Therapeutic potential of mesenchymal stem cells in neurodegenerative diseases

Table 1 Classification and characteristics of mesenchymal stem cells

Type	Advantage	Limitations	Ref.
BM-MSCs	First to be discovered, abundant sources, possesses good differentiation capacity and immune regulatory functions	Invasive collection process, age-related decline in proliferation capacity and differentiation potential	[76-79]
ADSCs	Abundant sources, relatively easy collection process	Cell quality influenced by the age, weight, and disease status of donor	[80,81]
UC-MSCs	Convenient collection, no ethical issues, strong proliferative capacity, high differentiation potential, and low immunogenicity	Requires establishment of cord blood banks for preservation and management	[82,83]
PMSCs	Easily accessible, convenient collection, limited ethical concerns and low immunogenicity	Placental tissue has complex origin and requires strict screening and processing, needs to be collected from a healthy mother giving birth to a healthy baby	[84]
DPSCs	No ethical concerns, low immunogenicity, and high regenerative potential	Limited opportunities for collection	[85,86]
MenSCs	No ethical concerns, low immunogenicity, and strong cell proliferation capacity	Proliferation capacity influenced by donor age, passage number, and storage time	[87,88]

BM-MSCs: Bone marrow-derived mesenchymal stem cells; ADSCs: Adipose-derived mesenchymal stem cells; UC-MSCs: Umbilical cord-derived mesenchymal stem cells; PMSCs: Placenta-derived mesenchymal stem cells; DPSCs: Dental pulp-derived mesenchymal stem cells; MenSCs: Menstrual blood-derived endometrial stem cells.

Table 2 Summary of therapeutic efficacy and safety of mesenchymal stem cells and their derivatives in Alzheimer’s disease

Animal model	Source	Type	Administration method	Main outcomes	Ref.
C57BL/6 mice with Aβ25-35	Mice	BM-MSCs	IV	Upregulate BDNF expression, downregulate GSK-3β activity, improve cognitive dysfunction	[116]
C57BL/6 mice with Aβ25-35	Mice	BM-MSCs	IV	Inhibit microglial activation, improve behavioral deficits, reduce neuroinflammatory cytokines	[115]
APP/PS1 mice	Human	hUC-MSCs, SHED, ADSCs	IV	Reduce amyloid plaques, improve behavioral deficits, and increase neuronal and Nissl body density in brain regions	[117]
APPswe/PS1dE9 mice	Human	OM-MSCs	SI	Alleviate AD symptoms and promote Aβ clearance	[118]
C57BL/6 mice with Aβ1-42	Human	BM-MSC-EVs	SI	Stimulate neurogenesis in the subventricular zone, alleviate cognitive impairment	[121]
C57BL/6 mice with STZ	Human	iPSC-MSC-sEVs	SI	Alleviate neuroinflammation, reduce amyloid deposition and neuronal apoptosis, and mitigate cognitive dysfunction	[120]
C57BL/6 mice with AlCl3	Mice	BM-MSC-EVs	IP	Regulate autophagy through the PI3K/AKT/mTOR pathway, promote Aβ degradation, modulate immunity, and improve memory and neurological dysfunction	[122]
C57BL/6 mice with AlCl3	Mice	ADSC	IV	Reduce amyloid deposition, mitigate cognitive dysfunction	[119]
Zebrafish with LPS	Human	ADSC-EVs	IV	Reduce LPS-induced inflammatory cytokines	[123]
C57BL/6 mice with Aβ1-42	Mice	BM-MSCs	IV	Induce mitophagy in neuronal cells, alleviating mitochondrial damage-mediated apoptosis and NLRP3 inflammasome activation	[125]
C57BL/6 mice with STZ	Mice	BM-MSC-Exos	SI	Modulate hippocampal glial cell activation, alleviate neuroinflammation, mitigate cognitive dysfunction	[127]
APP/PS1 mice	Human	hUC-MSCs	IV	Inhibit glial cell activation and oxidative stress	[128]
APP/PS1 mice	Mice	BM-MSCs	HIPP injection	Reduce number of Aβ plaques and increase M2 microglial polarization	[101]
C57BL/6 mice	Mice	BM-MSCs	SI	Stimulate endogenous neurogenesis	[130]
C57BL/6 mice with Aβ1-42	Human	OE-MSCs	IN	Upregulate BDNF and NMDAR; reduce neuronal loss	[132]
C57BL/6 mice with STZ	Human	hUC-MSC-Exos	IV	Increase adiponectin levels and protect neurons	[133]
C57BL/6 mice with AlCl3	Mice	ADSCs	IV	Reduce amyloid deposition, mitigate cognitive dysfunction	[119]
SH-SY5Y cell with Aβ1-40	Human	Exosomes derived from the serum of AD patients	Coculture	Reduce apoptosis through the PI3K/AKT signaling pathway	[134]
APP/PS1 mice	Human	hUC-MSCs	IV	Enhance targeting ability of hUC-MSCs and promote production of neuroprotective factors; improve cognitive function	[136]

