Abstract
Hematopoiesis produce every day billions of blood cells and takes place in the bone marrow (BM) by the proliferation and differentiation of hematopoietic stem cells (HSC). HSC are found mainly adjacent to the BM vascular sinusoids where endothelial cells and mesenchimal stromal cells promote HSC maintenance by producing a variety of factors. Other cell types that regulate HSC niches include sympathetic nerves, non–myelinating Schwann cells and a variety of mature hematopoietic cells such as macrophages, neutrophils, and megakaryocytes. This review will focus on the role of adrenergic signals, i.e. of catecholamines, in the regulation of the HSC niche. The available evidence is rather controversial possibly due to the fact that adrenergic receptors are expressed by many cellular components of the niche and also by the often neglected observation that catecholamines may be produced and released also by the BM cells themselves. In addition one has to consider that, physiologically, the sympathetic nervous system (SNS) activity follows a circadian rhythmicity as driven by the suprachiasmatic nucleus (SCN) of the hypothalamus but may be also activated by cognitive and non-cognitive environmental stimuli. The adrenergic modulation of hematopoiesis holds a considerable potential for pharmacological therapeutic approaches in a variety of hematopoietic disorders and for HSC transplantation however the complexity of the system demands further studies.
Similar content being viewed by others
References
Ahlqvist RP (1948) A study of the adrenotropic receptors. Am J Phys 153(3):586–600
Al-Sharea A, Lee MKS, Whillas A, Michell D, Shihata W, Nicholls AJ, Cooney OD, Kraakman MJ, Bertuzzo Veiga C, Jefferis AM, Jackson K, Nagareddy PR, Lambert G, Wong CHY, Andrews KL, Head GA, Chin-Dusting J, Murphy AJ (2018) Chronic sympathetic driven hypertension promotes atherosclerosis by enhancing hematopoiesis. Haematologica. pii: haematol.2018.192898. https://doi.org/10.3324/haematol.2018.192898.
Arranz L, Sánchez-Aguilera A, Martín-Pérez D, Isern J, Langa X, Tzankov A, Lundberg P, Muntión S, Tzeng YS, Lai DM, Schwaller J, Skoda RC, Méndez-Ferrer S (2014) Neuropathy of haematopoietic stem cell niche is essential for myeloproliferative neoplasms. Nature 512(7512):78–81. https://doi.org/10.1038/nature13383
Asri A, Sabour J, Akashi A, Soleimani M (2016) Homing in hematopoietic stem cells: focus on regulatory role of CXCR7 on SDF1a/CXCR4 axis. EXCLI J 15:134–143. https://doi.org/10.17179/excli2014-585
Benestad HB, Gundersen IS, Iversen PO, Haug E, Nja A (1998) No neuronal regulation of murine bone marrow function. Blood 91:1280
Berlinger DL, Lorton D, Lubhan C, Felten DL (2001) Innervation of lymphoid organs- association of nerves with cells of the immune system and their implication in disease. In: Adre R, Felten DL, Cohen N (eds). Psychoneuroimmunology , 3rd end Academic Press, San Diego, pp55–113.
