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Aging and disease    2017, Vol. 8 Issue (6) : 792-811     DOI: 10.14336/AD.2017.0428
Review |
The Effect of Traditional Chinese Medicine on Neural Stem Cell Proliferation and Differentiation
Qin Wei1, Chen Shiya1, Yang Shasha1, Xu Qian2, Xu Chuanshan3,*, Cai Jing2,*
1Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China
2College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China
3School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong
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Neural stem cells (NSCs) are special types of cells with the potential for self-renewal and multi-directional differentiation. NSCs are regulated by multiple pathways and pathway related transcription factors during the process of proliferation and differentiation. Numerous studies have shown that the compound medicinal preparations, single herbs, and herb extracts in traditional Chinese medicine (TCM) have specific roles in regulating the proliferation and differentiation of NSCs. In this study, we investigate the markers of NSCs in various stages of differentiation, the related pathways regulating the proliferation and differentiation, and the corresponding transcription factors in the pathways. We also review the influence of TCM on NSC proliferation and differentiation, to facilitate the development of TCM in neural regeneration and neurodegenerative diseases.

Keywords Neural stem cells      proliferation      differentiation      traditional Chinese medicine     
Corresponding Authors: Xu Chuanshan,Cai Jing   
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These authors contributed equally to this paper.

Issue Date: 01 December 2017
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Qin Wei
Chen Shiya
Yang Shasha
Xu Qian
Xu Chuanshan
Cai Jing
Cite this article:   
Qin Wei,Chen Shiya,Yang Shasha, et al. The Effect of Traditional Chinese Medicine on Neural Stem Cell Proliferation and Differentiation[J]. Aging and disease, 2017, 8(6): 792-811.
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MarkerPropertyAffected cell typeFunctionRefs.
Hopxatypical homeodomain only proteinNSCsregulates hippocampal neurogenesis by modulating Notch signaling[33]
Hes3basic helix-loop- helix geneNSCspromote the proliferation of NSCs
maintain the undifferentiated state of NSCs
[34, 35]
TRIP6zyxin family proteinsNSCspromote the self-renewal and proliferation of NSCs[36]
CycEcyclinNSCsregulate neurogenesis in the adult hippocampus[37]
JAM-Csurface proteinNSCsmaintain the pluripotency of NSCs[38]
PtdGlclipidNSCsidentify, isolate, and differentiate NSCs[39]
CD9transmembrane proteinNSPCshave an impact on the cell adhesion, migration, proliferation and differentiation[40, 41]
CD15transmembrane proteinNSPCspromote the survival of NSCs;
promote the differentiation of NSCs into oligodendroglia
[40, 42]
CD81transmembrane proteinNSPCscontrol the cell migration[40, 43]
S100βacid calcium binding proteinNSPCsregulate the proliferation of NSCs[44]
CD133transmembrane proteinNPCspromote the expansion of NSCs in vitro and its degree of specialization[45, 46]
CD24transmembrane proteinNPCsplay an important role in self-renewal;
maintain NSCs
[45, 47, 48]
Pax2paired box geneNPCsregulate the migration and proliferation of nerve cells[49]
NG2transmembrane proteoglycanNPCsregulate the migration of the oligodendrocyte precursor cells[50, 51]
Nestinintermediate filaments protein cytoskeletal proteinNSCs and NSPCsbe a marker for proliferating or migrating cells;
participate in cytoskeleton formation; remodel cells along with other structural proteins;
Musashi1RNA- binding proteinNSCs and NSPCsdetermine the fate of stem cells;
maintain the undifferentiated state of NSCs or NSPCs;
Tub-IIcytoskeleton proteinNSCs and NSPCsreflect the structural changes in the development of the brain[62, 63]
SOX2high-mobility group proteinsNSCs and NSPCsplay a role in self-renewal and maintenance of NSCs;
prevent the apoptosis of NSCs.
[56, 64, 65]
SOX1high-mobility group proteinsNSCs and NSPCspromote the self-renewal of NSCs[66-68]
Sp8zinc finger proteinNSCs and NSPCsmaintain the undifferentiated state of NSCs[69, 70]
S100A6ilow-molecular-weight calcium-binding proteinsNSCs and NPCspromote the neurogenesis in the hippocampus;
play an important role in the differentiation and maturation of astrocytes
Prox1homeobox transcription factorneuroblastsplay an important role in regulating the proliferation and differentiation of NSCs;
maintain the intermediate progenitor cells
[72, 73]
Cyc D1cyclinneuroblastspromote the proliferation of NSCs;
inhibit their differentiation
[74, 75, 204]
DCXmicrotubule-associated proteinneuroblastsregulate the migration of neural cells[76, 77]
Table 1  Markers of stem cell proliferation and differentiation in different stages.
TFsProtein familyPathwayIn vivo or in vitroEffect on NSCsAffected cell typeLocation of expressionRefs.
