Advances in treatment of neurodegenerative diseases: Perspectives for combination of stem cells with neurotrophic factors

Table 4 Combination therapy of stem cells with neurotrophic factors in amyotrophic lateral sclerosis

Cell types	Neurotrophic factors	Study design and outcome	Ref.
hNPCs	GDNF	hNPCs-GDNF were transplanted into the lumbar spinal cord of SOD1G93A ALS rats. Genetically-modified hNPCs were able to survive, integrate, and release GDNF in the spinal cord of SOD1G93A rats.	Klein et al[92], 2005
hNPCs	GDNF	hNPCs-GDNF were unilaterally transplanted into the spinal cord of SOD1G93A ALS rats. There was robust cellular migration into degenerated areas, efficient delivery of GDNF and remarkable preservation of motor neurons at early and end stages of the disease.	Suzuki et al[93], 2007
hNPCs	GDNF	hNPCs-GDNF were unilaterally transplanted into the motor cortex of SOD1G93A ALS rats. The hNPCs-GDNF matured into astrocytes, and released GDNF, which protected motor neurons, delayed disease pathology, and extended survival of theSOD1G93A rats.	Thomsen et al[94], 2018
hMSCs	GDNF	hMSCs-GDNF were transplanted bilaterally into three muscle groups of a fALS rat model. Transplanted cells survived within the muscle, released GDNF, and increased the number of neuromuscular connections. Direct muscle delivery of hMSCs-GDNF ameliorated motor neuron loss within the spinal cord, delayed disease progression, and increased overall lifespan by 28 d.	Suzuki et al[95], 2008
hNSCs	VEGF	hNSCs overexpressing VEGF were IT transplanted into SOD1G93A mice. Intrathecal hNSCs-VEGF transplantation significantly delayed disease onset and prolonged survival of the SOD1G93A mice.	Hwang et al[96], 2009
NSCs	NGF	Intranasal NGF administration combined with lateral ventricle NSCs transplantation to the SOD1G93AALS mice delayed onset, improved motor function and prolonged lifespan.	Zhong et al[97], 2017
hMSCs	GDNF; VEGF; IGF-I; BDNF	To determine whether multiple NTFs played a synergistic role of slowing disease progression, SOD1G93A rats were bilaterally muscularly transplanted with hMSCs-GDNF, hMSCs-VEGF, hMSCs-IGF-I, or hMSCs-BDNF. hMSCs-GDNF and hMSCs-VEGF prolonged survival and slowed the loss of motor function, and the combined delivery of GDNF and VEGF showed a strong synergistic effect.	Krakora et al[98], 2013
MPCs	BDNF; GDNF; VEGF; IGF-1	Hind legs transplantation of MPCs-MIX, a mixture of MPCs expressing BDNF, GDNF, VEGF, or IGF-1,decreased neuromuscular junction degeneration, increased axonal survival, delayed onset and prolonged lifespan of the SOD1 G93A mice.	Dadon-Nachum et al[99], 2015
MSCs	GDNF; BDNF; VEGF; HGF	To determine the safety and possible clinical efficacy of autologous MSCs-NTF cells transplantation in ALS patients. All patients were followed for 3 mo before the transplantation and for 6 mo after the transplantation. In the phase 1/2 part of the trial, 6 patients with early-stage ALS were injected IM and 6 patients with more advanced disease were transplanted IT. In the second stage, a phase 2a dose-escalating study, 14 patients with early-stage ALS received a combined IM and IT transplantation of autologous MSCs-NTF. Treatment of ALS patients with autologous MSCs-NTF cells by IT, IM, or combined (IT+IM) administration was safe and well tolerated. The rate of progression of forced vital capacity and ALS Functional Rating Scale-Revised score in the IT (or IT+IM)-treated patients were reduced.	Petrou et al[100], 2016 (clinical trials)

ALS: Amyotrophic lateral sclerosis; BDNF: Brain-derived neurotrophic factor; fALS: Familial amyotrophic lateral sclerosis: GDNF: Glial cell line-derived neurotrophic factor; HGF: Hepatocyte growth factor; hMSCs: Human mesenchymal stem cells; hNPCs: Human neural progenitor cells; hNPCs-GDNF: Lentivirus-modified hNPCs secreting GDNF; hNSCs: Human neural stem cells; IGF-1: Insulin-like growth factor-1; IM: Intramuscularly; IT: Intrathecally; MPCs: Muscle progenitor cells; MSCs-NTF: Neurotrophic factor secreting mesenchymal stem cells; NGF: Nerve growth factor; NSCs: Neural stem cells; NTF: Neurotrophic factor; VEGF: Vascular endothelial growth factor.