Black PH (2003) The inflammatory response is an integral part of the stress response: implications for atherosclerosis, insulin resistance, type II diabetes and metabolic syndrome X. Brain Behav Immun 17(5):350–364
Blank U, Karlsson S (2015) TGF-β signaling in the control of hematopoietic stem cell. Blood 125:3542–3550. https://doi.org/10.1182/blood-2014-12-618090
Budkowska M, Ostrycharz E, Wojtowicz A, Marcinowska Z, Woźniak J, Ratajczak MZ, Dołęgowska B (2018) A circadian rhythm in both complement Cascade (ComC) activation and Sphingosine-1-phosphate (S1P) levels in human peripheral blood supports a role for the ComC–S1P Axis in circadian changes in the number of stem cells circulating in peripheral blood. Stem Cell Rev 14(5):677–685. https://doi.org/10.1007/s12015-018-9836-7
Bylund DB, Eikenberg DC, Hieble JP, Langer SZ, Lefkowitz RJ, Minneman KP, Molinoff PB, Ruffolo RR Jr, Trendelenburg U (1994) International union of pharmacology nomenclature of adrenoceptors. Pharmacol Rev 46(2):121–136
Coiffard B, Diallo AB, Culver A, Mezouar S, Hammad E, Vigne C, Nicolino-Brunet C, Dignat-George F, Baumstarck K, Boucekine M, Leone M, Mege JL (2018, 2018 Aug 2) Circadian rhythm disruption and sepsis in severe trauma patients. Shock:1. https://doi.org/10.1097/SHK.0000000000001241
Cosentino M, Bombelli R, Ferrari M, Marino F, Rasini E, Maestroni GJ, Conti A, Boveri M, Lecchini S, Frigo G (2000) HPLC-ED measurement of endogenous catecholamines in human immune cells and hematopoietic cell lines. Life Sci 68(3):283–295
Courties G, Herisson F, Sager HB, Heidt T, Ye Y, Wei Y, Sun Y, Severe N, Dutta P, Scharff J, Scadden DT, Weissleder R, Swirski FK, Moskowitz MA, Nahrendorf M (2015) Ischemic stroke activates hematopoietic bone marrow stem cells. Circ Res 116(3):407–417. https://doi.org/10.1161/CIRCRESAHA.116.305207
Ding L, Saunders TL, Enikolopov G, Morrison SJ (2012) Endothelial and perivascular cells maintain haematopoietic stem cells. Nature 481(7382):457–462. https://doi.org/10.1038/nature10783
Feldman RS, Meyer JS, Quenzer LF (1997) Catecholamines, in principles of neuropsychopharmacology. Sinauer Associates Inc, Sunderland, pp 277–344
Felten DL, Felten SY, Carlson SL, Olschowka JA, Livnat S (1985) Noradrenergic and peptidergic innervation of lymphoid tissue. J Immune 135(2 Suppl):755s–765s.
Flierl MA, Rittirsch D, Huber-Lang M, Sarma JV, Ward PA (2008) Catecholamines-crafty weapons in the inflammatory arsenal of immune/inflammatory cells or opening pandora's box? Mol Med 14(3–4):195–204
Freeman JG, Ryan JJ, Shelburne CP, Bailey DP, Bouton LA, Narasimhachari N, Domen J, Siméon N, Couderc F, Stewart JK (2001) Catecholamines in murine bone marrow derived mast cells. J Neuroimmunol 119(2):231–238
Gauthier C, Tavernier G, Charpentier F, Langin D, Le Marec H (1996) Functional beta3-adrenoceptor in the human heart. J Clin Invest 98(2):556–562
Golan K, Vagima Y, Ludin A, Itkin T, Cohen-Gur S, Kalinkovich A, Kollet O, Kim C, Schajnovitz A, Ovadya Y, Lapid K, Shivtiel S, Morris AJ, Ratajczak MZ, Lapidot T (2012) S1P promotes murine progenitor cell egress and mobilization via S1P1-mediated ROS signaling and SDF-1 release. Blood 119(11):2478–2488
Guimarães S, Moura D (2001) Vascular adrenoceptors: an update. Pharmacol Rev 53(2):319–356
