Copyright ©The Author(s) 2020.
World J Stem Cells. May 26, 2020; 12(5): 323-338
Published online May 26, 2020. doi: 10.4252/wjsc.v12.i5.323
Table 1 Combination therapy of stem cells with neurotrophic factors in Alzheimer’s disease
Cell typesNeurotrophic factorsStudy design and outcomeRef.
NSCsNGFEmbryonic rat NSCs were separated and induced by NGF-PEG-PLGA-NPs in vitro, and were transplanted into AD rats(lateral ventricular injected with 192IgG-saporin). The Morris water maze was used to evaluate learning and memory, followed by immunohistochemical staining for basal forebrain cholinergic neurons, hippocampal synaptophysin, and AchE fibers. The rats in the combined treatment group showed significant improvement in spatial learning as compared to the untreated AD model animals. The treated rats also showed significantly higher number of basal forebrain cholinergic neurons and fibers with AchE positivity, and higher expression of hippocampal the rats in the NSCs group.Chen et al[25], 2015
BMSCsNGFWhen compared with BMSCs transplantation alone, BMSCs-NGF transplantated into the hippocampus of AD rats (bilaterally injected with Aβ) significantly improved learning and memory. The findings suggested efficient NGF delivery by BMSCs.Li et al[44], 2008
NSCsBDNFThe AD rat model was established by cutting the unilateral fibria-fornix of male rats. Lateral cerebral ventricle transplantation of the NSCs and NSCs-hBDNF provided behavioral amelioration of AD rats assessed via the Morris water maze, and the effect of NSCs-hBDNF was better than that of NSCs.Zhao et al[45], 2005
NSCsBDNFTransected rat basal forebrain BrdU-labeled NSCs transplantation followed by lateral ventricle BDNF injection led to labeled NSCs differentiation into neurons and astrocytes in the basal forebrain. The rats in the NSCs and BDNF combination group showed better improvement in the number of cholinergic neurons, and learning and memory as compared to the other groups.Xuan et al[46], 2008
MSCsBDNFBDNF gene-modified BM-MSCs were transplanted into the lateral ventricle of an AD rat model. Nerve cell damage in the CA1 region of the hippocampus was significantly attenuated. BDNF tyrosine kinase B mRNA and protein levels were significantly increased, and learning and memory were significantly improved.Zhang et al[47], 2012
MSCsBDNFA unique neuronal culture of familial-type AD neurons was made from the 5x familial-type AD mouse, an amyloid precursor protein/PS1 transgenic mouse model, to investigate progressive neurodegeneration associated with AD pathology and the efficacy of MSCs-BDNF. Analyses of the expression of BDNF, synaptic markers and survival/apoptotic signals indicated that pathological features of cultured neurons could accurately mimic AD pathology. The protective effect of MSCs was enhanced by MSCs-BDNF. The BDNF supplied from MSCs-BDNF was sufficient to prevent AD pathology.Song et al[48], 2015
NSCsBDNFHippocampus transplanted NSCs-BDNF integrated into the local brain circuits of the 16-mo-old Tg2576 mice, improved the engrafted cells’ viability, neuronal fate, neurite complexity, the synaptic density, and the cognitive deficits of the AD mice.Wu et al[49], 2016
hUC-MSCsBDNFRight hippocampus transplantation of BDNF-modified hUC-MSCs-derived cholinergic-like neurons significantly improved spatial learning and memory in the AD rats assessed by Morris water maze testing, increased the release of acetylcholine, enhanced the activation of astrocytes and microglia, reduced the expression of Aβ and BACE1, and inhibited neuronal apoptosis detected by Western blotting, immunohistochemistry, immunofluorescence assay, and TUNEL assay.Hu et al[50], 2019
Table 2 Combination therapy of stem cells with neurotrophic factors in Parkinson’s disease
Cell typesNeurotrophic factorsStudy design and outcomeRef.
