Regulation of Stem Cells by the Endocannabinoid System

  • Shuxian Jiang
  • Fu Yigong
  • Shalom Avraham
  • Alexandros Makriyannis
  • Hava Karsenty AvrahamEmail author
Part of the Stem Cells and Cancer Stem Cells book series (STEM, volume 6)


The endocannabinoids, endogenous lipid mediators of related chemical structure to the prototype exogenous cannabinoid Δ9-THC found in marijuana, have emerged as important mediators that regulate central and peripheral neural functions as well as immune responses. Endogenous and exogenous cannabinoid ligands bind to cannabinoid receptors: the predominant central cannabinoid receptor type 1 (CB1) and the peripheral cannabinoid receptor type 2 (CB2). CB1 and CB2 are members of the G-protein coupled receptor family. Cannabinoids were shown to modulate the immune system and to affect the migration of blood cells, such as T-cells, monocytes and myeloid leukemia cells, through CB receptors. Recent data indicate the potential role of cannabinoid ligands and receptors in the regulation of hematopoiesis and hematopoietic stem cell (HSC) migration and trafficking. These studies may lead to clinical applications of cannabinoid-based compounds as new HSC-mobilizer agents for therapeutic intervention in bone marrow failure.


Fatty Acid Amide Hydrolase Bone Marrow Failure Stem Cell Mobilization Hematopoietic Differentiation Primitive Stem Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors would like to thank Lili Wang for editing the manuscript.


