Table 2.
Effects of endogenous opioids on stem cell differentiation.
| Opioids/Agonists | Pre-Treatment | Antagonists | Opioid Receptor | Cell Type | Biological Effects | Ref. |
|---|---|---|---|---|---|---|
| Neural Differentiation | ||||||
| DAMGO U69,593 (10−7–10−6 M) |
RA neuralinduction | KOR-1 MOR-1 |
ESCs (from mouse blastocyst) ESCs (from ICM of 3.5-day-old mouse) |
MOR-1 and KOR-1 were expressed in undifferentiated ESCs and in RA-induced ESC-derived NPCs. Both opioids induced ESC neuronal differentiation activating ERK pathway. |
[104] | |
| DAMGO U69,593 (10−6 M) |
RA neural induction |
KOR MOR |
ESCs (from mouse blastocyst) |
Opioids reduced neurogenesis and astrogenesis in RA-induced ESC-NPCs through p38 MAPK and ERK pathways, respectively. Opioids stimulated oligodendrogenesis via both ERK and p38 signaling pathways. |
[107] | |
| DAMGO SNC80 U50,488H (10−7–3 × 10−5 M) |
DOR KOR MOR |
MEB5 (from 14.5-day-old mouse forebrains) |
Only the DOR agonist SNC80 promoted neural differentiation. | [110] | ||
| Neural induction |
Human USSCs and BM-MSCs |
Neural induction increased enkephalinergic markers (Ikaros, CREBZF, and PENK), especially in USSC-derived neuron-like cells. PDYN expression was enhanced in USSC-derived neuron-like cells. |
[111] | |||
| Dynorphin-A U50,488H (10−6 M) |
Neural induction with opioid/ agonist |
Nor-BNI (10−5 M) |
KOR | NSCs (from 8-week-old mouse hippocampus) |
NSCs expressed high levels of KOR. Opioid treatment decreased neurogenesis by modulating Pax6/Neurog2/NeuroD1 activities via upregulation of miR-7a expression. Opioid treatment did not alter astrogenesis and oligodendrogenesis. Opioid treatment did not affect proliferation and apoptosis. |
[113] |
| Morphine (10−5 M) |
Neural induction with opioid |
NSCs (from postnatal p0 mouse hippocampus) |
Morphine promoted neurogenesis, increased apoptosis, and decreased total cell number during the later stages of differentiation. Morphine increased glutathione/glutathione disulfide ratio and decreased S-adenosylmethionine/S-adenosylhomocysteine ratio. |
[112] | ||
| Hematopoietic and Vascular Differentiation | ||||||
| Beta-endorphin (1 to 1000 ng/mL) Dynorphin (1 ng/mL) Leu-enkephalin Met-enkephalin (100 ng/mL) |
EP (0.4 U/mL) induced erythropoiesis with opioid |
Mouse BM progenitor cells | In the presence of EP, opioids enhanced BM progenitor differentiation into CFU-e. |
[114] | ||
| TRK820 U50,488H (10−5 M) |
Vascular induction | KOR | ESstA-ROSA (engineered mouse ESCs) |
KOR agonists inhibited EC differentiation and 3D vascular formation in ESC-derived vascular progenitor cells. KOR agonists decreased the expression of Flk1 and NRP1 through inhibition of cAMP/PKA signaling in vascular progenitor cells. |
[121] | |
| Met-enkephalin (10−14 to 10−8 M) |
KOR DOR |
Mouse BM progenitor cells |
Met-enk upregulated the expression of KOR and DOR in BM-derived DCs. Met-enk induced BM-derived DCs to differentiate mainly towards the mDC subtype. Met-enk increased the expression of MHC class II molecules and the release of pro-inflammatory cytokines (IL-12p70, TNF-α). |
[115] | ||
| Hematopoietic and Vascular Differentiation | ||||||
| Morphine (10−4 M) |
Naloxone (10−4 M) |
Rat NSCs | Morphine reduced survival and clonogenicity, negatively affecting tubulogenesis properties of NSCs by the inhibition of neuro-angiogenesis trans-differentiation. |
[123] | ||
| Cardiac Differentiation | ||||||
| Dynorphin-B (10−9 to 10−6 M) |
DMSO 1% | KOR | Mouse ESCs | DMSO increased PDYN gene expression and dynorphin-B synthesis and secretion. Dynorphin-B elicited GATA-4 and Nkx-2.5 gene transcription and enhanced gene and protein expression of α-MHC and MLC-2V. |