Aβ: Amyloid-β; BM-MSCs: Bone marrow-derived mesenchymal stem cells; IV: Intravenous injection; BDNF: Brain-derived neurotrophic factor; GSK-3β: Glycogen synthase kinase-3 beta; APP: Amyloid precursor protein; hUC-MSCs: Human umbilical cord-derived mesenchymal stem cells; SHED: Stem cells from human exfoliated deciduous teeth; ADSCs: Adipose-derived mesenchymal stem cells; OM-MSCs: Olfactory mucosa mesenchymal stem cells; SI: Stereotaxic injection; AD: Alzheimer’s disease; BM-MSC-EVs: Bone marrow mesenchymal stem cell-derived extracellular vesicles; STZ: Streptozotocin; iPSC-MSC-sEVs: Induced pluripotent stem cells-derived mesenchymal stem cell-derived small extracellular vesicles; AlCl₃: Aluminum chloride; IP: Intraperitoneal injection; PI3K: Phosphatidylinositol 3-kinase; AKT: Proteinkinase B; mTOR: Mechanistic target of rapamycin; LPS: Lipopolysaccharide; ADSC-EVs: Adipose-derived mesenchymal stem cell-derived extracellular vesicles; BM-MSC-Exos: Bone marrow-derived mesenchymal stem cells-derived exosomes; NLRP3: NOD-like receptor family, pyrin domain containing 3; HIPP: Hippocampus; IN: Intranasal administration; OE-MSCs: Olfactory ecto-mesenchymal stem cells; NMDAR: N-methyl-D-aspartate receptor; hUC-MSC-Exos: Human umbilical cord-derived mesenchymal stem cell-derived exosomes.

Table 3 Summary of therapeutic efficacy and safety of mesenchymal stem cells and their derivatives in Parkinson’s disease

