Neurological Regulation of the Bone Marrow Niche

Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1212)


The bone marrow (BM) hematopoietic niche is the microenvironment where in the adult hematopoietic stem and progenitor cells (HSPCs) are maintained and regulated. This regulation is tightly controlled through direct cell-cell interactions with mesenchymal stromal stem (MSCs) and reticular cells, adipocytes, osteoblasts and endothelial cells, through binding to extracellular matrix molecules and through signaling by cytokines and hematopoietic growth factors. These interactions provide a healthy environment and secure the maintenance of the HSPC pool, their proliferation, differentiation and migration. Recent studies have shown that innervation of the BM and interactions with the peripheral sympathetic neural system are important for maintenance of the hematopoietic niche, through direct interactions with HSCPs or via interactions with other cells of the HSPC microenvironment. Signaling through adrenergic receptors (ARs), opioid receptors (ORs), endocannabinoid receptors (CRs) on HSPCs and MSCs has been shown to play an important role in HSPC homeostasis and mobilization. In addition, a wide range of neuropeptides and neurotransmitters, such as Neuropeptide Y (NPY), Substance P (SP) and Tachykinins, as well as neurotrophins and neuropoietic growth factors have been shown to be involved in regulation of the hematopoietic niche. Here, a comprehensive overview is given of their role and interactions with important cells in the hematopoietic niche, including HSPCs and MSCs, and their effect on HSPC maintenance, regulation and mobilization.


Bone Marrow Niche Endocannabinoids Hematopoiesis Neuropeptides Opioids Tachykinins 











adrenergic receptors


Brain-Derived Growth factor


bone marrow




Low affinity nerve growth factor receptor


Colony Forming Unit-Fibroblast


Colony Forming Unit-Granulocyte/Erythrocyte/Monocyte/Megakaryocyte


choline acetyltransferase




central nervous system


ciliary neurotrophic factor


endocannabinoid receptors




Stromal Derived Factor-1




Dendritic cells


dopamine receptors






extracellular matrix


endothelial cells




fatty acid amide hydrolase


Fibroblasts growth factor


fetal thymus organ cultures


Granulocyte-Colony Stimulating Factor


glial cell-line derived neurotrophic factor


Glial-derived Neurotrophic Factor


GDNF family of ligands


Granulocyte/Macrophage-Colony Stimulating Factor


G-protein coupled receptors


hematopoietic growth factors




hematopoietic stem cells


hematopoietic stem and progenitor cells




Leukemia inhibiting factor

LSK cells

LinSca+c-kit+ cells


Macrophage Inflammatory Protein-1alpha




mesenchymal stromal/stem cells




Nerve growth factor

NK cell

Natural Killer cell


Neurokinin A


Neurokinin B


Neurokinin receptors


Neuropeptide Y






opioid receptors


Oncostatin M


periarterial adventitial cells


Platelet-derived growth factor


rearranged during transfection receptor


receptor tyrosine kinase


Stem Cell Factor


sympathetic nervous system


Substance P


Transforming Growth Factor


tyrosine hydrolase






Toll-like receptors


Tumor necrosis factor receptor


Tumor Necrosis Factor alpha




tropomyosin receptor kinase


Umbilical Cord Blood


Vascular endothelial growth factor


Wild type



This manuscript was supported by grants from the Scientific and Technological Research Council of Turkey, project no 318S073 and the Hacettepe University, Scientific Research Project Coordination Unit TYL-2018-17435 and THD-2018-17209.

Conflicts of Interest

The authors declare no conflict of interest.