[136] | |
| Dynorphin-B (10−8 to 10−6 M) |
Cardiac induction |
KOR | GTR1-ESCs (engineered mouse ESCs) |
ESC plasma membranes and nuclei expressed KOR-specific opioid binding sites. ESC-derived cardiomyocytes showed an increase in dynorphin-B around the nucleus. Dynorphin-B induced an increase of GATA-4, Nkx-2.5, and PDYN gene expressions and promoted cardiogenesis by PKC signaling. |
[138,139] | |
| HBR cardiac induction (0.75 mg/mL) |
GTR1-ESCs (engineered mouse ESCs) |
HBR-induced ESC-derived cardiomyocytes enhanced GATA-4, Nkx-2.5, and PDYN gene transcriptions and the intracellular level of dynorphin-B. |
[141] | |||
| ELF-MF exposition during cardiac induction (50 Hz, 0.8 m Trms) |
GTR1-ESCs (engineered mouse ESCs) |
ELF-MF spontaneously induced cardiogenesis, upregulating GATA-4, Nkx-2.5, and PDYN gene expression and enhancing intracellular levels and secretion of dynorphin-B. |
[146] | |||
| Cardiac Differentiation | ||||||
| REAC exposition during cardiac induction (MF of 2.4 and 5.5 GHz) |
Mouse ESCs and human ASCs |
Both SCs committed to cardiac lineage and exposed to REAC increased the expression of GATA-4, Nkx-2.5, and PDYN gene. |
[147,148] | |||
| Dynorphin-B (10−7 M) |
Cardiac induction |
CPCs (from 11.5-day-oldembryonic mouseventricles) |
Dynorphin B promoted CPC differentiation into cardiomyocytes. | [149] | ||
| Dynorphin-A Dynorphin-B Met-enkephalins Leu-enkephalins (10−5 M) |
Cardiac induction |
DOR KOR |
Mouse ESCs | Both DOR and KOR increased during ESC differentiation. Dynorphin-B inhibited Oct-4 and increased Nkx-2.5 gene expression. Dynorphin-A, met-enkephalins, and leu-enkephalinsdid not affect ESC differentiation. |
[150] | |
DAMGO, [D-Ala2,MePhe4,Glyol5]-enkephalin; U69,593, N-methyl-2-phenyl-N-[(5R,7S,8S)-7-(pyrrolidin-1-yl)-1-oxaspiro[4.5]dec-8-yl]acetamide; RA, retinoic acid; KOR-1, κ opioid receptor isoform 1; MOR-1, μ opioid receptor isoform 1; ESCs, embryonic stem cells; ICM, inner cell mass; NPCs, neural progenitor cells; ERK, extracellular signal-regulated kinase; p38 MAPK, p38 mitogen-activated protein kinase; SNC80, [(+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide]; U50,488H, (–)-trans-(1S,2S)-U-50488 hydrochloride; Nor-BNI, nor-binaltorphimine; DOR, δ opioid receptor; MEB5, multipotent neural stem cells; USSCs, unrestricted somatic stem cells; BM-MSCs, bone marrow mesenchymal stem cells; Ikaros, IKAROS family zinc finger 1; CREBZF, CREB/ATF bZIP transcription factor; PENK, proenkephalin; PDYN, prodynorphin; NSCs, neural stem cells; Pax6, paired box 6; Neurog2, neurogenin 2; NeuroD1, neuronal differentiation 1; leu-enkephalin, leucine-enkephalin; met-enkephalin, methionine-enkephalin; EP, erythropoietin; CFU-e, colony-forming unit-erythroid; TRK820, 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl) acrylamido]morphinan hydrochloride; EC, endothelial cell; Flk1, fetal liver kinase 1/VEGF receptor 2; NRP1, neuropilin 1; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; DCs, dendritic cells; mDCs, myeloid dendritic cells; MHC, major histocompatibility complex; TNF-α, tumor necrosis factor alpha; IL-12p70, active heteodimer of interleukin 12. p53, tumor protein p53; DMSO, dimethyl sulfoxide; GATA-4, GATA binding protein 4; Nkx-2.5, Nkx homeobox 5; α-MHC, α-myosin heavy chain; MLC-2V, myosin light chain; PKC, protein kinase C; HBR, hyaluronan mixed esters of butyric and retinoic acids; ELF-MF, extremely low frequency magnetic fields; REAC, radio electric asymmetric conveyer; ASCs, adipose-derived mesenchymal stem cells; SCs, stem cells; CPCs, cardiac progenitor cells; Oct-4, octamer-binding transcription factor 4.