Dental Stem Cell-Derived Secretome/Conditioned Medium: The Future for Regenerative Therapeutic Applications

Table 2

Summary of the included studies investigating the effect of dental MSCs’ secretome/conditioned medium on treating skin and internal diseases.

Authors, year	Cell origin-contributing factor	Scaffold	Study model	Factors contained in dental MSC-CM	Factors promoted by dental MSC-C	Outcome
Treating cardiopulmonary injuries
SHED-CM
Wakayama et al., 2015 [126]	Human SHED-CM	-	In vivo mouse with acute lung injury.	-	CD206, Arginase-1, & Ym-1	Suppressed inflammatory chronic response of macrophage and promoted lung regeneration.
Yamaguchi et al., 2015 [127]	Human SHED-CM	-	In vivo mouse with ischemia-reperfusion.	VEGF, IGF-1, HGF, bFGF, SDF-1, EGF, & SCF.	↓ TNF-α, IL-6, & IL-1β.	Reduced the size of myocardial infarct, myocyte apoptosis and inflammatory cytokine.
Diabetes mellitus
SHED-CM
Izumoto-Akita et al., 2015 [128]	Human SHED-CM	-	In vivo diabetic mouse model.; In vitro	-	-	Increased insulin secretion, β-cell proliferation, and reduced apoptosis.
Immunological disorders
SHED-CM
Ishikawa et al., 2016 [129]	Human SHED-CM	-	In vivo model of rheumatoid arthritis.	HGF, IL-22, furin, IL-1RA, RAGE, OPG, MCP-1, & ED-Siglec-9.	RANKL, TRAP, Cathepsin K, RANK, NFATc1, OPG, CD206, Arginase-1, & Fizz1.	Promoted M2 anti-inflammatory state and inhibited osteoclastogenesis.
Gunawardena et al., 2019 [131]	Human SHED-CM	-	In vivo mouse model of alopecia.; In vitro	-	SDF-1, HGF, VEGF-A, PDGF-BB, IL-1α, IL-1β, TNF-α, TGF-β, bFGF, & BDNF.	Stimulation of hair growth.
Luo et al., 2019 [130]	Human SHED-EXs	-	In vitro TMJ osteoarthritis model.	CD9, CD63, TSG101, & MiR-100.	↓ IL-6, IL-8, MMP1, MMP3, MMP9, MMP13, ADAMTS5, MMP1, MMP9, MMP13, & mTOR.	Suppression of inflammation in TMJ osteoarthritis.
Treating skin injuries
Gingival MSC-CM
Shi et al., 2017 [171]	Human gingival MSC-EXs	Hydrogel	In vivo diabetic rat with skin defect.	-	CD34, Neurofilament 200	Improved skin healing via reepithelialization, collagen deposition, enhanced angiogenesis and neuronal ingrowth.
Hepatic regenerative potential
Dental pulp MSC-CM, dental follicle MSC-CM, & MSCs from apical papilla-CM
Hirata et al., 2016 [124]	Human SHED-CM	-	In vivo mouse with liver fibrosis.	HGF	mRNA of MMP13, ↓ collagen type 1 (a1 and a2), & α-smooth muscle actin mRNAs.	Inhibited chronic inflammation and hepatocytes apoptosis.
Matsushita et al., 2017 [125]	Human SHED-CM	-	In vivo rat with acute liver failure.	HGF, MMP-10, MCP-1, ANG, SCF, IGFBP-2, sIL-6R, EGFR, FSTN, MMP-3, spg130, GRO, MIP-1β, MIF, RAGE, TIMP-4, adipsin, OPG, CXCL16, IGFBP-1, BDNF, LAP, GDNF, sTNFR1, TGF-β2, FGF-7, MMP-13, MMP-9, Flt-3 L, Dkk-3, NID-1, VEGF-A, CTSS, HVEM, GDF-15, TIMP-1, B2M, EG-VEGF, β-IG-H3, TIMP-2, IL-6, MCP-3, PAI-1, uPAR, IGFBP-6, Dkk-1, MMP-1.	IL-10, TGF-β1, CD206, Arginase-1, VEGF, SCF, and IGF-1, FGF 7, TWEAK, HGF, & Wnt3a genes.	Enhanced the condition of the injured liver and induced anti-inflammatory M2-like hepatic macrophages.
Kumar et al., 2017 [64]	Human dental pulp MSC-CM	-	In vitro	LRP6, LRP10, LRP5, LRP4, GAS6.	-	Demonstrated the presence of hepatic lineage proteins.
	Human dental follicle MSC-CM			APC, PEG10, GAS6, OSM, HGFR.
	Human MSCs from apical papilla-CM			APC, ABCB4, APOA, GAS6, LRP4, LRP1, LRP1B, LRP8, LRP3, LRP4, APOC3, HNF4G.
	Human bone marrow MSC-CM			APC, PEG10, ABCB4, APOBR, APOA, LPA.

