathetic nerve signaling contributes to the HSC-activating effect of acute cerebral ischemia (Figure).Download figureDownload PowerPointFigure. Proposed mechanism of monocyte release from the bone marrow following stroke.3 Sympathetic nerve terminals, which end in the bone marrow, secrete noradrenaline after stroke. Noradrenaline binds to β3-adrenergic receptors (ADRB3) expressed on bone marrow stromal cells. In the resting bone marrow, vascular cell adhesion molecule 1 (VCAM-1) binds to the integrin α4β1 (VLA-4) to retain hematopoietic stem cells (HSCs) in the stem cell niche. Additionally, high concentrations of the bone marrow stromal C-X-C motif chemokine 12 (CXCL12) with high affinity to the receptor CXCR4 expressed on HSCs contribute to their retention. After stroke, expression of VCAM-1 and CXCL12 decreases by an yet undefined mechanism. As a result, HSCs, myeloid progenitor cells, such as granulocyte-macrophage progenitors (GMPs) and monocyte/dendritic cell progenitors (MDPs), and monocytes enter the blood circulation. Moreover, ADRB3 signaling enhances HSC proliferation, increases the myeloid transcription factor PU-1, and generates a myeloid bias with higher numbers of proinflammatory Ly6Chigh monocytes. Whether stroke-associated monocytosis stroke is protective by improving host defense or detrimental by worsening reperfusion injury and neuronal survival is currently unknown (both possibilities indicated).The current study completes a compelling series of studies by this same group demonstrating the disease-specific consequences of adrenergic signaling on HSC homeostasis4,5—a fundamental principle discovered by Frenette et al.6 This landmark study demonstrated that the chemokine stromal cell-derived factor 1/CXC-motif chemokine 12 (CXCL12), a factor required to retain HSCs in the bone marrow niche, is controlled by β3-, but not β2-, adrenergic signaling. Upon activation of β3-adrenergic receptor, the nuclear transcription factor Sp1 is dephosphorylated and degraded, most likely by cooperation of a serine protease and the S26 proteasome, resulting in downregulation of CXCL12 and impaired HSC retention.6,7 As an effect of this upstream activation by catecholamines, it was demonstrated that the appearance of HSC-enriched, lineage-negative, Sca-1+ c-Kit+ (LSK) cells in the blood circulation depends on circadian oscillations that correlate with sympathetic nerve outflow. Interestingly, HSC circulation in the blood stream was inversely correlated to CXCL12 expression in the bone marrow, and circadian variation was absent in animals deficient in genes of the molecular clock, such as genes encoding the transcription factor Aryl hydrocarbon receptor nuclear translocator-like, also known as Arntl or Bmal1. It is noteworthy that the particular cellular compartment in the bone marrow niche targeted by the nervous system remains to be fully identified. It has been demonstrated that cells of the endosteal bone marrow niche, such as osteoblasts, highly express CXCL12 to retain HSCs and progenitor cells by interaction with the chemokine receptor CXCR4 expressed on these cells. Notably, proteolytic cleavage of CXCR4 or CXCL12 itself can mobilize bone marrow stem cells.8,9 However, β3-adrenergic receptor is not expressed by osteoblasts,10 raising the possibility that other cells could be involved in mediating HSC mobilization after sympathetic activation. Interestingly, it has been proposed earlier that mesenchymal stem cells are regulated by β3-adrenergic signaling and thus represent a possible candidate cell type.5,11The authors of the current report expanded the concept that adrenergic signaling controls the bone marrow. Before the current report, they showed that this mechanism causes monocytosis during myocardial infarction4 and chronic stress.5 In addition to the mechanism presented in this report, they demonstrated earlier that bone marrow–derived monocytes infiltrate the atherosclerotic wall, aggravate local and systemic inflammation, and eventually enhance the probability of subsequent myocardial infarction. Notably, monocytes emanating from the bone marrow engrafted secondary niches, such as the spleen, to