Table 1.

Native MSC therapy in preclinical models of common neurodegenerative diseases

Condition	Model	Cell source	Administration route	Result	References
AD	APP/PS1 mice	BM	Intraventricular	Restoring cognitive deficits by upregulation of miR-146a and downregulation of NF-κB	[105]
AD	SAMP8 mice	UC	intraperitoneal	Restoring cognitive deficits mediated by HGF in the AD hippocampus following stimulation of cMet/AKT/GSK3β axis	[61]
AD	3xTg mice	UC	Intravenous	Improving the MSCs engraftment and neural recovery by combination therapy with resveratrol	[101]
AD	Rat	ESC	Intraarterial	Suppressing Aβ-induced cell death in the hippocampus in association with provoking the autophagolysosomal clearance of Aβ	[189]
AD	Rat	BM	Intravenous	Attenuation of memory and cognition impairment by melatonin-pretreated MSCs	[103]
AD	Rat	AT	Intravenous	Improving the learning, memory, and cognition by melatonin-pretreated MSCs	[102]
AD	3xTg mice	BM	Intraventricular	Inspiring a population of proliferating cells in the SVZ	[190]
AD	3xTg mice	BM	Intravenous	Alleviating the Tau phosphorylation and inflammation with no effect on Aβ-42 levels	[191]
AD	Amyloid β mice	UCB	Intracerebral	Restoring the learning, memory, and cognition	[192]
AD	5xFAD mice	BM	Intraventricular	Attenuation of learning impairment	[193]
AD	Amyloid β mice	BM	Intracerebral	Reduction in Aβ aggregates and supporting synaptic transmission	[194]
AD	APP/PS1 mice	UC	Intrathecal	Improving the endogenous adult hippocampal neurogenesis as a result of GDF-15 secretion	[62]
AD	5XFAD mice	WJ	Intrahippocampal	Promoting the proteasome activity and reducing the accumulation of ubiquitin-conjugated proteins mediated by MSC-secreted agouti-related peptide (AgRP)	[195]
PD	MPTP mice	BM	Intracranial	Marked synergistic impacts between electric stimulation and MSCs due to the enhanced levels of dopamine and reduced pro-inflammatory cytokines, restoring behavioral function	[196]
PD	MPTP mice	AT	Intravenous	Inducing alteration in dopamine transporter expression, promoting BDNF and GDNF levels in the striatum	[63]
PD	6-OHDA rat	BM	Intracarotid	No effect on motor impairment	[116]
PD	6-OHDA rat	BM	NA	Synergistic effect between G-CSF and MSCs by downregulation of pro-inflammatory cytokines, stimulating antioxidant enzymes and finally augmenting	[123]
PD	MPTP monkey	Endometrial	Intrastriatal	Enhancing the frequency of TH positive cells and also dopamine metabolite concentrations	[45]
PD	MPTP mice	Endometrial	Intracranial	Improvement of dopamine production	[108]
PD	6-OHDA rat	WJ	Intravenous	Restoring dopaminergic neurons and enhancement of the levels of BDNF and NGF	[64]
PD	Rat	BM	Intravenous	Restoring rotational behavior and enhancing TH-positive cell	[65]
PD	Rotenone rat	HED	Intravenous	PD recovery by modifying the cholinergic synapses, calcium signaling pathways, and axon guidance	[197]
PD	6-OHDA rat	BM	Intrastriatal	Improving the viability of striatal/nigral dopaminergic terminals concomitant with inducing neurogenesis in SVZ	[198]
PD	MG-132 rat	BM	Intravenous	Neuroprotective effects on dopaminergic neurons	[199]
PD	6-OHDA rat	BM	Intranigral	Differentiation into nestin-, neuron-specific enolase-, and GFAP-positive cells	[46]
PD	6-OHDA rat	BM	Intrastriatal	Partial rescue of dopaminergic pathway	[200]
PD	MPTP mice	BM	Intravenous	Neuroprotective effects on dopaminergic neurons, reducing blood–brain barrier damage and downregulation of neuroinflammation	[201]
PD	Rotenone rat	BM	Intranasal	Improved locomotor functions	[202]