ABCB4: phosphatidylcholine translocator; Adipsin: complement factor D; ANG: angiogenin; APC: adenomatous polyposis coli protein; APOA: apolipoprotein A; APOBR: apolipoprotein B receptor; APOC3: apolipoprotein C-III; B2M: β2-microglobulin; BDNF: brain-derived neurotrophic factor; bFGF: basic fibroblast growth factor; CD: cluster of differentiation; CM: conditioned medium; CTSS: cathepsin S; CXCL16; chemokine (C–X–C motif) ligand 16; Dkk-1: Dickkopf 1; Dkk-3: Dickkopf 3; ED-Siglec-9: ectodomain of sialic acid-binding Ig-like lectin-9; EGF: epidermal growth factor; EGFR: epithelial growth factor receptor; EG-VEGF: endocrine-gland-derived vascular endothelial growth factor; EXs: exosomes; FGF: fibroblast growth factor; Flt-3 L: Fms-like tyrosine kinase receptor-3; FSTN: follistatin; GAS6: growth arrest-specific protein 6; GDF-15: growth differentiation factor 15; GDNF: glial cell line-derived neurotrophic factor; GRO: chemokine (C–X–C motif) ligand 1; HGF: hepatocyte growth factor; HGFR: hepatocyte growth factor receptor; HNF4G: hepatocyte nuclear factor 4 gamma; HVEM: herpesvirus entry mediator; IGF-1: insulin-like growth factor 1; IGFBP: insulin-like growth factor binding protein; IL: interleukin; IL-1RA: interleukin-1 receptor antagonist; LAP: latency-associated peptide; LPA: lipoprotein A; LRP10: LDL receptor-related protein 10; LRP1B: low-density lipoprotein-related protein 1B; LRP3: LDL receptor-related protein 3; LRP4: LDL receptor-related protein 4; LRP5: LDL receptor-related protein 5; LRP6: LDL receptor-related protein 6; LRP8: LDL receptor-related protein 8; MCP-1: monocyte chemoattractant protein-1; MCP-3: monocyte chemoattractant protein-3; MIF: macrophage migration inhibitory factor; MIP-1β: macrophage inflammatory protein 1β; MMP: matrix metalloprotease; mRNA: messenger RNA; MSCs: mesenchymal stem cells; mTOR: mammalian target of rapamycin; NFATc1: nuclear factor of activated T cells 1; NID-1: nidogen-1; OPG: osteoprotegerin; OSM: oncostatin M; PAI-1: plasminogen activator inhibitor-1; PDGF: platelet-derived growth factor; PEG10: retrotransposon-derived protein; RAGE: receptor for AGEs; RANK: receptor activator of nuclear factor-κB; RANKL: receptor activator of nuclear factor-κB ligand; SCF: stem cell factor; SDF-1: stromal cell-derived factor 1; MSCs: mesenchymal stem cells; SHED: stem cells derived from human exfoliated deciduous teeth; sIL-6R: soluble interleukin-6 receptor; spg130: soluble glycoprotein 130; sTNFR1: soluble tumor necrosis factor receptor 1; TGF-β: transforming growth factor-β; TIMP: tissue inhibitor of metalloproteinases; TNF-α: tumor necrosis factor alpha; TRAP: tartrate-resistant acid phosphatase; TWEAK: TNF-related weak inducer of apoptosis; uPAR: urokinase plasminogen activator surface receptor; VEGF: vascular endothelial growth factor.