Animal model	Source	Type	Administration method	Main outcomes	Ref.
C57BL/6 mice with MPTP	Human	hUC-MSCs	IN	Inhibit activated glial cells, repair dopamine neuron degeneration, improve motor behavior in mice	[158]
C57BL/6 mice with 6-OHDA	Human	hUC-MSCs	IN	Upregulate SATB1, activate Wnt/β-catenin pathway, improve motor behavior, reduce neuronal damage	[159]
C57BL/6 mice with 6-OHDA	Human	hUC-MSCs	ST	Increase dopamine levels and improve motor dysfunction	[160]
C57BL/6 mice with 6-OHDA	Human	hUC-MSCs	ST	Improve rotational behavior, provide neuroprotection, exhibit anti-neuroinflammatory effects	[161]
C57BL/6 mice with 6-OHDA	Human	hUC-MSCs-BDNF	IV	Increase neuronal survival rate	[162]
C57BL/6 mice with 6-OHDA	Human	DPSCs	SI	Promote recovery of dopaminergic neurons, reduce dopaminergic neuron loss, improve motor behavior	[163]
C57BL/6 mice with 6-OHDA	Human	DPSCs	IV	Improve rotational and forelimb asymmetry behaviors, enhance anti-apoptotic Bcl-2/Bax axis	[164]
Zebrafish with 6-OHDA	Human	DPSCs	Yolk sac injection	Improve motor dysfunction	[166]
Zebrafish with rotenone	Mice	BM-MSCs	IV	Improve motor and behavioral performance	[167]
C57BL/6 mice with MPTP	Mice	BM-MSCs	IN	Restore dopaminergic neurons in the substantia nigra and nerve terminals in the striatum, improve motor deficits	[168]
C57BL/6 mice with 6-OHDA	Human	OE-MSCs	IN	Improve motor dysfunction	[169]
C57BL/6 mice with MnCl2	Human	hnmMSC-sEVs	IN	Restore motor dysfunction and enhance neurogenesis	[170]
C57BL/6 mice with MPTP	Human	hUC-MSC-Exos	IN	Increase number of dopaminergic neurons in the SNPC region, rescue death of substantia nigra dopaminergic neurons, alleviate inflammatory responses, and improve local microenvironment	[149]
C57BL/6 mice with 6-OHDA	Human	hUC-MSC-Exos	IV and LV	Repair damage to the nigrostriatal dopamine system, inhibit microglial activation	[150]
C57BL/6 mice with MPTP	Human	hUC-MSCs	IV	Alleviate dopaminergic neuron degeneration, exhibit anti-inflammatory effects	[151]
PD patients	Human	OM-MSCs	IT	Promote recovery of neural function, modulate neuroinflammation	[152]
C57BL/6 mice and cells with MPTP	Human	T-MSC-Exos	IV	Protect DA neurons through the Nox4-ROS-Nrf2 axis, maintain function of the nigrostriatal system, improve motor deficits, and reduce oxidative stress	[153]
C57BL/6 mice with MPTP	Human	BM-MSCs	IV	Reduce neuronal loss, damage, and inflammatory responses, inhibit cell apoptosis	[154]
C57BL/6 mice with MPTP	Human	ADSCs	SI	Secrete neuroprotective factors to prevent neuronal damage, reduce dopaminergic neuron loss and alleviate neuroinflammation; protect dopaminergic neurons	[155]
SH-SY5Y cells with rotenone	Human	NI-hADSC-CM	Coculture	Provide neuroprotection, alleviate αSN aggregation	[143]
Moderate PD patients	Human	BM-MSCs	IV	Safe, well tolerated, and not immunogenic	[142]
C57BL/6 mice with AAV 1/2A 53 T-a-syn	Human	BM-MSCs	SI	Reduce αSN levels; protect dopaminergic neurons, modulate microglial cells	[145]
C57BL/6 mice with rotenone	Mice	BM-MSCs	SI, IV	Improve motor function, protection of the nigrostriatal system, and improve striatal dopamine release	[146]

MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; hUC-MSCs: Human umbilical cord-derived mesenchymal stem cells; IN: Intranasal administration; 6-OHDA: 6-hydroxydopamine; SATB1: Special AT-rich sequence-binding protein-1; ST: Striatal transplantation; BDNF: Brain-derived neurotrophic factor; IV: Intravenous injection; DPSCs: Dental pulp-dirived mesenchymal stem cells; SI: Stereotaxic injection; Bcl-2: B-cell lymphoma 2; Bax: B-cell lymphoma 2-associated X protein; BM-MSCs: Bone marrow-derived mesenchymal stem cells; OE-MSCs: Olfactory ecto-mesenchymal stem cells; hnmMSC-sEVs: Human nasal mucosal mesenchymal stem cells derived small extracellular vesicles; SNPC: Substantia nigra pars compacta; hUC-MSCs-Exos: Human umbilical cord-derived mesenchymal stem cells derived exosomes; LV: Lateral ventricle injection; PD: Parkinson’s disease; OM-MSCs: Olfactory mucosa mesenchymal stem cells; T-MSC-Exos: Trophoblast stage-derived mesenchymal stem cell-derived exosomes; DA: DArgic; Nox4: NADPH oxidase 4; ROS: Reactive oxygen species; Nrf2: Nuclear factor erythroid 2-related factor 2; SH-SY5Y: Human neuroblastoma cell line SH-SY5Y; NI-hADSC-CM: Neural-induced human adipose tissue-derived stem cell-conditioned medium; αSN: α-synuclein.

