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Stem cells from human exfoliated deciduous teeth (SHED) have emerged as an alternative stem cell source for cell therapy and regenerative medicine because they are readily available, pose fewer ethical concerns, and have low immunogenicity and tumourigenicity. SHED offer a number of advantages over other dental stem cells, including a high proliferation rate with the potential to differentiate into multiple developmental lineages. The therapeutic effects of SHED are mediated by multiple mechanisms, including immunomodulation, angiogenesis, neurogenesis, osteogenesis, and adipogenesis. Since SHED are more potentially useful source of stem cells than BM-MSCs and DPSCs in cell therapy, therefore it could be suggested that the secretome derived from SHED could enhance tissue regeneration and repair and hence, considered as a suitable candidate for a cell-free approach in regenerative medicine and dentistry.
Type of Study | Purpose | Secreted Soluble Factors | Key Findings | References |
---|---|---|---|---|
In vitro (SHED vs DPSCs) |
To compare cytokine profiles produced by SHED and DPSCs. | IL-6, CNTF, CCL23, IGFBP2, IL-7, EGF, BMP6, IGFBP1, GM-CSF, Eotaxin1, IL-5, IFN-gamma, PARC, IL-2, BLC, BDNF, MCP-1 | SHED-derived secretome expressed more cytokines involved in odontogenesis, osteogenesis, and immunomodulation, while DPSCs-derived secretome expressed more cytokines involved in angiogenesis. | [20] |
In vitro (DPSCs) |
To investigate the potency of SHED-CM on DPSCs in pulp regeneration. | TGF-β, MMP, VEGF, FGF, Ils, BMP | SHED-CM showed a dose-dependent promotive effect on the proliferation, migration, and survival of DPSCs. Upregulation of marker genes for odontoblasts and osteogenesis and increased mineral deposition of impaired DPSCs in the presence of SHED-CM. |
[15] |
In vivo (Mouse calvarial bone defect model) |
To investigate the effect of SHED-CM on bone regeneration. | TIMP-1, OPG, OPN, M-CSF, MCP-1, HGF, ANG, VEGF-C, IL-6, BDNF, NT-3, BMP-4, BMP-2, bNGF, FGF-2, GDNF, PDGF-BB, EGF | Bone regeneration was improved in the defects treated with stem cells and CM compared to controls 8 weeks after transplantation. Mature bone formation and angiogenesis were confirmed with SHED-CM but not with stem cells or in controls. |
[11] |
In vitro (OA chondrocytes) |
To evaluate the regenerative effect of SHED-CM on OA chondrocytes for cartilage repair and regeneration. | TGF-β1, IL-10, IL-6 | SHED-CM protected chondrocytes by increasing matrix proteins and suppressed MMP-13 expression. SHED-CM attenuated the inflammatory assault induced by IL-1β. The regenerative effect of SHED-CM could be attributed to secreted factors modulating catabolic processes towards an anabolic phenotype by downregulating NF-κB. |
[13] |
In vitro (HUVECs) In vivo (Mouse Matrigel plug assays) Ex vivo (Rat aortic ring assay) |
To examine the beneficial effects of secreted factors from SHED on endothelial cells to promote angiogenesis. | n/a | SHED-CM significantly increased the proliferation of HUVECs. SHED-CM accelerated the migration of HUVECs in wound healing and Boyden chamber assays. SHED-CM induced complex tubular structures of HUVECs in a tube formation assay. SHED-CM significantly increased neovascularisation in rat aorta. The angiogenic effects of SHED-CM were equal to or greater than the effective concentration of VEGF. |
[10] |
In vitro (HUVECs) In vivo (Rat model of orthotopic dental pulp regeneration) |
To evaluate the effect of SHED-CM on the proliferation, differentiation, migration ability, cell death, gene expression, and production of VEGF. | n/a | SHED-CM significantly induced lower expression of 7AAD in HUVECs, whereas the expression of the Ki67 was similar in all groups. SHED-CM induced expression of VEGF-A. SHED-CM significantly induced higher VEGF synthesis than other media. SHED-CM induced the formation of vascularised connective tissue inside the root canal. |
[9] |
In vitro (Human breast cancer stem cells (BCSCs)) |
To evaluate the stemness and proliferation of human BCSCs after being supplemented with heated secretome from SHED. | n/a | The heated secretome of SHED contained activated TGF-β1, which increased the expression of stemness genes, OCT4, and ALDH1A1, as well as the proliferation of human BCSCs (ALDH+) via TGF-β1 paracrine signalling. | [21] |
In vivo (Rat with ALF) |
To study the multifaceted therapeutic benefit of SHED-CM in ALF in rats. | 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 | SHED-CM attenuated the ALF-induced inflammation by suppressing the proinflammatory cytokine levels (IL-6, TNFα, IL-1β, and iNOS), increasing the anti-inflammatory cytokine levels (IL-10 and TGF-β1), and M2 cell markers. SHED-CM promoted hepatocyte proliferation and inhibited apoptosis. SHED-CM induced angiogenesis. |
[4] |
In vitro (Myelin oligodendrocyte glycoprotein-specific CD4+ T cells) In vivo (A mouse model of multiple sclerosis (MS)) |