ALS	SOD1G93A mice	BM	Intravenous	Enhancing motor neuron frequency, and reducing denervation and myofibril atrophy	[203]
ALS	SOD1G93A mice	BM	Intravenous	Augmenting pathological scores	[136]
ALS	SOD1G93A mice	AT	Intravenous	Marked and durable impacts on motor function by improving bFGF and VEGF levels	[135]
ALS	SOD1G93A mice	NA	Intraventricular Intraspinal	Intraspinal administration of MSCs has superiority over intraventricular injection in terms of restoring functional activity	[137]
ALS	SOD1G93A mice	BM	Intraspinal Intravenous	Prolonged lifespan of treated mice	[133]
ALS	SOD1G93A rat	BM	Intracerebospinal	Prolonged lifespan induced by chimerization of the astroglial population in the lumbar spinal cord following stem cell transplantation	[139]
ALS	SOD1G93A mice	Muscle	Intraventricular	Sustained motor function	[134]
ALS	SOD1G93A mice	BM	Intraspinal	Sustained motor function and dampened neuroinflammation	[204]
ALS	SOD1G93A rat	BM	Intrathecal	Neuroprotective effects on motor neurons and neuromuscular junctions by downregulation of apoptosis, necroptosis, and autophagy pathway	[138]
ALS	SOD1G93A mice	UCB	Intramuscular	Downregulation of inflammation by targeting iNOS/NO signaling pathway	[58]
ALS	SOD1G93A mice	UC	Intraventricular	Downregulation of pro-inflammatory cytokine levels, upregulation of anti-inflammatory cytokine levels, and promotion of IGF-1 levels in the lumbar spinal cord	[59]
ALS	SOD1G93A mice	Amniotic	Intravenous	Prolonged survival, restored motor functions, and suppressed neuroinflammation	[205]
HD	Transgenic mice	BM	Intrastriatal	Improving BDNF levels in the striatum	[127]
HD	Transgenic rat	BM	Intrastriatal	Co-transplanting MSCs with NSCs led to more favorable behavioral sparing	[206]
HD	Transgenic mice	BM	Intranasal	Improved therapeutic benefits by MSCs preconditioning with mood stabilizers lithium and valproic acid	[131]
HD	Transgenic mice	UC	Intravenous	Reducing astrogliosis, and neuroinflammation by downregulation of NF-κB p65 phosphorylation	[207]
HD	3-NP rat	UC	intrastriatal	Improving motor function, enhancing striatal volume, and dendritic length in striatum mediated through the production of VEGF and GDNF by MSCs	[66]
HD	QA rat	BM	Intrastriatal	Reduced striatum atrophy	[208]
HD	3-NP rat	BM	Intrastriatal	Improvement in BDNF, collagen type I, and fibronectin levels in brain	[128]
HD	Transgenic mice	UC	Intrastriatal	Partial improvement of spatial memory	[209]
HD	QA rat	BM	Intravenous	Amelioration of motor and cognitive impairment	[210]

MSC, Mesenchymal stromal cells; AD, Alzheimer’s disease; PD, Parkinson’s disease; ALS, amyotrophic lateral sclerosis; HD, Huntington’s disease; BM, bone marrow; UC, umbilical cord; UCB, umbilical cord blood; AT, adipose tissue; ESC, embryonic stem cell; WJ, Wharton’s jelly; 6-OHDA, 6-hydroxydopamine; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 3-NP, 3-nitropropionic acid; QA, quinolinic acid; NF-kB, nuclear factor kappa B; HGF, hepatocyte growth factor; GSK-3β, glycogen synthase kinase-3β; Aβ, amyloid beta peptide; SVZ, subventricular zone; GDF-15, growth/differentiation factor-15; GDNF, glial cell line-derived neurotrophic factor; BDNF, brain-derived neurotrophic factor; TH, thymidine hydroxylase; G-CSF, granulocyte colony-stimulating factor; NGF, nerve growth factor; VEGF, vascular endothelial growth factor; bFGF, basic fibroblast growth factor; iNOS, inducible nitric oxide synthase; IGF-1, insulin like growth factor-1; GFAP, glial fibrillary acidic protein; NSCs, neural stem cells; miRs, microRNAs