Han J, Zou Z, Zhu C, Deng J, Wang J, Ran X, Shi C, Ai G, Li R, Cheng T, Su Y (2009) DNA synthesis of rat bone marrow mesenchymal stem cells through alpha1-adrenergic receptors. Arch Biochem Biophys 490(2):96–102. https://doi.org/10.1016/j.abb.2009.08.009
Hanoun M, Zhang D, Mizoguchi T, Pinho S, Pierce H, Kunisak Y, Lacombe J, Armstrong SA, Dührsen U, Frenette PS (2014) Acute myelogenous leukemia-induced sympathetic neuropathy promotes malignancy in an altered hematopoietic stem cell niche. Cell Stem Cell 15(3):365–375. https://doi.org/10.1016/j.stem.2014.06.020
Hasan S, Johnson NB, Mosier MJ, Shankar R, Conrad P, Szilagyi A, Gamelli RL, Muthumalaiappan K (2017) Myelo-erythroid commitment after burn injury is under β-adrenergic control via MafB regulation. Am J Physiol Cell Physiol 312(3):C286–C301. https://doi.org/10.1152/ajpcell.00139.2016
Hattori K, Heissig B, Tashiro K, Honjo T, Tateno M, Shieh JH, Hackett NR, Quitoriano MS, Crystal RG, Rafii S, Moore MA (2001) Plasma elevation of stem cell-derived factor-1 induces mobilization of mature and immature hematopoietic progenitor and stem cells. Blood 97(11):3354–3360
Heidt T, Sager HB, Courties G, Dutta P, Iwamoto Y, Zaltsman A, von Zur Muhlen C, Bode C, Fricchione GL, Denninger J, Lin CP, Vinegoni C, Libby P, Swirski FK, Weissleder R, Nahrendorf M. (2014) Chronic variable stress activates hematopoietic stem cells. Nat Med Jul;20(7):754–758. doi: https://doi.org/10.1038/nm.3589
Kaminski DA, Letterio JJ, Burrows PD (2002) Differential regulation of mouse B cell development by transforming growth factor beta1. Dev Immunol 9(2):85–95
Katayama Y, Battista M, Kao WM, Hidalgo A, Peired AJ, Thomas SA, Frenette PS (2006) Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell 124(2):407–421. https://doi.org/10.1016/J.cell.2005.10.041
Kawano Y, Fukui C, Shinohara M, Wakahashi K, Ishii S, Suzuki T, Sato M, Asada N, Kawano H, Minagawa K, Sada A, Furuyashiki T, Uematsu S, Akira S, Uede T, Narumiya S, Matsui T, Katayama Y (2017) G-CSF-induced sympathetic tone provokes fever and primes antimobilizing functions of neutrophils via PGE2. Blood 129(5):587–597. https://doi.org/10.1182/blood-2016-07-725754
Kunisaki Y, Bruns I, Scheiermann C, Ahmed J, Pinho S, Zhang D, Mizoguchi T, Wei Q, Lucas D, Ito K, Mar JC, Bergman A, Frenette PS (2013) Arteriolar niches maintain haematopoietic stem cell quiescence. Nature 502(7473):637–643. https://doi.org/10.1038/nature12612 Epub 2013 Oct 9
Laukova M, Vargovic P, Vlcek M, Lejavova K, Hudecova S, Krizanova O, Kvetnansky R (2013) Catecholamine production is differently regulated in splenic T- and B-cells following stress exposure. Immunobiology 218(5):780–789. https://doi.org/10.1016/j.imbio.2012.08.279
Letterio JJ, Geiser AG, Kulkarni AB, Dang H, Kong L, Nakabayashi T, Mackall CL, Gress RE, Roberts AB (1996) Autoimmunity associated with TGF-beta1-deficiency in mice is dependent on MHC class II antigen expression. J Clin Invest 98(9):2109–2119
Lucas D, Battista M, Shi PA, Isola L, Frenette PS (2008) Mobilized hematopoietic stem cell yield depends on species-specific circadian timing. Cell Stem Cell 3(4):364–366. https://doi.org/10.1016/j.stem.2008.09.004
Lucas D, Bruns I, Battista M, Mendez-Ferrer S, Magnon C, Kunisaki Y, Frenette PS (2012) Norepinephrine reuptake inhibition promotes mobilization in mice: potential impact to rescue low stem cell yields. Blood 119(17):3962–3965. https://doi.org/10.1182/blood-2011-07-367102