  1. Artico M, Bosco S, Cavallotti C, Agostinelli E, Giuliani-Piccari G, Sciorio S, Cocco L, Vitale M (2002) Noradrenergic and cholinergic innervation of the bone marrow. Int J Mol Med 10(1):77–80PubMedGoogle Scholar
  2. Auffray I, Chevalier S, Froger J, Izac B, Vainchenker W, Gascan H, Coulombel L (1996) Nerve growth factor is involved in the supportive effect by bone marrow--derived stromal cells of the factor-dependent human cell line UT-7. Blood 88(5):1608–1618PubMedGoogle Scholar
  3. Aydin G (2018) Detailed characterization of MSCs from different sources, their ability to support lymphohematopoiesis and the importance of CD271 antigen for their isolation. Hacettepe University, AnkaraGoogle Scholar
  4. Baldock PA, Sainsbury A, Couzens M, Enriquez RF, Thomas GP, Gardiner EM, Herzog H (2002) Hypothalamic Y2 receptors regulate bone formation. J Clin Invest 109(7):915–921. Scholar
  5. Baldock PA, Lee NJ, Driessler F, Lin S, Allison S, Stehrer B, Lin EJ, Zhang L, Enriquez RF, Wong IP, McDonald MM, During M, Pierroz DD, Slack K, Shi YC, Yulyaningsih E, Aljanova A, Little DG, Ferrari SL, Sainsbury A, Eisman JA, Herzog H (2009) Neuropeptide Y knockout mice reveal a central role of NPY in the coordination of bone mass to body weight. PLoS One 4(12):e8415. Scholar
  6. Bandari PS, Qian J, Oh HS, Potian JA, Yehia G, Harrison JS, Rameshwar P (2003) Crosstalk between neurokinin receptors is relevant to hematopoietic regulation: cloning and characterization of neurokinin-2 promoter. J Neuroimmunol 138(1–2):65–75PubMedGoogle Scholar
  7. Beaujouan JC, Torrens Y, Saffroy M, Kemel ML, Glowinski J (2004) A 25 year adventure in the field of tachykinins. Peptides 25(3):339–357. Scholar
  8. Benard A, Boue J, Chapey E, Jaume M, Gomes B, Dietrich G (2008) Delta opioid receptors mediate chemotaxis in bone marrow-derived dendritic cells. J Neuroimmunol 197(1):21–28. Scholar
  9. Benarroch EE (2012) Endogenous opioid systems: current concepts and clinical correlations. Neurology 79(8):807–814. Scholar
  10. Berger A, Frelin C, Shah DK, Benveniste P, Herrington R, Gerard NP, Zuniga-Pflucker JC, Iscove NN, Paige CJ (2013) Neurokinin-1 receptor signalling impacts bone marrow repopulation efficiency. PLoS One 8(3):e58787. Scholar
  11. Bidlack JM (2000) Detection and function of opioid receptors on cells from the immune system. Clin Diagn Lab Immunol 7(5):719–723. Scholar
  12. Boranic M, Krizanac-Bengez L, Gabrilovac J, Marotti T, Breljak D (1997) Enkephalins in hematopoiesis. Biomed Pharmacother 51(1):29–37PubMedGoogle Scholar
  13. Bothwell M (1995) Functional interactions of neurotrophins and neurotrophin receptors. Annu Rev Neurosci 18:223–253. Scholar
  14. Bracci-Laudiero L, Celestino D, Starace G, Antonelli A, Lambiase A, Procoli A, Rumi C, Lai M, Picardi A, Ballatore G, Bonini S, Aloe L (2003) CD34-positive cells in human umbilical cord blood express nerve growth factor and its specific receptor TrkA. J Neuroimmunol 136(1–2):130–139PubMedGoogle Scholar
  15. Brothers SP, Wahlestedt C (2010) Therapeutic potential of neuropeptide Y (NPY) receptor ligands. EMBO Mol Med 2(11):429–439. Scholar
  16. Bruckner K (2011) Blood cells need glia, too: a new role for the nervous system in the bone marrow niche. Cell Stem Cell 9(6):493–495. Scholar
  17. Burbach JP (2010) Neuropeptides from concept to online database Eur J Pharmacol 626(1):27–48. Scholar
  18. Burbach JPH (2011) Chapter 1: What are neuropeptides? In: Merighi A (ed). Scholar
  19. Calvo W, Forteza-Vila J (1969) On the development of bone marrow innervation in new-born rats as studied with silver impregnation and electron microscopy. Am J Anat 126(3):355–371. Scholar
  20. Caneva L, Soligo D, Cattoretti G, De Harven E, Deliliers GL (1995) Immuno-electron microscopy characterization of human bone marrow stromal cells with anti-NGFR antibodies. Blood Cells Mol Dis 21(2):73–85PubMedGoogle Scholar
  21. Cattoretti G, Schiro R, Orazi A, Soligo D, Colombo MP (1993) Bone marrow stroma in humans: anti-nerve growth factor receptor antibodies selectively stain reticular cells in vivo and in vitro. Blood 81(7):1726–1738PubMedGoogle Scholar
  22. Chesa PG, Rettig WJ, Thomson TM, Old LJ, Melamed MR (1988) Immunohistochemical analysis of nerve growth factor receptor expression in normal and malignant human tissues. J Histochem Cytochem 36(4):383–389. Scholar
  23. Cosentino M, Marino F, Maestroni GJ (2015) Sympathoadrenergic modulation of hematopoiesis: a review of available evidence and of therapeutic perspectives. Front Cell Neurosci 9:302. Scholar
