Cannabinoid receptor signaling in progenitor/stem cell proliferation and differentiation

Prog Lipid Res. 2013 Oct;52(4):633-50. doi: 10.1016/j.plipres.2013.05.004. Epub 2013 Sep 25.


Cannabinoids, the active components of cannabis (Cannabis sativa) extracts, have attracted the attention of human civilizations for centuries, much earlier than the discovery and characterization of their substrate of action, the endocannabinoid system (ECS). The latter is an ensemble of endogenous lipids, their receptors [in particular type-1 (CB1) and type-2 (CB2) cannabinoid receptors] and metabolic enzymes. Cannabinoid signaling regulates cell proliferation, differentiation and survival, with different outcomes depending on the molecular targets and cellular context involved. Cannabinoid receptors are expressed and functional from the very early developmental stages, when they regulate embryonic and trophoblast stem cell survival and differentiation, and thus may affect the formation of manifold adult specialized tissues derived from the three different germ layers (ectoderm, mesoderm and endoderm). In the ectoderm-derived nervous system, both CB1 and CB2 receptors are present in neural progenitor/stem cells and control their self-renewal, proliferation and differentiation. CB1 and CB2 show opposite patterns of expression, the former increasing and the latter decreasing along neuronal differentiation. Recently, endocannabinoid (eCB) signaling has also been shown to regulate proliferation and differentiation of mesoderm-derived hematopoietic and mesenchymal stem cells, with a key role in determining the formation of several cell types in peripheral tissues, including blood cells, adipocytes, osteoblasts/osteoclasts and epithelial cells. Here, we will review these new findings, which unveil the involvement of eCB signaling in the regulation of progenitor/stem cell fate in the nervous system and in the periphery. The developmental regulation of cannabinoid receptor expression and cellular/subcellular localization, together with their role in progenitor/stem cell biology, may have important implications in human health and disease.

Keywords: 2-AG; 2-arachidonoylglycerol; AEA; BDNF; CBD; CBG; CFU-GEMM; CREB; CSF; Cell commitment; Cell survival; DAGL; ECB; ECS; ERK; ES; Endocannabinoids; FAAH; FGF; GAD; GSK3β; HPC; HSC; ICM; L1-CAM; L1-cell adhesion molecule; MAGL; Membrane receptors; N-arachidonoylethanolamine; N-oleoylethanolamine; N-palmitoylethanolamine; NCAM; NGF; NP; Niche cues; OEA; PEA; PI3K; PKA; PPARγ; Protein kinases; RANKL; SVZ; THC; Transcription factors; VZ; brain derived neurotrophic factor; cAMP response element-binding protein; cannabidiol; cannabigerol; colony-forming unit: granulocyte, erythrocyte, macrophage, megakaryocyte; colony-stimulating factors; diacylglycerol lipase; embryonic stem; endocannabinoid; endocannabinoid system; extracellular-signaling regulated protein kinase; fatty acid amide hydrolase; fibroblast growth factor; glutamate decarboxylase; glycogen synthase kina; hematopoietic progenitor cells; hematopoietic stem cells; inner cell mass; mGluR; mTORC1; mammalian target of rapamycin complex 1; metabotropic glutamate receptors; monoacylglycerol lipase; nerve growth factor; neural cell adhesion molecule; neural progenitor/stem cell; peroxisome proliferator activated receptors; phosphoinositol 3-kinase; protein kinase-A; receptor activator of nuclear factor kappa-B ligand; subventricular zone; vGlut; ventricular zone; vesicular glutamate transporter; Δ(9)-tetrahydrocannabinol.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Cannabinoids / chemistry
  • Cannabinoids / metabolism
  • Cell Differentiation*
  • Cell Proliferation
  • Humans
  • Neurons / cytology
  • Neurons / metabolism
  • Receptors, Cannabinoid / chemistry
  • Receptors, Cannabinoid / metabolism*
  • Signal Transduction*
  • Stem Cells / cytology*
  • Stem Cells / metabolism


  • Cannabinoids
  • Receptors, Cannabinoid