Lucas D, Scheiermann C, Chow A, Kunisaki Y, Bruns I, Barrick C, Frenette PS (2013) Chemotherapy-induced bone marrow nerve injury impairs hematopoietic regeneration. Nat Med 19(6):695–703. https://doi.org/10.1038/nm.3155
Maestroni GJ (1995) Adrenergic regulation of haematopoiesis. Pharmacol Res 32(5):249–253
Maestroni GJ (2000) Neurohormones and catecholamines as functional components of the bone marrow microenvironment. Ann N Y Acad Sci 917:29–37
Maestroni GJ, Conti A (1994a) Noradrenergic modulation of lymphohematopoiesis. Int J Immunopharmacol 16(2):117–122
Maestroni GJ, Conti A (1994b) Modulation of hematopoiesis via alpha 1-adrenergic receptors on bone marrow cells. Exp Hematol 22(3):313–320
Maestroni GJ, Conti A, Pedrinis E (1992) Effect of adrenergic agents on hematopoiesis after syngeneic bone marrow transplantation in mice. Blood 80(5):1178–1182
Maestroni GJ, Togni M, Covacci V (1997) Norepinephrine protects mice from acute lethal doses of carboplatin. Exp Hematol 25(6):491–494
Maestroni GJ, Cosentino M, Marino F, Togni M, Conti A, Lecchini S, Frigo G (1998) Neural and endogenous catecholamines in the bone marrow. Circadian association of norepinephrine with hematopoiesis? Exp Hematol 26(12):1172–1177
Marino F, Cosentino M (2013) Adrenergic modulation of immune cells: an update. Amino Acids 45(1):55–71. https://doi.org/10.1007/s00726-011-1186-6
Marino F, Cosentino M, Bombelli R, Ferrari M, Maestroni GJ, Conti A, Lecchini S (1997) Measurement of catecholamines in mouse bone marrow by means of HPLC with electrochemical detection. Haematologica 82(4):392–394
Martínez A, Bono C, Megías J, Yáñez A, Gozalbo D, Gil ML (2018) Systemic candidiasis and TLR2 agonist exposure impact the antifungal response of hematopoietic stem and progenitor cells. Front Cell Infect Microbiol 8:309. https://doi.org/10.3389/fcimb.2018.00309
Massberg S, Von Andrian UH (2009) Novel trafficking routes for hematopoietic stem and progenitor cells. Ann N Y Acad Sci 1176:87–93. https://doi.org/10.1111/j.1749-6632.2009.04609.x
Méndez-Ferrer S, Lucas D, Battista M, Frenette PS (2008) Haematopoietic stem cell release is regulated by circadian oscillations. Nature 452(7186):442–447. https://doi.org/10.1038/nature06685
Méndez-Ferrer S, Chow A, Merad M, Frenette PS (2009) Circadian rhythms influence hematopoietic stem cells. Curr Opin Hematol 16(4):235–242. https://doi.org/10.1097/MOH.0b013e32832bd0f5
Morrison SJ, Scadden DT (2014) The bone marrow niche for haematopoietic stem cells. Nature 505(7483):327–334. https://doi.org/10.1038/nature12984
Muthu K, Iyer S, He L-K, Szilagyi A, Gamelli RL, Shankar R, Jones SB (2007) Murine hematopoietic stem cells and progenitors express adrenergic receptors. J Neuroimmunol 186(1–2):27–36
Nicholls AJ, Wen SW, Hall P, Hickey MJ, Wong CHY (2018) Activation of the sympathetic nervous system modulates neutrophil function. J Leukoc Biol 103(2):295–309. https://doi.org/10.1002/JLB
Okamura H (2007) Suprachiasmatic nucleus clock time in the mammalian circadian system. Cold Spring Harb Symp Quant Biol 72:551–556
Pasupuleti LV, Cook KM, Sifri ZC, Alzate WD, Livingston DH, Mohr AM (2014) Do all β-blockers attenuate the excess hematopoietic progenitor cell mobilization from the bone marrow following trauma/hemorrhagic shock? J Trauma Acute Care Surg 76(4):970–975. https://doi.org/10.1097/TA.0000000000000181.
