Table 2 Summary of dental-derived stem cell (DSC)-mediated neuroprotection

Alzheimer’s Diseases

In vitro

DPSC

Promoted regeneration of neuron cells by inducing cell proliferation, reducing apoptotic cell death, prolongation of dendrites, and by inhibiting phosphorylation of tau protein

Okadaic acid induced Alzheimer’s disease in SH-SY5Y cells

[41]

DPSCs cocultured with primary hippocampal and ventral mesencephalic showed high protection against β-amyloid protein by secreting neurological factors such as NGF, GDNF, BDNF, and BMP2

β-amyloid peptide (1–42)-treated primary culture of hippocampal neuron and mesencephalic cells

[42]

In vivo

SHED

Serum-free conditioned medium derived from SHEDs improved overall cognitive function by axonal elongation, neurotransmission, suppression of inflammation, and by induction of anti-inflammatory M2-like microglia

Aβ1–40 peptide infused in imprinting control region (ICR) mice

[39]

Parkinson’s disease

In vitro

SHED

SHED-derived exosomes prevented apoptosis by suppressing caspase activity by approximately 80%

6-OHDA-induced apoptosis in ReNcell VM human neural stem cell-derived dopaminergic neurons

[34]

Conditioned medium from SHED and, SHED derived dopaminergic neuron protected primary neurons against 6-OHDA toxicity and accelerated neurite outgrowth by paracrine mechanisms

Dopaminergic neuron

[45]

DPSC

DPSC protected mouse dopaminergic neurons by the release of neurotrophins such as BDNF and NGF

MPP⁺- or rotenone-treated mesencephalic cells

[43]

Human dental pulp cells attenuated 6-OHDA toxicity through expressing neuronal phenotype and releasing NGF, GDNF, BDNF, and BMP2

6-OHDA-treated primary culture of hippocampal neuron and mesencephalic cells

[44]

DPSCs through their immunomodulatory properties attenuated the proliferation and production of ROS and NO

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated coculture system of neuron and microglia

[28, 138]

In vivo

SHED

Dopaminergic neurons derived from SHED expressed BDNF, GDNF, NT3, and HGF when transplanted in Parkinsonian rats and improved the dopamine level

6-OHDA-induced Parkinsonian rat

[45]

SHED treatment prevented 6-OHDA-induced neuronal damage in rats contributing to the improvement of behavioral outcome. Cells showed neuronal and glial expression; moreover, SHED-derived differentiated spheres had a better outcome suggesting predifferentiation could be a key step for Parkinson’s Disease transplantation therapy

6-OHDA-induced Parkinsonian rat

[44]

Spinal cord injury (SCI)

In vitro

DPSC

DPSC-laden microcapsules transplanted into an organotypic SCI model; the cells survived for 10 days and demonstrated commitment to a neural lineage

Organotypic SCI model

[139]

In vivo

SHED

SHED transplantation in traumatic SCI rats reduced the cystic cavity area and glial scar and increased the neurofilament along with lower expression of TNF-α

Traumatic SCI in Wistar rats

[47]

SHED transplantation in SCI reduced early neuronal apoptosis, which contributed to tissue and motor neuron preservation and hindlimb functional recovery

Laminectomy followed by SCI in Wistar rats

[116]

Conditioned serum-free medium from SHEDs into rat injured spinal cord during the acute postinjury period caused remarkable functional recovery which was attributed to the immunoregulatory activity that induced anti-inflammatory M2-like macrophages

Laminectomy followed by SCI in Sprague-Dawley rats

[117]

SHEDs promote functional recovery when either SHED or SHED-induced neural cells were transplanted. The transplanted cells expressed neuronal and glial differentiation along with an increase in myelin basic protein and chondroitin sulfate proteoglycan NG2 and lower expression of GFAP

Laminectomy followed by SCI in Wistar rats

[48]

DPSC

DPSC engraftment enhanced the number of surviving motor neurons in a hemisected spinal cord through secreting various neurotrophic factors, e.g., NGF, BDNF, and GDNF

Laminectomy followed by SCI in Sprague-Dawley rats

[84]

DPSC inhibited the SCI-induced apoptosis of neurons, astrocytes, and oligodendrocytes, which improved the preservation of neuronal filaments and myelin sheaths. Paracrine mechanisms along with cell integration were the factors found in achieving recovery

Laminectomy followed by SCI in Sprague-Dawley rats

[20]

DPSCs transplanted together with chitosan scaffolds resulted in the marked recovery of hindlimb locomotor functions. The levels of BDNF, GDNF, basic NGF, and NT3 were found to be significantly higher in the DPSC/chitosan-scaffold group

Laminectomy followed by SCI in Sprague-Dawley rats

[37]

Significant improvement of limb function was observed when DPSCs were transplanted in dogs with chronic spinal cord injuries

Hemilaminectomy in dogs

[140]

DPSCs demonstrated potential in repairing the completely transected spinal cord and promoting functional recovery after injury by inhibiting the expression of IL-1β, the expression of RhoA to promote neurite regeneration, and SUR1 expression to reduce progressive hemorrhagic necrosis, and by differentiating into mature neurons and oligodendrocytes

Laminectomy followed by SCI in Sprague-Dawley rats

[141]

Stroke

In vitro

DPSC

Human DPSCs showed superior neuroprotective, migratory, and in-vitro angiogenic effects versus human BMMSCs in a comparative study between the two cell types by blocking reactive gliosis, ROS production, and inflammatory mediators, e.g., IL-1 β

Oxygen–glucose deprivation (OGD)-injured human astrocytes

[36, 65]

In vivo

SHED

Transplantation of SHEDs or the conditioned medium significantly improved the neurological outcome by inhibiting the expression of proinflammatory cytokines, e.g., TNF- α and IL-1 β, and apoptosis, and by enhancing the expression of anti-inflammatory cytokines, e.g,. IL-4, IL-6, IL-10, IL-13, and by reducing tissue loss

Hypoxia–ischemia brain injury was induced in postnatal day-5 mice

[55]

SHED-derived conditioned medium enhanced neurogenesis, migration and differentiation of endogenous NPCs, induced vasculogenesis, and ameliorated ischemic brain injury after permanent MCAO

Permanent MCAO in Sprague-Dawley rats

[19]

DPSC

Transplanted human DPSCs compared with human BM-MSCs in a rat stroke model had greater reduction in infarct volume. Administration of DPSCs to rats with stroke significantly decreased reactive gliosis compared with BM-MSCs

MCAO in Sprague-Dawley rats

[36]

Dental pulp-derived side population stem/progenitor cells enhance recovery of transient focal cerebral ischemia in rats by promoting migration and differentiation of the endogenous neuronal progenitor cells and induced vasculogenesis

Transient MCAO in Sprague-Dawley rats

[53]

Intracerebral transplantation of human DPSCs following focal cerebral ischemia in rats resulted in significant improvement in forelimb sensorimotor function at 4 weeks post-treatment through cell replacement and the paracrine effect

Transient MCAO in Sprague-Dawley rats

[21]