  1. Abel EL, Dintcheff BA, Day N (1980) Effects of marihuana on pregnant rats and their offspring. Psychopharmacology (Berl) 71(1):71–74CrossRefGoogle Scholar
  2. Aiuti A, Turchetto L, Cota M, Cipponi A, Brambilla A, Arcelloni C, Paroni R, Vicenzi E, Bordignon C, Poli G (1999) Human CD34(+) cells express CXCR4 and its ligand stromal cell-derived factor-1. Implications for infection by T-cell tropic human immunodeficiency virus. Blood 94(1):62–73PubMedGoogle Scholar
  3. Alger BE (2004) Endocannabinoids: getting the message across. Proc Natl Acad Sci USA 101(23):8512–8513PubMedCrossRefGoogle Scholar
  4. Barnett-Norris J, Lynch D, Reggio PH (2005) Lipids, lipid rafts and caveolae: their importance for GPCR signaling and their centrality to the endocannabinoid system. Life Sci 77(14):1625–1639PubMedCrossRefGoogle Scholar
  5. Challen GA, Little MH (2006) A side order of stem cells: the SP phenotype. Stem Cells 24(1):3–12PubMedCrossRefGoogle Scholar
  6. Chevaleyre V, Takahashi KA, Castillo PE (2006) Endocannabinoid-mediated synaptic plasticity in the CNS. Annu Rev Neurosci 29:37–76PubMedCrossRefGoogle Scholar
  7. Correa F, Mestre L, Molina-Holgado EO, Arévalo-Martín A, Docagne F, Romero E, Molina-Holgado F, Borrell J, Guaza C (2005) The role of cannabinoid system on immune modulation: therapeutic implications on CNS inflammation. Mini Rev Med Chem 5(7):671–675PubMedCrossRefGoogle Scholar
  8. Diaz-Laviada I, Ruiz-Llorente L (2005) Signal transduction activated by cannabinoid receptors. Mini Rev Med Chem 5(7):619–630PubMedCrossRefGoogle Scholar
  9. DiPersio JF, Stadtmauer EA, Nademanee A, Micallef IN, Stiff PJ, Kaufman JL, Maziarz RT, Hosing C, Früehauf S, Horwitz M, Cooper D, Bridger G, Calandra G, 3102 Investigators (2009) Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma. Blood 113(23):5760–5766Google Scholar
  10. Felder CC, Glass M (1998) Cannabinoid receptors and their endogenous agonists. Annu Rev Pharmacol Toxicol 38:179–200PubMedCrossRefGoogle Scholar
  11. Flomenberg N, DiPersio J, Calandra G (2005) Role of CXCR4 chemokine receptor blockade using AMD3100 for mobilization of autologous hematopoietic progenitor cells. Acta Haematol 114(4):198–205PubMedCrossRefGoogle Scholar
  12. Fride E (2005) Endocannabinoids in the central nervous system: from neuronal networks to behavior. Curr Drug Targets CNS Neurol Disord 4(6):633–642PubMedCrossRefGoogle Scholar
  13. Goessling W, Allen RS, Guan X, Jin P, Uchida N, Dovey M, Harris JM, Metzger ME, Bonifacino AC, Stroncek D, Stegner J, Armant M, Schlaeger T, Tisdale JF, Zon LI, Donahue RE, North TE (2011) Prostaglandin E2 enhances human cord blood stem cell xenotransplants and shows long-term safety in preclinical ­nonhuman primate transplant models. Cell Stem Cell 8:445–458PubMedCrossRefGoogle Scholar
  14. Grinspoon L (1997) Marijuana addiction. Science 277(5327):749; author reply 750–752PubMedCrossRefGoogle Scholar
  15. Guzman M (2003) Cannabinoids: potential anticancer agents. Nat Rev Cancer 3(10):745–755PubMedCrossRefGoogle Scholar
  16. Hillard CJ, Manna S, Greenberg MJ, DiCamelli R, Ross RA, Stevenson LA, Murphy V, Pertwee RG, Campbell WB (1999) Synthesis and characterization of potent and selective agonists of the neuronal cannabinoid receptor (CB1). J Pharmacol Exp Ther 289(3):1427–1433PubMedGoogle Scholar
  17. Huffman JW, Liddle J, Yu S, Aung MM, Abood ME, Wiley JL, Martin BR (1999) 3-(1′,1′-Dimethylbutyl)-1-deoxy-delta8-THC and related compounds: synthesis of selective ligands for the CB2 receptor. Bio Med Chem 7(12):2905–2914CrossRefGoogle Scholar
  18. Jiang S, Fu Y, Williams J, Wood J, Pandarinathan L, Avraham S, Makriyannis A, Avraham S, Avraham HK (2007) Expression and function of cannabinoid receptors CB1 and CB2 and their cognate cannabinoid ligands in murine embryonic stem cells. PLoS One 2(7):e641PubMedCrossRefGoogle Scholar
  19. Jiang S, Fu Y, Avraham HK (2011) Regulation of hematopoietic stem cell trafficking mobilization by the endocannabinoid system. Transfusion 51 (Suppl 4):65S–71SPubMedCrossRefGoogle Scholar
  20. Jo DY, Rafii S, Hamada T, Moore MA (2000) Chemotaxis of primitive hematopoietic cells in response to stromal cell-derived factor-1. J Clin Invest 105(1):101–111PubMedCrossRefGoogle Scholar
  21. Jorda MA, Verbakel SE, Valk PJ, Vankan-Berkhoudt YV, Maccarrone M, Finazzi-Agrò A, Löwenberg B, Delwel R (2002) Hematopoietic cells expressing the peripheral cannabinoid receptor migrate in response to the endocannabinoid 2-arachidonoylglycerol. Blood 99(8):2786–2793PubMedCrossRefGoogle Scholar
  22. Kaushansky K (2006) Lineage-specific hematopoietic growth factors. N Engl J Med 354(19):2034–2045PubMedCrossRefGoogle Scholar
  23. Lambert DM, Fowler CJ (2005) The endocannabinoid system: drug targets, lead compounds, and potential therapeutic applications. J Med Chem 48(16):5059–5087PubMedCrossRefGoogle Scholar
  24. Mackie K (2006) Cannabinoid receptors as therapeutic targets. Annu Rev Pharmacol Toxicol 46:101–122PubMedCrossRefGoogle Scholar
  25. Moore KA, Lemischka IR (2006) Stem cells and their niches. Science 311(5769):1880–1885PubMedCrossRefGoogle Scholar
  26. Oz M (2006) Receptor-independent actions of cannabinoids on cell membranes: focus on endocannabinoids. Pharmacol Ther 111(1):114–144PubMedCrossRefGoogle Scholar
  27. Pelus LM, Horowitz D, Cooper SC, King AG (2002) Peripheral blood stem cell mobilization. A role for CXC chemokines. Crit Rev Oncol Hematol 43(3):257–275PubMedCrossRefGoogle Scholar
  28. Pertwee RG (1999) Pharmacology of cannabinoid receptor ligands. Curr Med Chem 6(8):635–664PubMedGoogle Scholar
  29. Schatz AR, Lee M, Condie RB, Pulaski JT, Kaminski NE (1997) Cannabinoid receptors CB1 and CB2: a characterization of expression and adenylate cyclase modulation within the immune system. Toxicol Appl Pharmacol 142(2):278–287PubMedCrossRefGoogle Scholar
  30. Stem Cell Basics (2012) National Institutes of Health Stem Cell Reports. PubMedCrossRefGoogle Scholar
  31. Valverde O, Karsak M, Zimmer A (2005) Analysis of the endocannabinoid system by using CB1 cannabinoid receptor knockout mice. Handb Exp Pharmacol 168:117–145PubMedCrossRefGoogle Scholar
  32. Wotjak CT (2005) Role of endogenous cannabinoids in cognition and emotionality. Mini Rev Med Chem 5(7):659–670PubMedCrossRefGoogle Scholar
  33. Zurier RB (2003) Prospects for cannabinoids as anti-inflammatory agents. J Cell Biochem 88(3):462–466PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  • Shuxian Jiang
    • 1
  • Fu Yigong
    • 1
  • Shalom Avraham
    • 1
  • Alexandros Makriyannis
    • 2
  • Hava Karsenty Avraham
    • 1
    Email author
  1. 1.Department of Medicine, Beth Israel Deaconess Medical CenterHarvard Medical SchoolBostonUSA
  2. 2.Center for Drug Discovery, Department of Pharmaceutical Sciences, School of PharmacyNortheastern UniversityBostonUSA

Personalised recommendations