Petit I, Szyper-Kravitz M, Nagler A, Lahav M, Peled A, Habler L, Ponomaryov T, Taichman RS, Arenzana-Seisdedos F, Fujii N, Sandbank J, Zipori D, Lapidot T (2002) G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4. Nat Immunol 3(7):687–694
Powell ND, Sloan EK, Bailey MT, Arevalo JMG, Miller GE, Chen E, Cole SW (2013) Social stress up-regulates inflammatory gene expression in the leukocyte transcriptome via β-adrenergic induction of myelopoiesis. Proc Natl Acad Sci U S A 110(41):16574–16579. https://doi.org/10.1073/pnas.1310655110
Récalde A, Richart A, Guérin C, Cochain C, Zouggari Y, Yin KH, Vilar J, Drouet I, Lévy B, Varoquaux O, Silvestre JS (2012) Sympathetic nervous system regulates bone marrow-derived cell egress through endothelial nitric oxide synthase activation: role in postischemic tissue remodeling. Arterioscler Thromb Vasc Biol Mar 32(3):643–653. https://doi.org/10.1161/ATVBAHA.111.244392
Saba F, Soleimani M, Kaviani S, Abroun S, Sayyadipoor F, Behrouz S, Saki N (2015) G-CSF induces up-regulation of CXCR4 expression in human hematopoietic stem cells by beta-adrenergic agonist. Hematology 20(8):462–468. https://doi.org/10.1179/1607845414Y.0000000220
Scanzano A, Cosentino M (2015) Adrenergic regulation of innate immunity: a review. Front Pharmacol 6:171. https://doi.org/10.3389/fphar.2015.00171
Schofield R (1978) The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells 4(1–2):7–25
Shastri A, Budhathoki A, Barta SK, Kornblum N, Derman O, Battini R, Raghupathy R, Verma AK, Frenette PS, Braunschweig I, Janakiram M (2017) Stimulation of adrenergic activity by desipramine enhances hematopoietic stem and progenitor cell mobilization along with G-CSF in multiple myeloma: a pilot study. Am J Hematol 92(10):1047–1051. https://doi.org/10.1002/ajh.24843
Skurikhin EG, Pershina OV, Minakova MY, Dygai AM, Gol'dberg ED (2006) Monoaminergic regulation of proliferation and differentiation of granulomonocytopoietic precursors during neuroses. Bull Exp Biol Med 141(6):669–674
Taichman RS, Emerson SG (1994) Human osteoblasts support hematopoiesis through the production of granulocyte colony-stimulating factor. J Exp Med 179(5):1677–1682
Tang Y, Shankar R, Gamboa M, Desai S, Gamelli RL, Jones SB (2001) Norepinephrine modulates myelopoiesis after experimental thermal injury with sepsis. Ann Surg 233(2):266–275
Togni M, Maestroni G (1996) Hematopoietic rescue in mice via alpha 1-adrenoceptors on bone marrow B cell precursors. Int J Oncol 9(2):313–318
Tsunokuma N, Yamane T, Matsumoto C, Tsuneto M, Isono K, Imanaka-Yoshida K, Yamazaki H (2017) Depletion of neural crest-derived cells leads to reduction in plasma noradrenaline and alters B Lymphopoiesis. J Immunol 32198(1):156–169. https://doi.org/10.4049/jimmunol.1502592
Vasamsetti SB, Florentin J, Coppin E, Stiekema LCA, Zheng KH, Nisar MU, Sembrat J, Levinthal DJ, Rojas M, Stroes ESG, Kim K, Dutta P (2018) Sympathetic neuronal activation triggers myeloid progenitor proliferation and differentiation. Immunity 49(1):93–106.e7. https://doi.org/10.1016/j.immuni.2018.05.004
Wu X, Wang Z, Qian M, Wang L, Bai C, Wang X (2014) Adrenaline stimulates the proliferation and migration of mesenchymal stem cells towards the LPS-induced lung injury. J Cell Mol Med 18(8):1612–1622. https://doi.org/10.1111/jcmm.12283
Yamazaki S, Ema H, Karlsson G, Yamaguchi T, Miyoshi H, Shioda S, Taketo MM, Karlsson S, Iwama A, Nakauchi H (2011) Nonmyelinating Schwann cells maintain hematopoietic stem cell hibernation in the bone marrow niche. Cell 147(5):1146–1158. https://doi.org/10.1007/s12185-014-1588-9
Zhang J, Niu C, Ye L, Huang H, He X, Tong WG, Ross J, Haug J, Johnson T, Feng JQ, Harris S, Wiedemann LM, Mishina Y, Li L (2003) Identification of the haematopoietic stem cell niche and control of the niche size. Nature 425(6960):836–841
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
No conflict of interest applies to this work.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Maestroni, G.J.M. Adrenergic Modulation of Hematopoiesis. J Neuroimmune Pharmacol 15, 82–92 (2020). https://doi.org/10.1007/s11481-019-09840-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11481-019-09840-7