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

Table 4

Summary of the included studies investigating the effect of dental MSCs’ secretome/conditioned medium on bone regeneration.

Authors, year	Cell origin-contributing factor	Scaffold	Study model	Factors contained in dental MSC-CM	Factors promoted by dental MSC-CM	Outcome
Bone regeneration
Dental pulp MSC-CM
Paschalidis et al., 2014 [153]	Human dental pulp MSC-CM	-	In vitro	-	TGF-β1	Enhanced dental pulp MSCs viability, migration and mineralization potential.
Fujio et al., 2017 [154]	Human dental pulp MSC-CM	-	In vivo mouse with distraction osteogenesis.; In vitro	VEGF-A & angiopoietin-2	Osterix, SOX-5, & factor 8.	Hypoxic dental pulp MSC-CM enhanced angiogenesis and increased osteoblastic and chondrogenic markers expression.
Gingival MSC-CM
Diomede et al., 2018 [172]	Human gingival MSCs+; Human gingival MSC-CM	PLA	In vivo rat calvarial defect.; In vitro	ASF1A, GDF5, HDAC7, ID3, INTU, PDLIM7, PEX7, RHOA, RPL38, SFRP1, SIX2, SMAD1, SNAI1, SOX-9, BCAP29, BMP2K, DHRS3, FAM20C, TMEM64, FHL2, & TOB2.		Induction of new bone formation and osseointegration through expressing or upregulating genes involved in ossification or regulation of ossification.
Diomede et al., 2018 [177]	Human gingival MSCs+; Human gingival MSC-EVs; Human gingival MSCs+ PEI- Human gingival MSC-EVs	PLA	In vivo rat calvarial defect.; In vitro	FHL2, BMP2, TWSG1, CCDC47, FAM20C, ERCC2, LEP, TOB2, IMPAD1, CHRDL1, MINPP1, HIRA, MYBBP1A, JAG1, MEF2C, SUCO, SFRP1, SOX-9, SIX2, RHOA, PDLIM7, IFT80, SMAD1, HDAC7, ASF1A, ID3, SNAI1, PEX7, RPL38, BMP2K, and BCAP29.	RUNX2 & BMP2/4.	Improved bone healing by showing better osteogenic properties and exhibiting greater osteogenic inductivity.
Periodontal ligament MSC-CM
Diomede et al., 2018 [194]	Human periodontal ligament MSCs+; Human periodontal ligament MSC-EVs or human periodontal ligament MSC-PEI-EVs	Collagen membrane	In vivo rat calvarial defect; In vitro	-	TGF-B1, TGF-B2, BMP2, BMP4; MMP8, TUFT1, TFIP11, RUNX2 SOX-9.	Increased osteogenic potential and enhanced osseous regeneration and osseointegration processes.
Pizzicannella et al., 2019 [193]	Human periodontal ligament MSCs+; Human periodontal ligament MSC-CM or human periodontal ligament MSC-EVs or human periodontal ligament MSC-PEI-EVs	3D collagen membrane	In vivo rat calvarial defect; In vitro	-	VEGF, VEGFR2, RUNX2, COL1A1, BMP2, & BMP4.	Enhanced osseous regeneration, vascularization, and osseointegration.
Dental follicle MSC-CM & MSCs from apical papilla-CM
Kumar et al., 2018 [63]	Human dental pulp MSC-CM	-	In vitro	SAMD9, ADAM19, BMP7, ATP2B4, DSPP, BEST3, & LRP4.	-	Revealed the presence of osteogenic lineage proteins important for osteogenic differentiation.
	Human dental follicle MSC-CM			ATP2B4, MINPP1, ENAM, WISP2, COL27A, & ITGB3.	-
	Human MSCs from apical papilla-CM			FBN1, DDR2, ZNF423, SAMD9, ADAM19, BMP7, ATP2B4, USP9X, ZNF521, INHBA, ROR2, LRP4, COL27A, & ITGB3.	-
	Human bone marrow MSC-CM			FBN1, BMPR1A, DDR2, ZNF423, SAMD9.	-

3D: three dimensional; ADAM19: disintegrin and metalloproteinase domain-containing protein; ASF1A: anti-silencing function 1A histone chaperone; ATP2B4: plasma membrane calcium transporting ATPase 4; BCAP29: B-cell receptor-associated protein 29; BEST3: bestrophin-3; BMP: bone morphogenetic protein; BMP2K: BMP2-inducible kinase; BMPR1A: bone morphogenetic protein receptor type-1A; CCDC47: coiled-coil domain containing 47; CHRDL1: chordin-like 1; CM: conditioned medium; COL1A1: collagen type 1; COL27A1: collagen alpha-1(XXVII) chain; DDR2: discoidin domain receptor family, member 2; DSPP: dentin sialophosphoprotein; ENAM: enamelin; ERCC2: ERCC excision repair 2; TFIIH: core complex helicase subunit; EVs: extracellular vesicles; FAM20C: Golgi-associated secretory pathway kinase; FBN1: fibrillin 1; FHL2: four and a half LIM domains 2; GDF-5: growth differentiation factor 5; HDAC7: histone deacetylase 7; HIRA: histone cell cycle regulator; ID3: inhibitor of DNA binding 3; IFT80: intraflagellar transport 80; IMPAD1: inositol monophosphatase domain containing 1; INHBA: inhibin beta A chain inhibitor-1; ITGB3: integrin beta-3; JAG1: jagged 1; LEP: leptin; LRP4: LDL receptor-related protein 4; MEF2C: myocyte enhancer factor 2C; MSCs: mesenchymal stem cells; MINPP1: multiple inositol polyphosphate phosphatase 1; MMP: matrix metalloprotease; MYBBP1A: MYB-binding protein 1a; PDLIM7: PDZ and LIM domain 7; PEI: polyethylenimine; PEX7: peroxisomal biogenesis factor 7; PLA: polylactide; RHOA: Ras homolog family member A; ROR2: RTK-like orphan receptor 2; RPL38: ribosomal protein L38; RUNX2: runt-related transcription factor 2; SAMD9: sterile alpha motif domain containing protein 9; MSCs: mesenchymal stem cells; SFRP1: secreted frizzled-related protein 1; SIX2: SIX homeobox 2; SMAD1: SMAD family member 1;SNAI1: snail family transcriptional repressor 1; SOX: sex-determining region Y-box; SUCO: SUN domain-containing ossification factor; TFIP11: tuftelin-interacting protein 11; TGF-β: transforming growth factor-β; TOB2: transducer of ERBB2; TUFT1: tuftelin 1; TWSG1: twisted gastrulation BMP signaling modulator 1; USP9X: USP9X protein variant; VEGF: vascular endothelial growth factor; VEGFR2: vascular endothelial growth factor receptor 2; WISP2: WNT1-inducible signaling pathway protein 2; ZNF423: zinc finger protein 423; ZNF521: ZNF521 protein.