fill up the myeloid reservoir for later inflammatory events.4,12 In summary of all these studies, the authors provide evidence for the existence of a psycho-cellular vicious cycle, in which pain, anxiety, stress (and presumably circadian events) are potent drivers of bone marrow–derived monocytosis and HSC release with a myeloid bias, which in turn are likely to aggravate atherosclerosis and its complications like myocardial infarction and stroke.In the current work, the different imaging techniques used are of particular appeal. Several in vitro and in vivo imaging approaches directly visualize the inside of the bone marrow niche. Most illustratively, the authors induced experimental stroke in transgenic mice expressing the firefly enzyme luciferase under control of the cell cycle gene nuclear factor-Y–dependent cyclin B2 promoter. This whole body imaging approach allows monitoring and localizing proliferating, bioluminescent cells in living animals, including HSCs in the bone marrow. The authors also looked at the cell proliferation within the bone at the single cell level. To achieve this, they applied an elegant ex vivo imaging of LSK cell proliferation in the sternal bone 3 days after transient middle cerebral artery occlusion. LSKs, which were adoptively transferred 1 day before stroke induction, were labeled at a 1:1 ratio with the green fluorescent dye SP-DIOC and the red fluorescent dye CM-Dil. LSKs of both colors homed to the bone marrow. Remarkably, clusters of labeled cells found in the bone marrow were always of the same labeling color, but never in the expected 1:1 ratio of SP-DIOC and CM-Dil, suggesting that cell clusters were derived from locally proliferating LSKs. Moreover, the authors directly monitored stem cell proliferation by intravital microscopy in the skull bone at 2 different time points in the same animal. In using Nestin-GFP transgenic mice, many mesenchymal stem cells within the bone marrow niche are fluorescently marked and can be used as guide posts for identifying the same area in a second imaging session. The authors show fascinating pictures, in which proliferating, previously transferred HSCs, build clusters of stem cells only after stroke, but not after a sham procedure. In addition, the current work shows confocal imaging of increased expression of tyrosine hydroxylase—a rate limiting enzyme in norepinephrine synthesis—and its precise lining of bone marrow arterioles.Beyond the basic science appeal, the current study may contribute to a better understanding of and treatment for poststroke patients. One might propose that myeloid bias has been shaped by evolution because it provides a benefit to the host. It is not known whether this mechanism is protective or detrimental. One can speculate that an increased rate of infection after myocardial infarction, or stroke, such as pneumonia, urinary tract infection, and sepsis,13 would warrant an increased frequency and surveillance activity of innate immune cells. This hypothesis is supported by a study of Nguyen et al, who demonstrate that Bmal1 (Arntl) suppresses monocyte mobilization by repressing chemokine expression, such as CCL2. Notably, releasing monocytes from the bone marrow by inactivation of Bmal1 might directly contribute to host defense by conferring protection from listeria monocytogenes.14 On the other hand, stroke-associated monocytosis may represent a less-functional, myeloid-biased and malignancy-predisposing phenotype of the bone marrow as previously suggested.15,16 Monocyte released from the bone marrow are expected to aggravate reperfusion injury to the ischemic brain and worsen neuronal survival. The authors of the current study are well aware of this possible dichotomy and propose further studies to fully understand the consequences of the myeloid deployment after stroke. It will also be challenging to decipher the exact mechanism by which adrenergic signaling fuels HSC proliferation. Functional loss of CXCL12 can explain why HSCs are not retained in the niche any more—but how exactly does adrenergic signaling cause increased myeloid cell proliferation as observed by the authors in their model? This