Table 1.
Summary of the included studies investigating the effect of dental MSCs' secretome/conditioned medium on neurogenic regeneration.
| Authors, year | Cell origin-contributing factor | Scaffold | Study model | Factors contained in dental MSC-CM | Factors promoted by dental MSC-CM | Outcome |
|---|---|---|---|---|---|---|
| Neural regeneration and treating neural disorders | ||||||
| SHED-CM | ||||||
| Sakai et al., 2012 [109] | Human SHED-CM Human dental pulp MSC-CM |
- | In vivo spinal cord injury. In vitro. |
- | - | Promoted neural regeneration. |
| Inoue et al., 2013 [114] | Human SHED-CM | - | In vivo rat with cerebral ischemia. | DCX, NF, NeuN, & RECA1. | - | Promoted neuronal progenitor cells migration, differentiation, and vasculogenesis. |
| Yamagata et al., 2013 [113] | Human SHED-CM | - | In vivo hypoxic ischemic brain injury mouse. | IL-1β & TNF-α. | - | Improved neurological function, inhibited apoptosis, and decreased tissue loss. |
| Fujii et al., 2015 [119] | Human SHED-CM | - | In vivo Parkinson's disease model. In vitro |
- | - | Promoted neurite outgrowth of neurons and inhibited neuron apoptosis. |
| Jarmalaviciute et al., 2015 [120] | Human SHED-EXs and MVs | - | In vitro Parkinson's disease. | - | - | Stimulated neurite outgrowth of neurons and inhibited neuron apoptosis. |
| Matsubara et al., 2015 [112] | Human SHED-CM | - | In vivo rat with spinal cord injury. | M2 markers (IL-10, CD206) & M2-like macrophage inducers: MCP-1, Siglec-9, & IL-6. | - | Regenerated neurons suppressed inflammation which promoted functional recovery. |
| Mita et al., 2015 [117] | Human SHED-CM | - | In vivo Alzheimer's disease. In vitro. |
Ym-1, Arginase-1, & Fizz1. IL-10, mRNA of BDNF, NGF, & IGF. | - | Protected against neurodegeneration, improved cognitive functions, and inhibited neuroblastoma cell apoptosis. |
| Sugimura-Wakayama et al., 2015 [110] | Human SHED-CM | - | In vivo sciatic nerve defect. In vitro |
NGF, BDNF, NT-3, GDNF, CNTF, VEGF, & HGF. | NGF, BDNF, NT-3, CNTF, GDNF, VEGF, laminin, fibronectin, & collagen type IV. | Promoted axon regeneration, remyelination, and motor functional recovery. Increased Schwann cell proliferation, migration, and activation. |
| Shimojima et al., 2016 [118] | Human SHED-CM | - | In vivo multiple sclerosis mouse model. | ED–Siglec-9 & HGF. | mRNAs of Arginase-1 & CD206. ↓ mRNA of iNOS. |
Reduced axon injury, demyelination, and reduced inflammation. |
| Kano et al., 2017 [111] | Human SHED-CM | Collagen sponge | In vitro & in vivo peripheral nerve injury. | MCP-1 & sSiglec-9. | mRNAs of Arginase-1, Cd206, & Il-10. | Mediated neurological regeneration. Schwann cell proliferation, migration, and differentiation. |
| Li et al., 2017 [115] | Human SHED-EXs | - | In vivo rat with traumatic brain injury. In vitro |
CD9, CD63, & CD81. | ↓ TNF-α, IL-6, CD11b, CD68, mRNA of CD11b, CD86, CD16, MHCII, iNOS, CD206, IL-10, & Arginase-1. | Improved motor functional recovery and reduced neuroinflammation. |
| Asadi-Golshan et al., 2018 [116] | Human SHED-CM | Collagen hydrogel | In vivo rat spinal cord injury. | - | - | Enhanced neurological functional recovery. |
| Tsuruta et al., 2018 [122] | Human SHED-CM | - | In vivo superior laryngeal nerve injury dysphagia in rat. | Arginase-1, IL-10, Lif, Ccl2, NGF, BDNF, NTN, and mRNA VEGF. ↓ iNOS & IL-1β. |
Promoted axonal regeneration and enhanced angiogenesis. | |
| Narbute et al., 2019 [121] | Human SHED-EVs | - | In vivo rat with Parkinson's disease. | - | - | Suppression of gait impairments and normalization of tyrosine hydroxylase expression. |
