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

Table 1 Combination therapy of stem cells with neurotrophic factors in Alzheimer’s disease

Cell types	Neurotrophic factors	Study design and outcome	Ref.
NSCs	NGF	Embryonic 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
BMSCs	NGF	When 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
NSCs	BDNF	The 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
NSCs	BDNF	Transected 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
MSCs	BDNF	BDNF 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
MSCs	BDNF	A 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
NSCs	BDNF	Hippocampus 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-MSCs	BDNF	Right 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

Aβ: Beta-amyloid; AchE: Acetylcholine esterase; AD: Alzheimer’s disease; BDNF: Brain-derived neurotrophic factor; BM-MSCs: Bone marrow-mesenchymal stromal cells; BMSCs: Bone marrow stromal cells; BMSCs-NGF: Nerve growth factor gene-modified bone marrow stromal cells; BrdU: 5'-Bromo-2'-deoxyuridine; hUC-MSCs: Human umbilical cord-mesenchymal stem cells; MSCs: Mesenchymal stem cells; MSCs-BDNF: Brain-derived neurotrophic factor-modified mesenchymal stem cells; NGF: Nerve growth factor; NGF-PEG-PLGA-NPs: Nerve growth factor-poly(ethylene glycol)-poly (lactic-co-glycolic acid)-nanoparticles; NSCs: Neural stem cells; NSCs-hBDNF: Human brain-derived neurotrophic factor-modified neural stem cells; TUNEL: TdT-mediated dUTP nick end labeling.