Table 3.

Overview of studies involving SHED secretome.

Secretome Type	Administration	Preclinical Model	Factors Contained in Secretome	Results	Ref.
EVs	-	SV40 human microglial cell line treated with LPS or polarized toward M1 or M2	-	↓ NF-κB signaling ↑ glycolytic activity in M0, M1, and M2 cells	[74]
EVs	-	Human microglial cells	-	↑ intracellular Ca2+ and ATP release, motility through P2X4 receptor/milk fat globule-epidermal growth factor-factor VIII (MFG-E8)-dependent mechanisms	[75]
CM from DAergic-neuron-like differentiated and undifferentiated SHEDs	-	Cerebellar granule neurons treated with 6-OHDA	-	CM obtained from differentiated SHEDs protect primary neurons against 6-OHDA toxicity and accelerated neurite outgrowth	[76]
CM	Intravenous injection	Lewis rats treated with rotenone	IGFBP-6, TIMP-2, TIMP-1, TGF-β1, IGFBP-2, IGFBP-4, BMP-5	100 µg/mL of SHED-CM induced the maximal improvement of motor deficits ↑ tyrosine hydroxylase ↓ synuclein levels, Iba-1 positive cells and CD4 levels	[77]
EXOs and MVs from SHEDs grown in standard culture conditions or on laminin-coated three-dimensional alginate micro-carriers	-	Dopaminergic neurons differentiated from ReNcell VM human neural stem cells treated with 6-OHDA	-	EXOs, but not MVs, derived from SHEDs grown on laminin-coated three-dimensional alginate micro-carriers suppressed apoptosis	[78]
EVs	Intranasal	Male Wistar rats treated with 6-OHDA	-	↑ motor function	[79]
CM	Intranasally 24 h after i.c.v. injection of A𝛽1−40	Mice receiving an i.c.v. injection of A𝛽1−40 peptide	-	↑ cognitive function and neurotrophic factors. ↓ oxidative stress	[80]
CM	Intravenous at day 14 postimmunization (peak of EAE)	EAE induced C57BL/6J mice	ED–Siglec-9 and HGF	↓ demyelination and axonal injury, inflammatory cell infiltration and proinflammatory cytokine expression	[81]
CM	Intrathecally	Sprague Dawley rats with spinal cord contusion injury	79 proteins of which 28 involved in neuroregenerative processes; MCP-1 and ED-Siglec-9 may be involved in M2-like macrophage differentiation	↑ functional recovery ↓ pro-inflammatory cytokines	[82]
CM alone or loaded on collagen hydrogel	Intraspinal injection	Sprague Dawley rats subjected to SCI	-	CM on collagen hydrogel ↑ functional recovery	[83]
CM alone or loaded on collagen hydrogel	Intraspinal injection	Sprague Dawley rats subjected to SCI	-	CM on collagen hydrogel: ↑ volume of preserved white and gray matter and the total number of neurons and oligodendrocytes ↓ lesion volume and lesion length	[84]
CM	Intravenous administration 5 days after peripheral nerve injury	Male C57BL/6J mice subjected to peripheral nerve injury made by the transection of the L4 spinal nerve	-	↓ allodynia and activation of microglia and astrocytes	[85]
CM	CM loaded on the collagen sponge placed in the nerve gap	Female Sprague Dawley with rat facial nerves transection	MCP-1 and ED-Siglec-9	↑ neurological function	[86]
CM	Silicon conduits containing CM	Schwann cells and dorsal root ganglia; male Wistar/ST rats subjects to sciatic nerve transection	NGF, BDNF, NT-3, GDNF, CNTF, VEGF, and HGF	In vitro: ↑ proliferation, migration, and expression of neuron-, ECM-, and angiogenesis-related genes, neurite outgrowth of dorsal root ganglia and increased cell viability In vivo: ↑ axon regeneration, myelination, motor function. ↓ muscle atrophy	[87]
EXOs	-	BV-2 cells treated with LPS; Wistar rats subjected to TBI	-	↑ motor function	[88]
CM	Intranasally 3 days after MCAO	Sprague Dawley rats subjected to permanent MCAO	-	↓ motor disability and infarct volume	[89]
CM	Intracerebral administration 24 h after hypoxia-ischemia	ICR mice with hypoxia-ischemia brain injury	-	↑ neurological function and survival rate	[90]
CM	Injection into soleus muscles twice a week over a period of 4 weeks twelve weeks after the induction of diabetes	Dorsal root ganglion neurons; C57BL/6 mice treated with streptozotocin	NGF, BDNF, FGF2 and VEGF in fraction > 6 kDa	In vitro: ↑ neurite outgrowth In vivo: ↓ decline in sensory nerve conduction velocities	[91]
CM	Intravenous simultaneously with the superior laryngeal nerve damage	Male Wistar/ST rats subjected to superior laryngeal nerve damage	-	↑ functional recovery, myelination and axonal regeneration	[92]

6-OHDA, 6-hydroxy-dopamine; Aβ, amyloid β; BDNF, brain-derived neurotrophic factor; BMP, bone morphogenetic protein; CM, conditioned medium; CNTF, ciliary neurotrophic factor; EAE, experimental autoimmune encephalomyelitis; ECM, extracellular matrix; ED-Siglec-9, ectodomain of sialic-acid-binding Ig-like lectin-9; EXOs, exosomes; EVs, extracellular vesicles; FGF, fibroblast growth factor; GDNF, glial-cell-derived neurotrophic factor; HGF, hepatocyte growth factor; i.c.v., intracerebroventricular; IGFBP, insulin-like growth factor binding protein; LPS, lipopolysaccharide; MCP, Monocyte Chemoattractant Protein; MVs, microvesicles; NF-κB, Nuclear Factor kappa-light-chain-enhancer of activated B cells; NGF, nerve growth factor; NT, neurotrophin; OGD, oxygen-glucose deprivation; SHEDs, stem cells from human exfoliated deciduous teeth; MCAO, middle cerebral artery occlusion; SCI, spinal cord injury; TBI, traumatic brain injury; TGF, transforming growth factor; TIMP, tissue inhibitor of metalloproteinase; VEGF, vascular endothelial growth factor; ↑, increase/improvements; ↓, reduction.