| Dental pulp MSC-CM | ||||||
| Ishizaka et al., 2013 [106] | Porcine dental pulp MSC-CM | - | In vitro | - | - | Triggered antiapoptotic activity on fibroblast and promoted neurite outgrowth of human neuroblastoma cell line. |
| Mead et al., 2014 [66] | Human dental pulp MSC-CM | - | In vitro retinal nerve damage. | NGF, BDNF, & VEGF. | - | Showed the presence of different neurotrophic factors. |
| Ahmed et al., 2016 [148] | Human dental pulp MSC-CM | - | In vitro Alzheimer's disease. | VEGF, RANTES, fractalkine, FLT-3, GM-CSF, MCP-1, & neprilysin. | Bcl-2 & Bax. | Inhibited apoptosis in neuroblastoma cell line and increased its viability. |
| Yamamoto et al., 2016 [147] | Human dental pulp MSC-CM | - | In vitro nerve section. | - | - | Induced proliferation, differentiation, and migration of Schwann cells and inhibited their apoptosis. |
| Gervois et al., 2017 [146] | Human dental pulp MSC-CM | - | In vitro | - | - | Induced recruitment, neuronal maturation, and neuritogenesis of human neuroblastoma cells. |
| Song et al., 2017 [69] | Human dental pulp MSC-CM | Endothelial cell medium gel | In vitro model of ischemia. | - | - | Increased the number and total length of tubular structures in HUVECs. |
| Chen et al., 2019 [151] | Rat dental pulp MSC-CM | - | In vivo rat with aneurysmal subarachnoid hemorrhage. | IGF-1, TGF-β, TIMP1, & 2. | - | Improvement of microcirculation and neuroinflammation. |
| Makino et al., 2019 [150] | Rat dental pulp MSC-CM | - | In vivo rat with diabetic polyneuropathy. In vitro |
- | - | Exhibited neuroprotective, anti-inflammatory, and angiogenic actions. Increased proliferation of HUVEC in vitro. |
| Wang et al., 2019 [149] | Human dental pulp MSC-CM | - | In vivo mouse with amyotrophic lateral sclerosis. | - | - | Improved neuromuscular junction innervation and motor neuron survival. |
| Gingival MSC-CM | ||||||
| Rajan et al., 2017 [170] | Human gingival MSC-CM | - | In vitro neuron degenerative diseases. | NGF, NT-3, IL-10, & TGF-β. | Bcl-2, IL-10, BDNF, & NT-3. ↓ SOD-1, iNOS, COX-2; TNF-α, cleaved caspase-3, & Bax. | Suppression of neural cell apoptosis, oxidative stress, and inflammation. |
| Mao et al., 2019 [168] | Human gingival MSC-EVs Human gingival MSC-CM |
- | In vivo mouse with sciatic nerve injury. In vitro |
- | Postsynaptic AChR clusters in NMJ, β-tubulin III, S100β, GFAP, c-JUN, Notch1, SOX-2, EGR2/KROX-20, PCNA, BrdU. | Promoted proliferation, migration of Schwann cells, axonal regeneration, and functional recovery. |
| Rao et al., 2019 [169] | Human gingival MSC-EXs | - | In vivo rat with sciatic nerve injury. In vitro |
- | Neurofilament 200, S100, & CCK8. | Promoted increase in number of nerve fibers, myelin formation, recovery of muscle and nerve function, Schwann cell proliferation, and cell axon growth. |
| Zhang et al., 2019 [173] | Human gingival MSC-EXs | SIS-ECM | In vivo critical-sized tongue defect in rats. | - | CK14, CK8, NTPdase 2, PLC-β2, AADC, UCH-L1/PGP9.5, BDNF, P2X3, & Shh. | Promoted tongue lingual papillae recovery and taste bud regeneration and re-innervation. |
| Periodontal ligament MSC-CM | ||||||
| Rajan et al., 2016 [175] | Multiple sclerosis human periodontal ligament MSC-CM Multiple sclerosis human periodontal ligament MSC-EVMs Human periodontal ligament MSC-CM Human periodontal ligament MSC-EVMs. |
- | In vivo mouse with multiple sclerosis. | - | IL-10, TGF-β ↓ IL-4, IL-17, IFN-γ, TNF-α, IL-6, IL-1β, STAT1, p53, caspase-3, & Bax. |