  24. Cox G, Boxall SA, Giannoudis PV, Buckley CT, Roshdy T, Churchman SM, McGonagle D, Jones E (2012) High abundance of CD271(+) multipotential stromal cells (MSCs) in intramedullary cavities of long bones. Bone 50(2):510–517. Scholar
  25. Diaz-Laviada I, Ruiz-Llorente L (2005) Signal transduction activated by cannabinoid receptors. Mini Rev Med Chem 5(7):619–630PubMedGoogle Scholar
  26. Felten SY, Felten DL, Bellinger DL, Olschowka JA (1992) Noradrenergic and peptidergic innervation of lymphoid organs. Chem Immunol 52:25–48PubMedGoogle Scholar
  27. Fitch SR, Kimber GM, Wilson NK, Parker A, Mirshekar-Syahkal B, Gottgens B, Medvinsky A, Dzierzak E, Ottersbach K (2012) Signaling from the sympathetic nervous system regulates hematopoietic stem cell emergence during embryogenesis. Cell Stem Cell 11(4):554–566. Scholar
  28. Fonseca-Pereira D, Arroz-Madeira S, Rodrigues-Campos M, Barbosa IA, Domingues RG, Bento T, Almeida AR, Ribeiro H, Potocnik AJ, Enomoto H, Veiga-Fernandes H (2014) The neurotrophic factor receptor RET drives haematopoietic stem cell survival and function. Nature 514(7520):98–101. Scholar
  29. Garcia-Garcia A, Korn C, Garcia-Fernandez M, Domingues O, Villadiego J, Martin-Perez D, Isern J, Bejarano-Garcia JA, Zimmer J, Perez-Simon JA, Toledo-Aral JJ, Michel T, Airaksinen MS, Mendez-Ferrer S (2019) Dual cholinergic signals regulate daily migration of hematopoietic stem cells and leukocytes. Blood 133(3):224–236. Scholar
  30. Gerard NP, Bao L, Xiao-Ping H, Gerard C (1993) Molecular aspects of the tachykinin receptors. Regul Pept 43(1–2):21–35PubMedGoogle Scholar
  31. Gol’dberg ED, Zakharova O, Dygai AM, Simanina EV, Agafonov VI (1987) Modulating effect of enkephalins on hemopoieis under stress. Biull Eksp Biol Med 103(5):589–590PubMedGoogle Scholar
  32. Gowran A, McKayed K, Campbell VA (2013) The cannabinoid receptor type 1 is essential for mesenchymal stem cell survival and differentiation: implications for bone health. Stem Cells Int 2013:796715. Scholar
  33. Greco SJ, Corcoran KE, Cho KJ, Rameshwar P (2004) Tachykinins in the emerging immune system: relevance to bone marrow homeostasis and maintenance of hematopoietic stem cells. Front Biosci 9:1782–1793PubMedGoogle Scholar
  34. Han D, Li X, Fan WS, Chen JW, Gou TT, Su T, Fan MM, Xu MQ, Wang YB, Ma S, Qiu Y, Cao F (2017) Activation of cannabinoid receptor type II by AM1241 protects adipose-derived mesenchymal stem cells from oxidative damage and enhances their therapeutic efficacy in myocardial infarction mice via Stat3 activation. Oncotarget 8(39):64853–64866. Scholar
  35. Hempstead BL, Martin-Zanca D, Kaplan DR, Parada LF, Chao MV (1991) High-affinity NGF binding requires coexpression of the trk proto-oncogene and the low-affinity NGF receptor. Nature 350(6320):678–683. Scholar
  36. Herzog H, Hort YJ, Shine J, Selbie LA (1993) Molecular cloning, characterization, and localization of the human homolog to the reported bovine NPY Y3 receptor: lack of NPY binding and activation. DNA Cell Biol 12(6):465–471. Scholar
  37. Higuchi S, Ii M, Zhu P, Ashraf M (2012) Delta-opioid receptor activation promotes mesenchymal stem cell survival via PKC/STAT3 signaling pathway. Circ J 76(1):204–212PubMedGoogle Scholar
  38. Hirabayashi A, Nishiwaki K, Taki K, Shimada Y, Ishikawa N (1994) Effects of neuropeptide Y on lung vascular permeability in the pulmonary circulation of rats. Eur J Pharmacol 256(2):227–230PubMedGoogle Scholar
  39. Holzer P (1988) Local effector functions of capsaicin-sensitive sensory nerve endings: involvement of tachykinins, calcitonin gene-related peptide and other neuropeptides. Neuroscience 24(3):739–768PubMedGoogle Scholar
  40. Idris AI, van ’t Hof RJ, Greig IR, Ridge SA, Baker D, Ross RA, Ralston SH (2005) Regulation of bone mass, bone loss and osteoclast activity by cannabinoid receptors. Nat Med 11(7):774–779. Scholar
  41. Idris AI, Sophocleous A, Landao-Bassonga E, van’t Hof RJ, Ralston SH (2008) Regulation of bone mass, osteoclast function, and ovariectomy-induced bone loss by the type 2 cannabinoid receptor. Endocrinology 149(11):5619–5626. Scholar
  42. Idris AI, Sophocleous A, Landao-Bassonga E, Canals M, Milligan G, Baker D, van’t Hof RJ, Ralston SH (2009) Cannabinoid receptor type 1 protects against age-related osteoporosis by regulating osteoblast and adipocyte differentiation in marrow stromal cells. Cell Metab 10(2):139–147. Scholar