Table 4 Summary of therapeutic efficacy and safety of mesenchymal stem cells and their derivatives in Huntington’s disease

Animal model	Source	Type	Administration method	Main outcomes	Ref.
R62 mice	Human	hUC-MSCs	IP	Regulate microglia; improve neurological dysfunction	[171]
R62 mice	Mice	BM-MSCs	IN	Improve neuroinflammation and dopaminergic signaling, increase survival rate	[172]
C57BL/6 mice with 3-NP	Human	hUC-MSCs	SI	Decrease gliosis, ameliorate motor coordination and muscle activity, along with an increase in striatal volume and dendritic length of the striatum	[173]
C57BL/6 mice with 3-NP	Mice	BM-MSCs	IV	Inhibit 3-NP-induced neurological insults via modulation of the Ca2+/CaN/NFATc4 and Wnt/β-catenin signaling pathways	[174]
C57BL/6 mice with 3-NP	Human	DPSCs	IV	Neuroprotection	[175]

R62 mice: HTT exon1-62Q knock-in mice; hUC-MSCs: Human umbilical cord-derived mesenchymal stem cells; IP: Intraperitoneal injection; BM-MSCs: Bone marrow-derived mesenchymal stem cells; IN: Intranasal administration; 3-NP: 3-nitropropionic acid; SI: Stereotaxic injection; IV: Intravenous injection; CaN: Calcineurin; NFATc4: Nuclear factor of activated t-cells c4; DPSCs: Dental pulp-derived mesenchymal stem cells.

Table 5 Summary of therapeutic efficacy and safety of mesenchymal stem cells and their derivatives in amyotrophic lateral sclerosis

Animal model	Source	Type	Administration method	Main outcomes	Ref.
In vitro SIM-A9 hSOD1 (G93A) microglial cells	Mice	ADSCs	Coculture	Reduce metabolic activity of microglia, decrease iNOS+ cells, and increase CD206+ cells	[176]
BV-2 cells with SOD 1-G93 A	Human	hUC-MSC-CM	IV	Extend lifespan and reduce expression of pro-inflammatory cytokines and iNOS	[178]
SOD 1G 93 A mice	Human	BM-MSCs	IV	Mediate anti-inflammatory responses through the CX3CL1/CX3CR1 axis	[179]
SOD 1G 93 A mice	Mice	BM-MSCs	IV	Upregulate expression of Nrf2 and NQO1, promote antioxidant responses, and reduce accumulation of reactive oxygen species	[180]
ALS patients	Human	BM-MSCs	IT	Feasible and safe	[181]
ALS patients	Human	BM-MSCs	IT, IV	Feasible and safe	[182]
ALS patients	Human	BM-MSCs	IT	Feasible and safe	[183]
hSOD 1 G93 A mice	Human	hUC-MSCs	IM	Extend lifespan; enhance motor function	[184]
ALS cell model expressing TDP-43 mutant M337V	Human	hUC-MSCs	Coculture	Activate the Nrf-2/HO-1 axis to exert antioxidant and neuroprotective effects	[185]
SOD 1G 93 A-NSC 34 cell model	Human	hUC-MSCs	Coculture	Inhibit the NF-κB/Bcl-2 signaling pathway; reduce cell apoptosis	[186]
ALS patients	Human	hUC-MSCs	IT	Feasible and safe	[187]
ALS patients	Human	ADSCs	LP	Feasible and safe	[188]
ALS patients	Human	hUC-MSCs	IN	Feasible and safe, lifespan extended by 2-fold	[189]
SOD 1G 93 A rat	Human	BM-MSCs	IT, IM	Increase survival of motor neurons	[190]
SOD 1G 93 A mice	Mice	BM-MSCs	IV	Reduce astrocyte activation and expression of neuroinflammatory factors	[180]
SOD 1G 93 A rat	Not mentioned	BM-MSCs	IV	Prolong survival period and protect the motor function	[191]
SOD 1G 93 A mice	Human	ADSCs	IV	Delay disease progression, prolong survival rate, and enhance neuron survival	[192]
SOD 1G 93 A mice	Human	iPSC-sEVs	IN	Improve motor performance and survival time	[193]