Promoted anti-inflammatory, immunosuppressive effects and downregulated apoptosis-related genes. |
| Giacoppo et al., 2017 [176] | Hypoxia—human periodontal ligament MSC-CM | - | In vivo mouse with multiple sclerosis. In vitro |
NT-3, IL-10, & TGF-β | IL-37, caspase-1, IL-10, BDNF, NT-3, Bcl-2; Beclin-1, LC3; phosphorylation of PI3K, Akt, & mTOR. ↓ IL-17, IFN-γ, JNK, TNF-α, iNOS, COX-2, cleaved caspase- 3, & Bax. |
Clinical and histologic features of the disease were diminished via modulation of inflammation, oxidative stress, and apoptotic pathways. |
| Rajan et al., 2017 [192] | Multiple sclerosis human periodontal ligament MSC-CM Multiple sclerosis human periodontal ligament MSC-EMVs |
- | In vivo mouse with multiple sclerosis. | Substantial level of IL-10, TGF-β, & SDF-1α Less amount of IL-15, MCP-1, and MIP-1α. |
↓ NALP3, cleaved caspase-1, IL-1β, IL-18, TLR-4, & NF-κB. | Promoted anti-inflammatory and immunosuppressive effects. |
| Dental follicle MSC-CM & MSCs from apical papilla-CM | ||||||
| Kumar et al., 2017 [65] | Human dental pulp MSC-CM Human dental follicle MSC-CM Human MSCs from apical papilla-CM |
- | In vitro | GM-CSF, IFN-γ, TGF-β, NGF, BDNF, NT-3 | MFI, MAP-2, β-tubulin III, nestin, and SOX-1 | Enhanced neural differentiation. |
AADC: aromatic l-amino acid decarboxylas; AChR: acetylcholine receptor; Akt: protein kinase B; Bax: Bcl-2-associated X protein; Bcl-2: B-cell lymphoma 2; BDNF: brain-derived neurotrophic factor; BrdU: bromodeoxyuridine; CCK8: Cell Count Kit-8; Ccl2: chemokine C-C motif ligand; CD: cluster of differentiation; CM: conditioned medium; CNTF: ciliary neurotrophic factor; COX-2: cyclooxygenase 2; DCX: doublecortin; ED-Siglec-9: ectodomain of sialic acid-binding Ig-like lectin-9; EGR2/KROX: early growth response gene; EVs: extracellular vesicles; EXs: exosomes; Fizz 1: resistin-like molecule alpha 1; FLT-3: Fms-related tyrosine kinase 3; GDN: glial cell line-derived neurotrophic factor; GFAP: glial fibrillary acidic protein; GM-CSF: granulocyte-macrophage colony-stimulating factor; MSCs: mesenchymal stem cells; HGF: hepatocyte growth factor; HUVECs: human umbilical vascular endothelial cells; IGF: insulin-like growth factor; IL: interleukin; iNOS: inducible nitric oxide synthase; JNK: c-Jun N terminal kinases; Lif: leukemia inhibitory factor; MAP-2: microtubule associated protein 2; MCP-1: monocyte chemoattractant protein-1; MHC: major histocompatibility complex; MIP-1α: macrophage inflammatory protein-1α; mTOR: mammalian target of rapamycin; MVs: microvesicles; NALP3: NACHT domain-, leucine-rich repeat-, and PYD-containing protein 3; NeuN: hexaribonucleotide binding protein 3; NF: nuclear factor; NF-κB: nuclear factor, kappa light chain enhancer of activated B-cells; NGF: nerve growth factor; Notch 1: neurogenic locus notch homolog protein; NT-3: neurotrophin 3; NTN: neurturin; NTPdase 2: ectonucleotidases; P2X3: purinergic receptor P2X3; p53: tumor protein p53; PCNA: proliferating cell nuclear antigen; MSCs: stem cells; PI3K: phosphoinositide 3- kinases; PLC-β2: phospholipase c β2; RANTES: chemokine (c-c motif) ligand 5 (CCL5); RECA1: homolog of bacteria RecA; S100β: S 100 calcium-binding protein β; SDF-1α: stromal cell-derived factor 1α; Shh: sonic hedgehog; Siglrc-9: sialic acid-binding immunoglobulin type lectins-9; SOD-1: superoxide dismutase; SOX: sex-determining region Y-box; STAT1: signal transducer and activator of transcription 1; TLR: Toll-like receptor; TNF: tumor necrosis factor; UCH-L1/PGP9.5: ubiquitin carboxyterminal hydrolase isozyme 1; VEGF: vascular endothelial growth factor.