  43. Igura K, Haider H, Ahmed RP, Sheriff S, Ashraf M (2011) Neuropeptide y and neuropeptide y y5 receptor interaction restores impaired growth potential of aging bone marrow stromal cells. Rejuvenation Res 14(4):393–403. Scholar
  44. Ip NY (1998) The neurotrophins and neuropoietic cytokines: two families of growth factors acting on neural and hematopoietic cells. Ann N Y Acad Sci 840:97–106PubMedGoogle Scholar
  45. Ip NY, Stitt TN, Tapley P, Klein R, Glass DJ, Fandl J, Greene LA, Barbacid M, Yancopoulos GD (1993) Similarities and differences in the way neurotrophins interact with the Trk receptors in neuronal and nonneuronal cells. Neuron 10(2):137–149PubMedGoogle Scholar
  46. Jiang S, Alberich-Jorda M, Zagozdzon R, Parmar K, Fu Y, Mauch P, Banu N, Makriyannis A, Tenen DG, Avraham S, Groopman JE, Avraham HK (2011a) Cannabinoid receptor 2 and its agonists mediate hematopoiesis and hematopoietic stem and progenitor cell mobilization. Blood 117(3):827–838. Scholar
  47. Jiang S, Fu Y, Avraham HK (2011b) Regulation of hematopoietic stem cell trafficking and mobilization by the endocannabinoid system. Transfusion 51(Suppl 4):65S–71S. Scholar
  48. Jones E, English A, Churchman SM, Kouroupis D, Boxall SA, Kinsey S, Giannoudis PG, Emery P, McGonagle D (2010) Large-scale extraction and characterization of CD271+ multipotential stromal cells from trabecular bone in health and osteoarthritis: implications for bone regeneration strategies based on uncultured or minimally cultured multipotential stromal cells. Arthritis Rheum 62(7):1944–1954. Scholar
  49. Jorda MA, Verbakel SE, Valk PJ, Vankan-Berkhoudt YV, Maccarrone M, Finazzi-Agro A, Lowenberg B, Delwel R (2002) Hematopoietic cells expressing the peripheral cannabinoid receptor migrate in response to the endocannabinoid 2-arachidonoylglycerol. Blood 99(8):2786–2793PubMedGoogle Scholar
  50. Joshi DD, Dang A, Yadav P, Qian J, Bandari PS, Chen K, Donnelly R, Castro T, Gascon P, Haider A, Rameshwar P (2001) Negative feedback on the effects of stem cell factor on hematopoiesis is partly mediated through neutral endopeptidase activity on substance P: a combined functional and proteomic study. Blood 98(9):2697–2706PubMedGoogle Scholar
  51. Jung WC, Levesque JP, Ruitenberg MJ (2017) It takes nerve to fight back: The significance of neural innervation of the bone marrow and spleen for immune function. Semin Cell Dev Biol 61:60–70. Scholar
  52. Kalinkovich A, Spiegel A, Shivtiel S, Kollet O, Jordaney N, Piacibello W, Lapidot T (2009) Blood-forming stem cells are nervous: direct and indirect regulation of immature human CD34+ cells by the nervous system. Brain Behav Immun 23(8):1059–1065. Scholar
  53. Kang HS, Trzaska KA, Corcoran K, Chang VT, Rameshwar P (2004) Neurokinin receptors: relevance to the emerging immune system. Arch Immunol Ther Exp 52(5):338–347Google Scholar
  54. 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. Scholar
  55. Kieffer BL, Evans CJ (2009) Opioid receptors: from binding sites to visible molecules in vivo. Neuropharmacology 56(Suppl 1):205–212. Scholar
  56. Klassert TE, Pinto F, Hernandez M, Candenas ML, Hernandez MC, Abreu J, Almeida TA (2008) Differential expression of neurokinin B and hemokinin-1 in human immune cells. J Neuroimmunol 196(1–2):27–34. Scholar
  57. Klassert TE, Patel SA, Rameshwar P (2010) Tachykinins and Neurokinin Receptors in Bone Marrow Functions: Neural-Hematopoietic Link. J Receptor Ligand Channel Res 2010(3):51–61PubMedPubMedCentralGoogle Scholar
  58. Knight JM, Szabo A, Zhao S, Lyness JM, Sahler OJ, Liesveld JL, Sander T, Rizzo JD, Hillard CJ, Moynihan JA (2015) Circulating endocannabinoids during hematopoietic stem cell transplantation: a pilot study. Neurobiol Stress 2:44–50. Scholar
  59. Kose S, Aerts-Kaya F, Kopru CZ, Nemutlu E, Kuskonmaz B, Karaosmanoglu B, Taskiran EZ, Altun B, Uckan Cetinkaya D, Korkusuz P (2018) Human bone marrow mesenchymal stem cells secrete endocannabinoids that stimulate in vitro hematopoietic stem cell migration effectively comparable to beta-adrenergic stimulation. Exp Hematol 57:30–41 e31. Scholar
  60. Krizanac-Bengez LJ, Breljak D, Boranic M (1996) Suppressive effect of met-enkephalin on bone marrow cell proliferation in vitro shows circadian pattern and depends on the presence of adherent accessory cells. Biomed Pharmacother 50(2):85–91PubMedGoogle Scholar
  61. Kuci S, Kuci Z, Kreyenberg H, Deak E, Putsch K, Huenecke S, Amara C, Koller S, Rettinger E, Grez M, Koehl U, Latifi-Pupovci H, Henschler R, Tonn T, von Laer D, Klingebiel T, Bader P (2010) CD271 antigen defines a subset of multipotent stromal cells with immunosuppressive and lymphohematopoietic engraftment-promoting properties. Haematologica 95(4):651–659. Scholar