SOD1: Superoxide dismutase 1; ADSCs: Adipose-derived mesenchymal stem cells; iNOS: Inducible nitric oxide synthase; CD206: Cluster of differentiation 206; SOD 1-G93 A: Superoxide dismutase 1 with glycine 93 to alanine mutation; hUC-MSC-CM: Human umbilical cord-derived mesenchymal stem cell-conditioned medium; IV: Intravenous injection; BM-MSCs: Bone marrow-derived mesenchymal stem cells; CX3CL1: C-X3-C motif chemokine ligand 1; CX3CR1: C-X3-C motif chemokine receptor 1; Nrf2: Nuclear factor erythroid 2-related factor; NQO1: NAD(P)H quinone dehydrogenase 1; ALS: Amyotrophic lateral sclerosis; IT: Intrathecal injection; hUC-MSCs: Human umbilical cord-derived mesenchymal stem cells; IM: Intramuscular injection; TDP-43: Transactive response DNA-binding protein 43; HO-1: Heme oxygenase-1; NF-κB: Nuclear factor-kappa B; Bcl-2: B-cell lymphoma 2; LP: Lumbar puncture; iPSC-sEVs: Induced pluripotent stem cell-derived small extracellular vesicles.

Table 6 Summary of therapeutic efficacy and safety of mesenchymal stem cells and their derivatives in Niemann-Pick disease type C

Animal model	Source	Type	Administration method	Main outcomes	Ref.
NP-C GsbsGFP mice	Mice	BM-MSCs	IV	Improve degenerative loss of Purkinje neurons	[194]
BALB/c npcnih (NPC) mice	Mice	BM-MSCs	Cerebellum injection	Promote neuronal networks with functional synaptic transmission	[195]
BALB/c npcnih (NPC) mice	Mice	BM-MSCs	Cerebellum injection	Upregulate fusion ability of Purkinje neurons and donor-derived BM-MSCs	[196]
BALB/c npcnih (NPC) mice	Mice	BM-MSCs	Cerebrum injection	Modulate endogenous NPC NSCs, stimulate NSC proliferation and neuronal differentiation	[199]
BALB/c npcnih (NPC) mice	Mice	BM-MSCs	Cerebellum injection	Inhibit activation of astrocytes and microglia, reduce inflammation	[197]
BALB/c npcnih (NPC) mice	Mice	BM-MSCs	Cerebellum injection	Release bioactive neurotrophic factors, modulate sphingolipid metabolism of endogenous NPC Purkinje neurons	[198]
BALB/c npcnih (NPC) mice	Mice	ADSCs	Cerebellum injection	Rescue Purkinje neurons, restore motor coordination, and alleviate inflammatory responses	[201]
BALB/c npcnih (NPC) mice	Human	hUC-MSCs	HIPP injection	Stimulate endogenous neurogenesis, diminish intracellular cholesterol accumulation, and safeguard motor functionality	[200]
BALB/c npcnih (NPC) mice	Human	hUC-MSCs	IN	Reduce cholesterol levels, decrease loss of Purkinje cells in the cerebellum, delay motor dysfunction	[202]
Npc1KO N2a cells	Human	MenSCs-CM	Coculture	Increase survival rate, significantly alleviate inflammatory responses and apoptosis	[203]

NPC: Nimman-Pick disease type C; BM-MSCs: Bone marrow-derived mesenchymal stem cells; IV: Intravenous injection; NSCs: Neural stem cells; ADSCs: Adipose-derived mesenchymal stem cells; hUC-MSCs: Human umbilical cord-derived mesenchymal stem cells; HIPP: Hippocampus; IN: Intranasal administration; Npc1^KO N2a cells: Npc1 gene knockout neuro-2a cells; MenSC-CM: Menstrual blood-derived endometrial stem cell conditioned medium.