To investigate the efficacy of SHED-CM in treating experimental autoimmune encephalomyelitis, a mouse model of MS. | n/a | In vitro: SHED-CM inhibited the proliferation of myelin oligodendrocyte glycoprotein-specific CD4+ T cells. In vivo: SHED-CM exhibited significantly improved disease scores, reduced demyelination, and axonal injury. SHED-CM reduced inflammatory cell infiltration and proinflammatory cytokine expression (IFN-γ, IL-17, and TNF-α) in the spinal cord. |
[7] |
In vitro (Schwann cells and DRG cells) In vivo (Rat model of sciatic nerve transection) |
To investigate the effect of SHED-CM in the regeneration of the peripheral nerve. | NT-3, NGF, CNTF, HGF, GDNF, BDNF, VEGF | In vitro: SHED-CM significantly increased proliferation, migration, and the expression of neuron-, extracellular matrix (ECM)-, and angiogenesis-related genes in Schwann cells. SHED-CM stimulated the neuritogenesis of DRG cells and increased cell viability. SHED-CM enhanced tube formation in an angiogenesis assay. In vivo: SHED-CM promoted axon regeneration and functional recovery. SHED-CM reduced muscle atrophy. |
[8] |
In vitro (Cerebellar granule neurons (CGNs) isolated from newborn rats) |
To evaluate the trophic actions of SHED-CM and dSHED-CM on neurite outgrowth and apoptosis in CGNs isolated from newborn rats. | n/a | SHED-CM or dSHED-CM significantly suppressed the 6-OHDA-induced apoptosis in CGNs isolated from newborn rats. Neurite outgrowth was significantly enhanced by SHED-CM and dSHED-CM. |
[18] |
In vitro (Glutamate-induced neurons from the cortices of C57BL/6 mice embryos) In vivo (A mouse model of Aβ-induced AD) |
To investigate the therapeutic benefits of a serum-free SHED-CM in a mouse model of AD. | n/a | SHED-CM attenuated the proinflammatory (IL-1β, TNF-α, and iNOS) and induced anti-inflammatory M2-like microglia. SHED-CM improved cognitive function. SHED-CM inhibited oxidative-nitrosative stress (3-NT and iNOS) in the cerebral parenchyma. SHED-CM promoted the expression of multiple neurotrophic factors (BDNF, NGF, and IGF-1). SHED-CM suppressed glutamate-induced neuronal death. |
[17] |
In vivo (A mouse model of I/R) |
To investigate the impact of SHED-CM on myocardial injury in a mouse model of I/R. | VEGF, IGF-1, HGF, bFGF, SDF-1, EGF, SCF | SHED-CM reduced the size of myocardial infarct, inhibited myocyte apoptosis, and suppressed inflammatory cytokine levels (IL-6, IL-1β, and TNFα). | [3] |
In vivo (A rat model of SCI) |
To investigate the effect of SHED-CM in a rat model of SCI. | MCP-1, ED-Siglec-9 |
SHED-CM improved functional recovery after SCI. SHED-CM suppressed expressions of proinflammatory cytokines (IL-1β, TNF-α, and iNOS) and induced anti-inflammatory M2-like macrophages. |
[5] |
In vivo (A mouse model of streptozocin-induced diabetes) |
To investigate the effect of factors secreted by SHED on β-cell function and survival. | n/a | SHED-CM suppressed inflammatory chronic response of macrophage. SHED-CM promoted lung regeneration. SHED-CM increased insulin secretion, β-cell proliferation, and reduced apoptosis. |
[2] |
In vivo (A mouse model of BLM-induced ALI) |
To investigate the effects of SHED-CM in a mouse model of BLM-induced ALI. | n/a | SHED-CM attenuated lung injury and weight loss in BLM-treated mice and improved their survival rate. SHED-CM attenuated the BLM-induced proinflammatory response and promoted the induction of anti-inflammatory M2-like lung macrophage. SHED-CM suppressed the BLM-induced tissue damage and inhibited the expression of α-SMA. SHED-CM promoted the M2 differentiation of bone marrow-derived macrophages in vitro. |
[6] |
In vivo (Rat model of pMCAO) |
To investigate the effects of SHED-CM in a rat model of pMCAO. | n/a | SHED-CM improved motor function recovery. SHED-CM increased the expression of doublecortin (DCX), neurofilament, neuronal nuclei, and rat endothelial cell antigen in the peri-infarct area. SHED-CM induced the migration of NPCs from the subventricular zone to the peri-infarct area. |
[16] |
In vivo (A mouse model of perinatal HI-induced brain injury) |
To investigate the effects of SHED-CM for the treatment of neonatal HI brain injury. | n/a | SHED-CM exhibited significant reductions in apoptosis and tissue loss. SHED-CM improved neurological functions. |
[1] |
The properties of SHED-derived secretome make it an attractive tool for use in regenerative medicine. Its immunomodulatory effects, its ability to promote tissue regeneration and angiogenesis, and its lower risk of tumour formation and immune rejection make it a promising alternative to live cell therapy. However, further research is needed to understand the mechanisms underlying these properties fully and to optimise their production and use. With further research and development, the secretome of SHED has the potential to become a valuable tool in the field of regenerative medicine.