  62. Kulkarni-Narla A, Walcheck B, Brown DR (2001) Opioid receptors on bone marrow neutrophils modulate chemotaxis and CD11b/CD18 expression. Eur J Pharmacol 414(2–3):289–294PubMedGoogle Scholar
  63. Kuntz A, Richins CA (1945) Innervation of the bone marrow. J Comp Neurol 83:213–222PubMedGoogle Scholar
  64. Kuo LE, Abe K, Zukowska Z (2007) Stress, NPY and vascular remodeling: Implications for stress-related diseases. Peptides 28(2):435–440. Scholar
  65. Lapidot T, Kollet O (2010) The brain-bone-blood triad: traffic lights for stem-cell homing and mobilization. Hematology Am Soc Hematol Educ Program 2010:1–6. Scholar
  66. Lee NJ, Herzog H (2009) NPY regulation of bone remodelling. Neuropeptides 43(6):457–463. Scholar
  67. Lee NJ, Doyle KL, Sainsbury A, Enriquez RF, Hort YJ, Riepler SJ, Baldock PA, Herzog H (2010) Critical role for Y1 receptors in mesenchymal progenitor cell differentiation and osteoblast activity. J Bone Miner Res 25(8):1736–1747. Scholar
  68. Levi-Montalcini R, Angeletti PU (1963) Essential role of the nerve growth factor in the survival and maintenance of dissociated sensory and sympathetic embryonic nerve cells in vitro. Dev Biol 6:653–659PubMedGoogle Scholar
  69. Lin S, Boey D, Herzog H (2004) NPY and Y receptors: lessons from transgenic and knockout models. Neuropeptides 38(4):189–200. Scholar
  70. Liu K, Castillo MD, Murthy RG, Patel N, Rameshwar P (2007) Tachykinins and hematopoiesis. Clin Chim Acta 385(1–2):28–34. Scholar
  71. Liu S, Jin D, Wu JQ, Xu ZY, Fu S, Mei G, Zou ZL, Ma SH (2016) Neuropeptide Y stimulates osteoblastic differentiation and VEGF expression of bone marrow mesenchymal stem cells related to canonical Wnt signaling activating in vitro. Neuropeptides 56:105–113. Scholar
  72. Lu B, Pang PT, Woo NH (2005) The yin and yang of neurotrophin action. Nat Rev Neurosci 6(8):603–614. Scholar
  73. Lucas D, Scheiermann C, Chow A, Kunisaki Y, Bruns I, Barrick C, Tessarollo L, Frenette PS (2013) Chemotherapy-induced bone marrow nerve injury impairs hematopoietic regeneration. Nat Med 19(6):695–703. Scholar
  74. Luder E, Ramer R, Peters K, Hinz B (2017) Decisive role of P42/44 mitogen-activated protein kinase in Delta(9)-tetrahydrocannabinol-induced migration of human mesenchymal stem cells. Oncotarget 8(62):105984–105994. Scholar
  75. Lundberg P, Allison SJ, Lee NJ, Baldock PA, Brouard N, Rost S, Enriquez RF, Sainsbury A, Lamghari M, Simmons P, Eisman JA, Gardiner EM, Herzog H (2007) Greater bone formation of Y2 knockout mice is associated with increased osteoprogenitor numbers and altered Y1 receptor expression. J Biol Chem 282(26):19082–19091. Scholar
  76. Maccarrone M, Bab I, Biro T, Cabral GA, Dey SK, Di Marzo V, Konje JC, Kunos G, Mechoulam R, Pacher P, Sharkey KA, Zimmer A (2015) Endocannabinoid signaling at the periphery: 50 years after THC. Trends Pharmacol Sci 36(5):277–296. Scholar
  77. Maestroni GJ (1998) kappa-Opioid receptors in marrow stroma mediate the hematopoietic effects of melatonin-induced opioid cytokines. Ann N Y Acad Sci 840:411–419PubMedGoogle Scholar
  78. Maestroni GJ, Conti A (1994) Modulation of hematopoiesis via alpha 1-adrenergic receptors on bone marrow cells. Exp Hematol 22(3):313–320PubMedGoogle Scholar
  79. Maestroni GJ, Conti A, Pedrinis E (1992) Effect of adrenergic agents on hematopoiesis after syngeneic bone marrow transplantation in mice. Blood 80(5):1178–1182PubMedGoogle Scholar
  80. Maestroni GJ, Zammaretti F, Pedrinis E (1999) Hematopoietic effect of melatonin involvement of type 1 kappa-opioid receptor on bone marrow macrophages and interleukin-1. J Pineal Res 27(3):145–153PubMedGoogle Scholar
  81. Marino F, Cosentino M, Bombelli R, Ferrari M, Maestroni GJ, Conti A, Lecchini S, Frigo G (1997) Measurement of catecholamines in mouse bone marrow by means of HPLC with electrochemical detection. Haematologica 82(4):392–394PubMedGoogle Scholar
  82. Matsuda H, Coughlin MD, Bienenstock J, Denburg JA (1988) Nerve growth factor promotes human hemopoietic colony growth and differentiation. Proc Natl Acad Sci U S A 85(17):6508–6512. Scholar
  83. McAllister AK (2001) Neurotrophins and neuronal differentiation in the central nervous system. Cell Mol Life Sci 58(8):1054–1060. Scholar
  84. Mendez-Ferrer S, Lucas D, Battista M, Frenette PS (2008) Haematopoietic stem cell release is regulated by circadian oscillations. Nature 452(7186):442–447. Scholar
