TABLE 1.

Therapies of LSDs and some neurodegenerative diseases using MSCs.

Disease	Study subject	MSCs dosage, route of administration and duration of therapy	Therapy results	References
Krabbe disease	Twitcher mouse model	1 × 105 cells in 2 µl	Anatomical integration, with no tumor formation. Xenografts remained viable in both normal and twitcher mouse brain, exhibiting differentiation into astrocytes, neurons and oligodendrocytes	Croitoru-Lamoury et al. (2006)
		Intracerebral injection
		35 days
		20,000 cells in 1 μl per hemisphere	Moderate improvements in life expectancy and motor function. Decrease in markers of inflammation, macrophage infiltration, and microglial activation. Decelerated deterioration in the twitcher brain	Ripoll et al. (2011)
		Intraventricular injections
		40 days
MLD	Patients with MLD	2–10 × 106 cells/kg	Well tolerance and no toxicity of MSCs infusion. Clear evidence of improvement of nerve conduction velocity in 4/6 patients	Koç et al. (1999)
		Intravenous injection
		24 months
	Patient with MLD	5 × 106 CD34 + cells/kg followed by the infusion of 1 × 106 cells/kg of MSCs	Stabilization of all previous neurological manifestations with no further deterioration. Aryl-Sulfatase-A levels increased to normal values 16 months after transplantation	Meuleman et al. (2008)
		40 months
NP	BALB/c npcnih (NP-C) mice	0.5 × 106 cells in 3 µl	The transplanted cells infused with Purkinje neurons resulting in preventing their loss	Bae et al. (2005b)
		Intracerebral injection
		4 weeks
		1 × 105 cells in 3 μl	Reduction of sphingosine accumulations in mutant Purkinje neurons. Transplanted cells also promoted survival of neurons and decreased neuronal apoptosis	Lee et al. (2010b)
		Intracerebral injection
		1 week
		Dose unidentified	Decreased inflammatory response as a result of suppression of astro/microglial activation by transplanted MSCs	Bae et al. (2005b)
		Intracerebral transplantation
		4 weeks
		1 × 106 cells in 3 μl	Promoted survival of Purkinje neuron, inhibition of cholesterol accumulation or cerebellar apoptotic cell death	Lee et al. (2010b)
		Intracerebral injection
		1 week
MPS VII or Sly syndrome	MPS VII mice	1 × 104 cells in 2 μl	Catabolism of GAGs accumulated in the cornea	Coulson-Thomas, Caterson, and Kao (2013)
		Intrastromal injection
		Three different time frames for different groups of animals: 10, 6 and 2 weeks, respectively
Fabry disease	Fabry ko mice	5 × 106 cells	Reduction in lipid accumulation, delivering the deficient enzyme to different organs	Campbell et al. (2002)
		Bilateral injection into thigh muscles
		4 weeks
PD	Wistar rats	30 × 103 in 3 μl	Improvement in motor functions, increasing in cells expressing tyrosine hydroxylase, which catalyzes the formation of L-dopa	Mostafavi et al. (2019)
		Intracerebral injection
		8 weeks
	Sprague-Dawley rats	23,000 cells in 8 μl and 1,80,000 cells in 8 μl in two groups of rats	Increase of neuroblast migration in the lesioned striatum, with multiple signs of MSCs potentials in promoting reparative mechanisms	Cova et al. (2010)
		Intracerebral transplantation
		4 weeks
AD	C57BL/6 mice	1 × 106 cells in 2 μl	Significant reduction in Aβ levels following transplantation	Lee Jong Kil et al. (2009)
		Intracerebral injection
		1 month
	C57BL/6J mice	∼1×106 cells in 500 µl	Improving spatial learning ability and memory function in the mice	Jiao et al. (2016)
		Intravenous injection
		3 weeks
	APP/PS1 double transgenic AD model mice	1 × 105 cells in 3 μl	Modulation of microglial activation, alleviating the disease symptoms and cognitive regression	Ma et al. (2013)
		Intracerebral injection
		25 days
ALS	Patients with ALS	In phase 1 and 2 of the trial: Intramuscular (IM) injections at 24 separate sites (1 × 106 cells/site) or intrathecal (IT) administration of 1 × 106/kg cells	Indications of possible clinical improvement following transplantation, as 87% of the patients were found to be responders according to different clinical parameters like ALS Functional Rating Scale–Revised or forced vital capacity	Petrou et al. (2016)
		In phase 2a
		Both IT and IM administration in 3 dosing cohorts
		(Low dose: 1 × 106cells/kg IT and 24 × 106 cells IM; mid-dose
		1.5 × 106 cells/kg IT and 36 × 106 cells IM; and high dose: 2 × 106 cells/kg IT and 48 × 106 cells IM)
		3 months
MS	Patients with MS	Single IV infusion of 1–2 × 106/Kg body weight BMSCs (6 months follow up)	Well-tolerated cell infusion, no treatment-related serious adverse events, or evidence of disease activation were found after 6 months	Cohen et al. (2018)
		140 × 106 UCBSCs intravenously over seven visits (20 × 106 UCBSCs/day) separated by 1–4 days	UCBSCs transplantation was safe and feasible. No serious adverse events were recorded in patients. Improvement of symptoms was found 1 month after transplantation, and in some cases also after 1 year. Recorded improvements included expanded disability status scale (EDSS) scores, bladder, bowel, and sexual dysfunctions, improvement in walk times, general perspective of a positive health change and improved quality of life. 15 out of 18 patients showed inactive lesions in the brain and the cervical spinal cord after 1 year, and one patient showed close-to a complete brain plaques resolution	Riordan et al. (2018)
		Four infusions	No severe adverse events were recorded during 10-year follow-up, and combined administration was found to be safe and feasible, but also needed to be confirmed by future clinical trials in a larger cohort	Lu et al. (2020)
		Day 0: 40 ml of UCBSCs (4 × 107 cells) infused intravenously
		Days 7, 14 and 21, respectively: 20 ml UCBSCs (2 × 107 cells) intravenously injected combined with 1 ml (2 × 107cells) intrathecally injected
HD	Transgenic HD mice of the R6/2 line	5 × 105 cells in 2 µl	Significantly slowed striatal degeneration and behavioral impairment	Lee Soon-Tae et al. (2009)
		Intracerebral injection
		12.5 weeks
	C57/B6 and R6/2-J2 mice	3 × 106 cells	Significant decrease of motor impairment. An increase in survival rate, as the transplanted MSCs were found to induce neural proliferation in the lesioned regions of the brain, and also the migration of microglia and neuroblasts to those regions	Lin et al. (2011)
		Unilateral intrastriatal injection
		16 weeks