may indeed be explained by previous studies showing that adrenergic receptors are expressed on myeloid cells throughout different stages of myeloid differentiation to regulate activation, motility, and proliferation, particularly of HSCs.17,18 Notably, β3-receptors are restricted to bone marrow stromal cells, whereas β2-receptors are highly expressed within the hematopoietic and the stromal compartment.7 Consistent with this, the authors of the current study observed that genetic deletion of β3-adrenergic receptor abolishes the turnover of HSCs, whereas downstream progenitor cells remained responsive to norepinephrine. Whether this activation was dependent on β2-receptor signaling and confined to monocyte progenitors (and not lymphoid cells) was not tested, but the existence of β2-receptors on both HSCs and monocyte precursors may provide a plausible explanation for the effects observed. Also, synergistic activation of both β2- and β3 receptors may be required for the activation and proliferation of some, but not of all subpopulations of bone marrow stem cells as previously suggested.7 Conversely, it is also possible that the myeloid bias observed in the current study is the result of a failure of lymphoid progenitors to respond to the inflammatory stimuli, resulting in overwhelming production of myeloid cells.After stroke, the clinical outcome inversely correlates with leukocytosis in some studies, proposing that preventing monocytosis may be beneficial for patients.19 In the current study, the authors suggest that at least some of the remote catecholamine effects on the bone marrow are mediated by β3-adrenergic signaling—a target accessible by existing pharmacological strategies. However, whether modulation of stress-associated bone marrow hyperactivity can be prevented by β-blockers will have to be investigated in further studies. In clinical practice, β-receptor blocking drugs with specificity for cardiac expressed β1-receptors have superseded earlier strategies using nonselective β1-/β2-blockers, which also target β2-receptors in the GI-tract, bronchi, blood vessels, and muscles. In particular, specific β1-blockers have proven effective in the treatment of hypertension and after myocardial infarction. In this regard, blockade of cardiac β-receptors can mitigate the effects of toxic levels of catecholamines in the acute and chronic scenario and prolong life by preventing heart failure.20 The new perspective now provided by Courties et al may initiate a search for drugs that specifically target the unwanted catecholamine signaling in HSCs and myeloid precursors. Such drugs would need to target the bone marrow or the myeloid limb of differentiating leukocyte precursors because β3-receptors are widely expressed in other tissues, including adipose tissue and the myocardium, where their inhibition could precipitate unwanted side effects.21Sources of FundingD. Wolf was supported by DFG WO1994/1. K. Ley was supported by multiple grants from National Heart, Lung, and Blood Institute.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Klaus Ley, MD, Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle Dr, La Jolla, CA 92037. E-mail [email protected]References1. Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010.Lancet. 2012; 380:2095–2128. doi: 10.1016/S0140-6736(12)61728-0.CrossrefMedlineGoogle Scholar2. Urra X, Ariño H, Llull L, Amaro S, Obach V, Cervera Á, Chamorro Á. The outcome of patients with mild stroke improves after treatment with systemic thrombolysis.PLoS One. 2013; 8:e59420. doi: 10.1371/journal.pone.0059420.CrossrefMedlineGoogle Scholar3. Courties G, Herisson F, Sager HB, et al. Ischemic stroke activates hematopoietic bone marrow stem cells.Circ Res. 2015; 116:407–417. doi: 10.1161/CIRCRESAHA.116.305207.LinkGoogle Scholar4. Dutta P, Courties G, Wei Y, et al. Myocardial infarction accelerates atherosclerosis.Nature. 2012; 487:325–329. doi: 10.1038/nature11260.CrossrefMedlineGoogle Scholar5. Heidt T, Sager HB, Courties G, et al. 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Identification of splenic reservoir monocytes and their deployment to inflammatory sites.Science. 