MSCsGDNFMSCs-GDNF transplantation induced a pronounced local trophic effect in the denervated striatum of the 6-OHDA PD rat model.Moloney et al[62], 2010
MSCsGDNFStriatum transplantation of GDNF-releasing Notch-induced BM-MSCs(SB623 cells) significantly decreased amphetamine-induced rotation and promoted DA fiber activation of the 6-OHDA PD rat model.Glavaski-Joksimovic et al[63], 2010
MSCsGDNFThe intrastriatal transplantation of BMSCs-GDNF significantly rescued the DA neurons from lactacystin-induced neurotoxicity, with regard to behavioral recovery and striatal dopamine level increase of the lactacystin-lesioned PD rat model, established by intrastriatum transplantation of BMSCs-GDNF followed by lactacystin induction of a lesion at the median forebrain bundles 1 wk later.Wu et al[64], 2010
MSCsGDNFMSCs-GDNF were transplanted into the unilateral striatum and SN of cynomolgus monkeys (PD monkey model) to investigate the protective function of MSCs-GDNF against MPTP-induced injury. Monkeys in the MSCs-GDNF group showed spared contralateral limbs’ motor function and had higher dopamine level and enhanced dopamine uptake in the striatum of the grafted hemisphere.Ren et al[65], 2013
MSCsGDNFThe lipopolysaccharide-lesioned PD rat model was used to assess the ability of MSCs-GDNF to protect against lipopolysaccharide-induced neuroinflammation, neurodegeneration, and behavioral impairment. Both experimental groups received a unilateral intrastriatal transplantation of either MSCs-GDNF or MSCs-green fluorescent protein. Protection and/or sprouting of the dopaminergic neuron terminals was induced by the secreted GDNF in the striatum of PD rats.Hoban et al[66], 2015
MSCsBDNFThe signals and/or molecules that regulate BDNF expression/delivery were investigated in hMSCs cultures and the effect of epigenetically generated BDNF-secreting hMSCs were evaluated for their impact on intact and lesioned SN. Results showed that the amphetamine-induced motor symptoms were stabilized.Somoza et al[67], 2010
MSCsBDNF; GDNFThe intrastriatum transplantation of NTF-SCs posterior to the 6-OHDA lesion led to an obvious amelioration of amphetamine-induced rotations, and the damaged striatal dopaminergic nerve terminal network was regenerated.Sadan et al[68], 2009
HUVMSCsNGFAs compared to HUVMSCs-derived dopaminergic-like cells alone, combination with NGF significantly promoted the cell survival, increased the dopaminergic content, and improved motor function of PD rats.Li et al[69], 2010
Table 3 Combination therapy of stem cells with neurotrophic factors in Huntington's disease
Cell typesNeurotrophic factorsStudy design and outcomeRef.
MSCsBDNF; NGFBM-MSCs were genetically engineered to overexpress BDNF and/or NGF, and were then injected into the striata of 4-mo-old YAC128 transgenic and wild-type mice to determine the effects on motor function. Transplantation of MSCs-BDNF may slowdown neurodegenerative processes and provide behavioral sparing in the YAC128 mouse model of HD.Dey et al[79], 2010
MSCsBDNFMSCs-BDNF were intrastriatially transplanted into YAC128 and R6/2 transgenic (immune-suppressed HD model) mice. MSCs-BDNF transplantation reduced anxiety, decreased striatal atrophy in the YAC128 mice and prolonged the mean lifespan and increased neurogenesis of the R6/2 mice.Pollock et al[80], 2016
ESCs-derived NPCsBDNFESCs-derived BDNF-overexpressing NPCs were transplanted into a quinolinic acid-lesioned model and two transgenic mouse lines (R6/2 and N171-82Q). NPCs-BDNF had a significant effect on motor function recovery in quinolinic acid-lesioned mice, while the genetic mouse model had only slight improvement. Adult neurogenesis was preserved in a BDNF-dependent manner.Zimmermann et al[81], 2016
Table 4 Combination therapy of stem cells with neurotrophic factors in amyotrophic lateral sclerosis
Cell typesNeurotrophic factorsStudy design and outcomeRef.
hNPCsGDNFhNPCs-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
hNPCsGDNFhNPCs-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
hNPCsGDNFhNPCs-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
hMSCsGDNFhMSCs-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
hNSCsVEGFhNSCs 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
NSCsNGFIntranasal 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
hMSCsGDNF; VEGF; IGF-I; BDNFTo 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
MPCsBDNF; GDNF; VEGF; IGF-1Hind 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
MSCsGDNF; BDNF; VEGF; HGFTo 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)