  85. Mendez-Ferrer S, Battista M, Frenette PS (2010) Cooperation of beta(2)- and beta(3)-adrenergic receptors in hematopoietic progenitor cell mobilization. Ann N Y Acad Sci 1192:139–144. Scholar
  86. Mo FM, Offertaler L, Kunos G (2004) Atypical cannabinoid stimulates endothelial cell migration via a Gi/Go-coupled receptor distinct from CB1, CB2 or EDG-1. Eur J Pharmacol 489(1–2):21–27. Scholar
  87. Morrison SJ, Scadden DT (2014) The bone marrow niche for haematopoietic stem cells. Nature 505(7483):327–334. Scholar
  88. Morteau O, Lu B, Gerard C, Gerard NP (2001) Hemokinin 1 is a full agonist at the substance P receptor. Nat Immunol 2(12):1088. Scholar
  89. Muthu K, Iyer S, He LK, 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. Scholar
  90. Nan YS, Feng GG, Hotta Y, Nishiwaki K, Shimada Y, Ishikawa A, Kurimoto N, Shigei T, Ishikawa N (2004) Neuropeptide Y enhances permeability across a rat aortic endothelial cell monolayer. Am J Physiol Heart Circ Physiol 286(3):H1027–H1033. Scholar
  91. Nowicki M, Miskowiak B (2003) Substance P–a potent risk factor in childhood lymphoblastic leukaemia. Leukemia 17(6):1096–1099. Scholar
  92. Nowicki M, Miskowiak B, Ostalska-Nowicka D (2003) Detection of substance P and its mRNA in human blast cells in childhood lymphoblastic leukaemia using immunocytochemistry and in situ hybridisation. Folia Histochem Cytobiol 41(1):33–36PubMedGoogle Scholar
  93. Nowicki M, Ostalska-Nowicka D, Kondraciuk B, Miskowiak B (2007) The significance of substance P in physiological and malignant haematopoiesis. J Clin Pathol 60(7):749–755. Scholar
  94. Nykjaer A, Willnow TE, Petersen CM (2005) p75NTR--live or let die. Curr Opin Neurobiol 15(1):49–57. Scholar
  95. Ofek O, Karsak M, Leclerc N, Fogel M, Frenkel B, Wright K, Tam J, Attar-Namdar M, Kram V, Shohami E, Mechoulam R, Zimmer A, Bab I (2006) Peripheral cannabinoid receptor, CB2, regulates bone mass. Proc Natl Acad Sci U S A 103(3):696–701. Scholar
  96. Park MH, Jin HK, Min WK, Lee WW, Lee JE, Akiyama H, Herzog H, Enikolopov GN, Schuchman EH, Bae JS (2015a) Neuropeptide Y regulates the hematopoietic stem cell microenvironment and prevents nerve injury in the bone marrow. EMBO J 34(12):1648–1660. Scholar
  97. Park MH, Min WK, Jin HK, Bae JS (2015b) Role of neuropeptide Y in the bone marrow hematopoietic stem cell microenvironment. BMB Rep 48(12):645–646PubMedPubMedCentralGoogle Scholar
  98. Park MH, Lee JK, Kim N, Min WK, Lee JE, Kim KT, Akiyama H, Herzog H, Schuchman EH, Jin HK, Bae JS (2016) Neuropeptide Y Induces Hematopoietic Stem/Progenitor Cell Mobilization by Regulating Matrix Metalloproteinase-9 Activity Through Y1 Receptor in Osteoblasts. Stem Cells 34(8):2145–2156. Scholar
  99. Patinkin D, Milman G, Breuer A, Fride E, Mechoulam R (2008) Endocannabinoids as positive or negative factors in hematopoietic cell migration and differentiation. Eur J Pharmacol 595(1–3):1–6. Scholar
  100. Pelletier L, Angonin R, Regnard J, Fellmann D, Charbord P (2002) Human bone marrow angiogenesis: in vitro modulation by substance P and neurokinin A. Br J Haematol 119(4):1083–1089PubMedGoogle Scholar
  101. Peng S, Zhou YL, Song ZY, Lin S (2017) Effects of Neuropeptide Y on Stem Cells and Their Potential Applications in Disease Therapy. Stem Cells Int 2017:6823917. Scholar
  102. Pennefather JN, Lecci A, Candenas ML, Patak E, Pinto FM, Maggi CA (2004) Tachykinins and tachykinin receptors: a growing family. Life Sci 74(12):1445–1463PubMedGoogle Scholar
  103. 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. Scholar
  104. Quirici N, Soligo D, Bossolasco P, Servida F, Lumini C, Deliliers GL (2002) Isolation of bone marrow mesenchymal stem cells by anti-nerve growth factor receptor antibodies. Exp Hematol 30(7):783–791PubMedGoogle Scholar
  105. Rameshwar P, Gascon P (1995) Substance P (SP) mediates production of stem cell factor and interleukin-1 in bone marrow stroma: potential autoregulatory role for these cytokines in SP receptor expression and induction. Blood 86(2):482–490PubMedGoogle Scholar
  106. Rameshwar P, Gascon P (1996) Induction of negative hematopoietic regulators by neurokinin-A in bone marrow stroma. Blood 88(1):98–106PubMedGoogle Scholar
  107. Rameshwar P, Ganea D, Gascon P (1993a) In vitro stimulatory effect of substance P on hematopoiesis. Blood 81(2):391–398PubMedGoogle Scholar
  108. Rameshwar P, Gascon P, Ganea D (1993b) Stimulation of IL-2 production in murine lymphocytes by substance P and related tachykinins. J Immunol 151(5):2484–2496PubMedGoogle Scholar