2009; 325:612–616. doi: 10.1126/science.1175202.CrossrefMedlineGoogle Scholar13. Westendorp WF, Nederkoorn PJ, Vermeij JD, Dijkgraaf MG, van de Beek D. Post-stroke infection: a systematic review and meta-analysis.BMC Neurol. 2011; 11:110. doi: 10.1186/1471-2377-11-110.CrossrefMedlineGoogle Scholar14. Nguyen KD, Fentress SJ, Qiu Y, Yun K, Cox JS, Chawla A. Circadian gene Bmal1 regulates diurnal oscillations of Ly6C(hi) inflammatory monocytes.Science. 2013; 341:1483–1488. doi: 10.1126/science.1240636.CrossrefMedlineGoogle Scholar15. Beerman I, Seita J, Inlay MA, Weissman IL, Rossi DJ. Quiescent hematopoietic stem cells accumulate DNA damage during aging that is repaired upon entry into cell cycle.Cell Stem Cell. 2014; 15:37–50. doi: 10.1016/j.stem.2014.04.016.CrossrefMedlineGoogle Scholar16. Pang WW, Price EA, Sahoo D, Beerman I, Maloney WJ, Rossi DJ, Schrier SL, Weissman IL. Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age.Proc Natl Acad Sci U S A. 2011; 108:20012–20017. doi: 10.1073/pnas.1116110108.CrossrefMedlineGoogle Scholar17. Spiegel A, Shivtiel S, Kalinkovich A, Ludin A, Netzer N, Goichberg P, Azaria Y, Resnick I, Hardan I, Ben-Hur H, Nagler A, Rubinstein M, Lapidot T. Catecholaminergic neurotransmitters regulate migration and repopulation of immature human CD34+ cells through Wnt signaling.Nat Immunol. 2007; 8:1123–1131. doi: 10.1038/ni1509.CrossrefMedlineGoogle Scholar18. Kavelaars A, van de Pol M, Zijlstra J, Heijnen CJ. Beta 2-adrenergic activation enhances interleukin-8 production by human monocytes.J Neuroimmunol. 1997; 77:211–216.CrossrefMedlineGoogle Scholar19. Nardi K, Milia P, Eusebi P, Paciaroni M, Caso V, Agnelli G. 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Cardioprotective effect of beta-3 adrenergic receptor agonism: role of neuronal nitric oxide synthase.J Am Coll Cardiol. 2012; 59:1979–1987. doi: 10.1016/j.jacc.2011.12.046.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Marchini T, Mitre L and Wolf D (2021) Inflammatory Cell Recruitment in Cardiovascular Disease, Frontiers in Cell and Developmental Biology, 10.3389/fcell.2021.635527, 9 van der Heijden C, Groh L, Keating S, Kaffa C, Noz M, Kersten S, van Herwaarden A, Hoischen A, Joosten L, Timmers H, Netea M and Riksen N (2020) Catecholamines Induce Trained Immunity in Monocytes In Vitro and In Vivo, Circulation Research, 127:2, (269-283), Online publication date: 3-Jul-2020. Schultze J, Mass E and Schlitzer A (2019) Emerging Principles in Myelopoiesis at Homeostasis and during Infection and Inflammation, Immunity, 10.1016/j.immuni.2019.01.019, 50:2, (288-301), Online publication date: 1-Feb-2019. Horváth E, Huțanu A, Orădan A, Chiriac L, Muntean D, Nagy E and Dobreanu M (2019) N-3 polyunsaturated fatty acids induce granulopoiesis and early monocyte polarization in the bone marrow of a tMCAO rat model, Revista Romana de Medicina de Laborator, 10.2478/rrlm-2019-0004, 27:1, (51-61), Online publication date: 1-Jan-2019., Online publication date: 1-Jan-2019. Moon G, Cho Y, Kim D, Sung J, Son J, Kim S, Cha J and Bang O (2018) Serum-mediated Activation of Bone Marrow–derived Mesenchymal Stem Cells in Ischemic Stroke Patients, Cell Transplantation, 10.1177/0963689718755404, 27:3, (485-500), Online publication date: 1-Mar-2018. Xue G, Han X, Ma X, Wu H, Qin Y, Liu J, Hu Y, Hong Y and Hou Y (2016) Effect of Microenvironment on Differentiation of Human Umbilical Cord Mesenchymal Stem Cells into Hepatocytes In Vitro and In Vivo , BioMed Research International, 10.1155/2016/8916534, 2016, (1-13), . Wolf D, Zirlik A and Ley K (2015) Beyond vascular inflammation—recent advances in understanding atherosclerosis, Cellular and Molecular Life Sciences, 10.1007/s00018-015-1971-6, 72:20, (3853-3869), Online publication date: 1-Oct-2015. January 30, 2015Vol 116, Issue 3 Advertisement Article InformationMetrics © 2015 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.114.305678PMID: 25634966 Originally publishedJanuary 30, 2015 KeywordshematopoiesismonocytesEditorialbone marrowstem cellsstrokePDF download Advertisement SubjectsAnimal Models of Human DiseasePathophysiology" @default.
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