Neural stem cells for Parkinson’s disease management: Challenges, nanobased support, and prospects

Table 1 Experimental studies on the therapeutic role of neural stem cells in Parkinson’s disease models

Cells type	Model	Effects	Ref.
Undifferentiated NSCs line C17.2	6-OHDA rat model	Striatum deposition	Yang et al[32]
		↑ Expression of β-tubulin III, NSE, NeuN
		↑ TH- and AADC-positive cells
		↓ Motor behaviour deficits
hCNSPCs	6-OHDA rat model	Striatum deposition	Svendsen et al[33]
		↑ Expression of β-tubulin III
		↑ TH- and hGFAP-positive cells
		↓ Motor behavior deficits
hNSCs	6-OHDA mice model	Striatum deposition	Zuo et al[35]
		↓ IL-1 β, IL-2, and TNF-a
		↑ IL-10
		↓ Motor behavior deficits
hfNSC line (HB1.F3)	6-OHDA rat model	Striatum deposition	Yasuhara et al[37]
		↑ Expression of nestin, HuD, β-tubulin III-positive, MAP2-positive, and NeuN positive and HuC negative
		↑ TH-positive cells
		↓ Motor behavior deficits
hNFG-GFP-OBNSCs	6-OHDA rat model	Striatum deposition normal histoarchitecture of the striatum	Marei et al[38]
		↑ Striatal neurons
		↓ Necrotic cells
		↓ Motor behavior deficits
human dental papilla-derived stem cells and hbNSCs	6-OHDA rat model	Striatum deposition	Yoon et al[40]
		↑ MAP2- positive cells
		↑ TH- and GIRK2-positive cells
		↔ No differences behavioral amelioration
hbNSCs	6-OHDA rat model	Striatum deposition	Shin et al[41]
		↑ TH- and human β2 microglobulin-positive cells
		↔ No differences behavioral amelioration
hNSCs	MPTP-induced monkeys	Striatum deposition	Redmond et al[43]
		↑ TH- and DAT- positive cells
		↑ DA level
		↓ Motor behavior deficits
hpNSCs	MPTP-induced monkeys	Striatum deposition	Gonzalez et al[44]
		↑ Striatal DA concentration, TH- positive cells, TH fiber innervation
		↓ Behavior deficit

6-OHDA: 6-hydroxydopamine; AADC: Aromatic L-amino decarboxylase; DA: Dopamine; DAergic: Dopaminergic; DAT: Dopamine transporter; GIRK2: G Protein-activated inward rectifier potassium channel 2; hNSCs: Human NSCs; hbNSCs: Human brain-derived NSCs; hfNSCs: Human fetal-derived NSCs; hGFAP: Human glial fibrillary acidic protein; hNFG-GFP-OBNSCs: Olfactory bulb neural stem cells (OBNSCs) genetically engineered to express hNGF and GFP; hpNSCs: Human parthenogenetic stem cell-derived NSCs; HuC: Very early neuronal marker; HuD: Postmitotic neuronal marker; MAP2: Microtubule-associated protein 2; MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NSE: Neuron-specific enolase; NeuN: Matured neuronal marker; NPCs: Neural progenitor cells; TH: Tyrosine hydroxylase; TNF-α: Tumor necrosis factor- α.

Table 2 Experimental studies on the therapeutic role of alternative stem cell sources in Parkinson’s disease models

Stem cells source	Model	Effects	Ref.
hPESC line	MPTP-induced monkeys	Striatum deposition	Wang et al[93]
Q-CTS-hESC-1		↑ DA level
		↑ Expression of TH-, hNCAM and GIRK2-positive cells
		↑ Behavioral improvement
NPCs	6-OHDA rat model	↑ DA level	Song et al[94]
		↑ Nurr1 and Foxa2 transcription factors
		Improvement in behavior is not mentioned
hiPSC lines	6-OHDA rat model	Striatum deposition	Song et al[95]
		↑ DAergic neurons density
		↑ Behavioral amelioration
MSCs	6-OHDA rat model	↑ TH-positive fibers in the striatum and TH-positive neurons in the SNpc	Wang et al[96]
		↑ Therapeutic effects of SDF-1α
		↑ Behavioral amelioration
hMSCs	6-OHDA rat model	striatum deposition	Cova et al[97]
		↑ DAergic neuron density
		↑ Ki67/ PCNA – positive cells level
		↑ Dcx expression
		None of the grafted cells were TH- or DAT-positive
		Improvement in behavior is not mentioned

6-OHDA: 6-hydroxydopamine; DA: Dopamine; DAergic: Dopaminergic; DAT: Dopamine transporter; Dcx: Double cortin; GIRK2: G protein-activated inward rectifier potassium channel 2; hMSCs: Human adult MSCs; hiPSC: Human iPSC; hPESC: Human parthenogenetic ESCs; hNCAM: Human specific neural cell adhesion molecule; PCNA: Proliferating cell nuclear antigen; MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NPCs: Neural progenitor cells; Ki67: Proliferating cell nuclear antigen, SDF-1α: Stromal cell-derived factor 1α; SNpc: Substantia nigra pars compacta; TH: Tyrosine hydroxylase.

Table 3 Clinical trials for cell-based therapy in Parkinson’s disease

Study identifier	Cell type	Aim of the study
NCT03119636[62]	hESC-NPCs	Safety and efficacy evaluation of intracerebral transplantation
NCT05635409[63]	hESC-DA neurons	Safety and tolerability evaluation of intraputamenal transplantation
NCT02452723[64]	ISC-hpNSC®	Safety evaluation of intracerebral transplantation
NCT03815071[65]	iPS-NSCs	Safety and efficacy evaluation
UMIN000033564[66]	iPSC-derived dopaminergic progenitors	Safety and efficacy of transplantation into the corpus striatum
NCT03128450[67]	hNSCs	Safety and efficacy evaluation of nasal delivery
NCT03309514[68]	NSC-derived neurons	Safety and efficacy evaluation of intracerebral injection
NCT01898390[69]	hVMT	Safety and efficacy evaluation
NCT02795052[70]	BMSC	Efficacy evaluation of intravenous and intranasal delivery
NCT00976430[71]	BMSC	Safety and efficacy evaluation
NCT03724136[72]	BMSC	Efficacy evaluation of intravenous and intranasal delivery on cognitive impairment
NCT03684122[73]	Umbilical cord derived MSCs differentiated into NSCs	Safety evaluation of intrathecal and intravenous injections

BMSC: Bone-marrow-derived stem cell; iPS-NSC cells: Pluripotent stem-cell-derived neural stem cells; ISC-hpNSC^®: Human parthenogenetic stem-cell-derived neural stem cells developed by international stem cell corporation; hNSCs: Human neural stem cells; hVMT: Human ventral mesencephalon tissue; hESC-NPCs: Human embryonic stem cells-derived neural precursor cells.