  109. Rameshwar P, Poddar A, Gascon P (1997) Hematopoietic regulation mediated by interactions among the neurokinins and cytokines. Leuk Lymphoma 28(1–2):1–10. Scholar
  110. Rezaee F, Rellick SL, Piedimonte G, Akers SM, O’Leary HA, Martin K, Craig MD, Gibson LF (2010) Neurotrophins regulate bone marrow stromal cell IL-6 expression through the MAPK pathway. PLoS One 5(3):e9690. Scholar
  111. Rogers ML, Beare A, Zola H, Rush RA (2008) CD 271 (P75 neurotrophin receptor). J Biol Regul Homeost Agents 22(1):1–6PubMedGoogle Scholar
  112. Rossi F, Bernardo ME, Bellini G, Luongo L, Conforti A, Manzo I, Guida F, Cristino L, Imperatore R, Petrosino S, Nobili B, Di Marzo V, Locatelli F, Maione S (2013) The cannabinoid receptor type 2 as mediator of mesenchymal stromal cell immunosuppressive properties. PLoS One 8(11):e80022. Scholar
  113. Rozenfeld-Granot G, Toren A, Amariglio N, Nagler A, Rosenthal E, Biniaminov M, Brok-Simoni F, Rechavi G (2002) MAP kinase activation by mu opioid receptor in cord blood CD34(+)CD38(−) cells. Exp Hematol 30(5):473–480PubMedGoogle Scholar
  114. Ruhl T, Kim BS, Beier JP (2018) Cannabidiol restores differentiation capacity of LPS exposed adipose tissue mesenchymal stromal cells. Exp Cell Res 370(2):653–662. Scholar
  115. Satoh M, Minami M (1995) Molecular pharmacology of the opioid receptors. Pharmacol Ther 68(3):343–364PubMedGoogle Scholar
  116. Schmuhl E, Ramer R, Salamon A, Peters K, Hinz B (2014) Increase of mesenchymal stem cell migration by cannabidiol via activation of p42/44 MAPK. Biochem Pharmacol 87(3):489–501. Scholar
  117. Scutt A, Williamson EM (2007) Cannabinoids stimulate fibroblastic colony formation by bone marrow cells indirectly via CB2 receptors. Calcif Tissue Int 80(1):50–59. Scholar
  118. Shahrokhi S, Ebtekar M, Alimoghaddam K, Sharifi Z, Ghaffari SH, Pourfathollah AA, Kheirandish M, Mohseni M, Ghavamzadeh A (2010) Communication of substance P, calcitonin-gene-related neuropeptides and chemokine receptor 4 (CXCR4) in cord blood hematopoietic stem cells. Neuropeptides 44(5):385–389. Scholar
  119. Sharp BM, Roy S, Bidlack JM (1998) Evidence for opioid receptors on cells involved in host defense and the immune system. J Neuroimmunol 83(1–2):45–56PubMedGoogle Scholar
  120. Simone MD, De Santis S, Vigneti E, Papa G, Amadori S, Aloe L (1999) Nerve growth factor: a survey of activity on immune and hematopoietic cells. Hematol Oncol 17(1):1–10PubMedGoogle Scholar
  121. Singh P, Hoggatt J, Kamocka MM, Mohammad KS, Saunders MR, Li H, Speth J, Carlesso N, Guise TA, Pelus LM (2017) Neuropeptide Y regulates a vascular gateway for hematopoietic stem and progenitor cells. J Clin Invest 127(12):4527–4540. Scholar
  122. Smith M, Wilson R, O’Brien S, Tufarelli C, Anderson SI, O’Sullivan SE (2015) The Effects of the Endocannabinoids Anandamide and 2-Arachidonoylglycerol on Human Osteoblast Proliferation and Differentiation. PLoS One 10(9):e0136546. Scholar
  123. Sousa DM, Herzog H, Lamghari M (2009) NPY signalling pathway in bone homeostasis: Y1 receptor as a potential drug target. Curr Drug Targets 10(1):9–19PubMedGoogle Scholar
  124. Sousa DM, Baldock PA, Enriquez RF, Zhang L, Sainsbury A, Lamghari M, Herzog H (2012) Neuropeptide Y Y1 receptor antagonism increases bone mass in mice. Bone 51(1):8–16. Scholar
  125. 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 (2007) Catecholaminergic neurotransmitters regulate migration and repopulation of immature human CD34+ cells through Wnt signaling. Nat Immunol 8(10):1123–1131. Scholar
  126. Stead RH, Bienenstock J, Stanisz AM (1987) Neuropeptide regulation of mucosal immunity. Immunol Rev 100:333–359PubMedGoogle Scholar
  127. Steidl U, Bork S, Schaub S, Selbach O, Seres J, Aivado M, Schroeder T, Rohr UP, Fenk R, Kliszewski S, Maercker C, Neubert P, Bornstein SR, Haas HL, Kobbe G, Tenen DG, Haas R, Kronenwett R (2004) Primary human CD34+ hematopoietic stem and progenitor cells express functionally active receptors of neuromediators. Blood 104(1):81–88. Scholar
  128. Tabarowski Z, Gibson-Berry K, Felten SY (1996) Noradrenergic and peptidergic innervation of the mouse femur bone marrow. Acta Histochem 98(4):453–457. Scholar
  129. Taga T (1996) Gp130, a shared signal transducing receptor component for hematopoietic and neuropoietic cytokines. J Neurochem 67(1):1–10PubMedGoogle Scholar
  130. Teixeira L, Sousa DM, Nunes AF, Sousa MM, Herzog H, Lamghari M (2009) NPY revealed as a critical modulator of osteoblast function in vitro: new insights into the role of Y1 and Y2 receptors. J Cell Biochem 107(5):908–916. Scholar
