Phytocannabinoid-induced priming and differentiation of mesenchymal stem cells: Therapeutic potential

Table 1 Experimental conditions and outcomes of phytocannabinoid-based priming in mesenchymal stem cells

Cell	Phytocannabinoid	Period of priming	Stress/inflammatory condition	Dose	Effect	Notes	Limitation	Ref.
GMSCs (human)	Pure CBD (> 99%)	24 hours	No	5 μM	Downregulated the expression of genes IL6ST, IL-1β, and IL-18	CBD modulated the expression of 5843 genes in GMSCs and downregulated the expression of genes correlated to inflammation, apoptosis and innate immune responses. CBD attenuated activation of the NLRP3 inflammasome, accompanied by a decline in NLRP3, CASP1, and IL-18 expression	No in vivo evaluation	[7]
AT-MSCs (human)	CBD (not specified)	48 hours	LPS (10 μg/mL)	3 μM	Multiplex immunoassay and ELISA showed that CBD + LPS did not alter the release of cytokines and growth factors (IL-2, IL-5, IL-6, IL-18, TNF-α, TGF-β, VEGF, IGF) compared to the LPS group	An increase in IL-6 and VEGF levels and a decrease in IGF were observed in the CBD group compared to the unstimulated control group	Receptors mediating the observed effects were not investigated. No in vivo evaluation	[34]
AT-MSCs (human)	CBD (1089161 - Sigma-Aldrich)	24 hours	Tunicamycin	5 μM	Decreased IL-4 and increased gene and protein expression of IL-6 compared with the tunicamycin-treated group. CBD significantly reduced the number of senescent cells	Increased gene expression of IL-1β, IL-4, and IL-6, and decreased expression of TNF-α and IL-10 compared with the control group. CBD reduced apoptosis and promoted proliferation in pretreated cells	Receptors mediating the observed effects were not investigated. No in vivo evaluation	[42]
DPMSCs (human)	CBD (not specified)	24 hours	TNF-α (50 ng/mL)	2.5 μM	CBD treatment reduced TNF-α-induced gene expression of TNF-α, IL-6, and IL-1β	CBD treatment upregulated the gene expression of pro-angiogenic markers and restored TNF-α-inhibited viability and migration	Absence of cytokine protein analysis. Receptors mediating the observed effects were not investigated. No in vivo evaluation	[47]
AT-MSCs (canine)	CBD-rich cannabis extract (28.12% CBD and 0.8% THC)	24 hours	No	2.25 μM and 225 nM	Gene expression analysis showed decreased BDNF (2.25 μM), increased HGF (2.25 μM and 225 nM), and increased IDO (2.25 μM). Multiplex assay revealed a reduction in IL-8 and MCP-1 levels (2.25 μM)	No significant differences were observed in the gene expression of GDNF, IL-10, TNF-α, IFN-γ, or PTGES2 compared to the control. CBD did not alter cell morphology and viability	Lack of protein-level analysis of additional cytokines and neurotrophic factors. Receptors mediating the observed effects were not investigated. No in vivo evaluation	[43]
AT-MSCs (equine)	CBD-rich cannabis extract (28.12% CBD and 0.8% THC)	24 hours	No	5 μM and 7 μM	Gene expression analysis showed decreased IL-1β and IL-6 (7 μM) and increased IL-10, IFN-γ, and TNF-α (5 μM)	No significant changes were observed at 5 μM for IL-1β and IL-6, or at 7 μM for IL-10, IFN-γ, and TNF-α compared with the control. CBD did not alter cell morphology, viability, metabolic activity, or β-galactosidase activity	Absence of cytokine protein analysis. No in vivo evaluation	[28]
BM-MSCs (mice)	THC (Sigma Aldrich)	24 hours	LPS-stimulated microglia (in vitro)/CCI model in mice (in vivo)	1 μM (chosen after testing 0.5-10 μM)	Enhanced immunomodulatory effect: Lowered release of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-8) from microglia; increased IL-10; improved outcomes in pain behavior (hyperalgesia, allodynia) in CCI mice; reduced cytokine expression in ipsilateral sciatic nerve	Mechanism involves CB2 receptor; ERK and Akt signaling pathways	Long-term or dose-dependent effects not evaluated	[8]

GMSCs: Gingival mesenchymal stem cells; CBD: Cannabidiol; IL: Interleukin; NLRP3: Nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain- containing receptor 3; CASP1: Caspase-1; AT-MSCs: Adipose tissue-derived mesenchymal stem cells; LPS: Lipopolysaccharide; ELISA: Enzyme-linked immunosorbent assay; TNF-α: Tumor necrosis factor-alpha; TGF-β: Transforming growth factor β; VEGF: Vascular endothelial growth factor; IGF: Insulin-like growth factor; DPMSCs: Dental pulp mesenchymal stem cells; THC: Δ⁹-tetrahydrocannabinol; BDNF: Brain-derived neurotrophic factor; HGF: Hepatocyte growth factor; IDO: Indoleamine 2,3-dioxygenase; MCP-1: Monocyte chemoattractant protein-1; GDNF: Glial cell line-derived neurotrophic factor; IFN-γ: Interferon-gamma; PTGES2: Prostaglandin E synthase 2; BM-MSCs: Bone marrow-derived mesenchymal stem cells; CCI: Chronic constriction injury; CB2: Cannabinoid receptor type 2; ERK: Extracellular signal-regulated kinase; Akt: Protein kinase B.