  131. Tian M, Broxmeyer HE, Fan Y, Lai Z, Zhang S, Aronica S, Cooper S, Bigsby RM, Steinmetz R, Engle SJ, Mestek A, Pollock JD, Lehman MN, Jansen HT, Ying M, Stambrook PJ, Tischfield JA, Yu L (1997) Altered hematopoiesis, behavior, and sexual function in mu opioid receptor-deficient mice. J Exp Med 185(8):1517–1522. Scholar
  132. Tsuda T, Wong D, Dolovich J, Bienenstock J, Marshall J, Denburg JA (1991) Synergistic effects of nerve growth factor and granulocyte-macrophage colony-stimulating factor on human basophilic cell differentiation. Blood 77(5):971–979PubMedGoogle Scholar
  133. Ulum B (2019) Assessment of the role of Neuropeptide Y in the regulation of hematopoietic stem cells. Middle East Technical University, AnkaraGoogle Scholar
  134. Valk P, Verbakel S, Vankan Y, Hol S, Mancham S, Ploemacher R, Mayen A, Lowenberg B, Delwel R (1997) Anandamide, a natural ligand for the peripheral cannabinoid receptor is a novel synergistic growth factor for hematopoietic cells. Blood 90(4):1448–1457PubMedGoogle Scholar
  135. Waldhoer M, Bartlett SE, Whistler JL (2004) Opioid receptors. Annu Rev Biochem 73:953–990. Scholar
  136. Wang Y, Zhang D, Ashraf M, Zhao T, Huang W, Ashraf A, Balasubramaniam A (2010) Combining neuropeptide Y and mesenchymal stem cells reverses remodeling after myocardial infarction. Am J Physiol Heart Circ Physiol 298(1):H275–H286. Scholar
  137. Wang L, Yang L, Tian L, Mai P, Jia S, Yang L, Li L (2017) Cannabinoid Receptor 1 Mediates Homing of Bone Marrow-Derived Mesenchymal Stem Cells Triggered by Chronic Liver Injury. J Cell Physiol 232(1):110–121. Scholar
  138. Wee NKY, Sinder BP, Novak S, Wang X, Stoddard C, Matthews BG, Kalajzic I (2019) Skeletal phenotype of the neuropeptide Y knockout mouse. Neuropeptides 73:78–88. Scholar
  139. Wheway J, Mackay CR, Newton RA, Sainsbury A, Boey D, Herzog H, Mackay F (2005) A fundamental bimodal role for neuropeptide Y1 receptor in the immune system. J Exp Med 202(11):1527–1538. Scholar
  140. Whyte LS, Ryberg E, Sims NA, Ridge SA, Mackie K, Greasley PJ, Ross RA, Rogers MJ (2009) The putative cannabinoid receptor GPR55 affects osteoclast function in vitro and bone mass in vivo. Proc Natl Acad Sci U S A 106(38):16511–16516. Scholar
  141. Wollank Y, Ramer R, Ivanov I, Salamon A, Peters K, Hinz B (2015) Inhibition of FAAH confers increased stem cell migration via PPARalpha. J Lipid Res 56(10):1947–1960. Scholar
  142. Wu J, Liu S, Meng H, Qu T, Fu S, Wang Z, Yang J, Jin D, Yu B (2017) Neuropeptide Y enhances proliferation and prevents apoptosis in rat bone marrow stromal cells in association with activation of the Wnt/beta-catenin pathway in vitro. Stem Cell Res 21:74–84. Scholar
  143. Xie J, Xiao D, Xu Y, Zhao J, Jiang L, Hu X, Zhang Y, Yu L (2016) Up-regulation of immunomodulatory effects of mouse bone-marrow derived mesenchymal stem cells by tetrahydrocannabinol pre-treatment involving cannabinoid receptor CB2. Oncotarget 7(6):6436–6447. Scholar
  144. Yamaguchi M, Levy RM (2016) beta-Caryophyllene promotes osteoblastic mineralization, and suppresses osteoclastogenesis and adipogenesis in mouse bone marrow cultures in vitro. Exp Ther Med 12(6):3602–3606. Scholar
  145. Yamazaki K, Allen TD (1990) Ultrastructural morphometric study of efferent nerve terminals on murine bone marrow stromal cells, and the recognition of a novel anatomical unit: the “neuro-reticular complex”. Am J Anat 187(3):261–276. Scholar
  146. 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. Scholar
  147. Zhang Y, Paige CJ (2003) T-cell developmental blockage by tachykinin antagonists and the role of hemokinin 1 in T lymphopoiesis. Blood 102(6):2165–2172. Scholar
  148. Zhang Y, Lu L, Furlonger C, Wu GE, Paige CJ (2000) Hemokinin is a hematopoietic-specific tachykinin that regulates B lymphopoiesis. Nat Immunol 1(5):392–397. Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Graduate School of Health Sciences, Department of Stem Cell SciencesHacettepe UniversityAnkaraTurkey
  2. 2.Center for Stem Cell Research and DevelopmentHacettepe UniversityAnkaraTurkey
  3. 3.Faculty of Arts and Sciences, Department of Biological SciencesMiddle East Technical UniversityAnkaraTurkey
  4. 4.Faculty of Health Sciences, Department of Medical BiologyAtilim UniversityAnkaraTurkey
  5. 5.Faculty of Medicine, Department of Histology and EmbryologyHacettepe UniversityAnkaraTurkey

Personalised recommendations