Hes1bHLHNotchIn vivo and in vitroPlay a role in maintenance of NSCs;
Inhibit the differentiation of NSCs into neurons; Have an effect on the maintenance and self-renewal of NSPCs
NSCs and NSPCsSVZ, SGZ[81-87]
Hes5bHLHNotchIn vitropromote the proliferation of NSCsNSCs and NSPCsSVZ[88-90]
Mash1bHLHNotchIn vivo and in vitroPromote the differentiation of NPCsNSPCs and NPCsSVZ, SGZ[91-96]
NeuroDbHLHNotchIn vivo and in vitroDetermine the fate and differentiation of cells; Determine the survival of neuronsNSPCs and NPCsSGZ, SVZ, VZ[97-102]
zfp488ZFPNotchIn vivoPromote the differentiation of NSCs into the oligodendrocytesNSCs and NSPCsSVZ[103, 104]
Ngn1bHLHNotchIn vivoPromote neurogenesis;
Play a specific role in the maintenance of NSPCs; Promote the differentiation of NPCs in vivo
NSPCs and NPCsSVZ[105, 106]
Ngn2bHLHNotchIn vivo and in vitroPlay a regulatory role in neurogenesis;
Control the balance of the maintenance and differentiation of NSPCs
NSPCsVZ, SVZ[107, 108]
Fezf2ZFPNotchIn vivo and in vitroHas a role in the maintenance and differentiation of NSCsNSCs, NSPCs and NPCsSVZ, VZ[109, 110]
Hey1bHLHNotchIn vivoPlay a role in the maintenance of NSCsNPCsVZ, SVZ[111-113]
Gsx2HOMNotchIn vivoReduce the ability of NSCs to proliferate and self-renew;
Reduce the transformation of NSCs into neurons and glial cells
NSCs and NSPCsSVZ, VZ[114-116]
Pax6HOMWntIn vivo and in vitroControl the balance of the maintenance and differentiation of NSCs;
Play an important role in maintenance, self-renewal and multi-directional differentiation of NSCs
NSCs and NSPCsSVZ, OB, SGZ, VZ[121-126]
Emx2HOMWntIn vivo and in vitroControl the proliferation and migration of NPCNSCs and NPCsSVZ, VZ[127-129]
Dix2HOMWntIn vivo and in vitroPromote the neurogenesis and proliferationNPCsSVZ, OB[130, 131]
Pax3HOMWntIn vivo and in vitroRegulate the differentiation of NSCs;
Determine the fate of cells; Maintain the undifferentiated state of NSCs.
Oct4POUWntIn vivo and in vitroPlay an important role in the maintenance of the pluripotency of NSCs;
Promote the proliferation and self-renewal of NSCs
Prox1HOMWntIn vivo and in vitroPromote the proliferation of NSCs;
Play an important role in the maintenance of intermediate progenitor cells
NSPCsSGZ[141, 142]
Nkx2.2HOMShhIn vivoPromote the differentiation of oligodendrocytesNSPCs and NPCsSVZ, OB[152-156]
Gli-1ZFPShhIn vivo and in vitroPromote the proliferation of NPCsNPCsSVZ, SGZ[158-162]
Sox2HMGBMPIn vivo and in vitroPlay a role in self-renewal and maintenance of NSCs;
Prevent the apoptosis of NSCs
NPCs and NSCsSVZ, SGZ, VZ[167-172]
Olig2bHLHBMPIn vivo and in vitroInduce the differentiation of NSCs into oligodendrocytes;
Promote the maturation of the differentiated cells.
Table 2  The main transcription factors and associated signaling pathways in NSC proliferation and differentiation.
ClassificationTCMAffected cell typeEffect on NSCsMain mechanismsIn vivo or in vitroRefs.
Compound Chinese medicinal preparationsBuyangHuanwu DecoctionNSCs and NSPCsPromote the proliferation and differentiation of NSCs and NSPCsDecrease the content of Ca2+ in the cells, and increase the expression of NF and GFAP.In vivo and in vitro[177-179]
Jiawei Sini SanNPCsPromote the proliferation of NPCs and inhibit apoptosisThe expression of nestin, beta-tubulin-III, and fibrillary acidic protein glial were significantly increasedIn vitro[180]
Shengyu decoctionNSCs and NSPCsPromote the proliferation of NSCs/NSPCs and their differentiation into neuronsIncrease the expression of TN-C, GDNF, NCAM, and NGF, and inhibits the expression of Nogo-AIn vivo[181]
FuzhiSanNSPCsPromote the proliferation of NSPCs; Improve the survival rate of newborn cellsPromote the neurogenesis in hippocampusIn vivo[182]
XiehuoBushenDecocfionNSCsPromote the survival and differentiation of NSCsEnhance the expression of IL-4 mRNA, and down-regulate the expression of IFN-gama mRNAIn vivo and in vitro[27]
PMC-12NSPCsPromote the proliferation of NSPCs in the hippocampus;
Improve the survival rate of newborn nerve cells
Increased levels of BDNF, p-CREB and synaptophysinIn vivo[183]
Single herbSalvia miltiorrhiza BgeNSCsPromote the differentiation of induced multifunctional NSCs into neurons in vitro; Promote the survival, collection and differentiation of NSCs derived from multifunctional stem cellIncrease the expression of nestin and
In vivo and in vitro[22]
Sambucus williamsii HanceNSCsPromotethe differentiationof NSCs into neuronsUp-regulate the expression of Tuj1 and nestin genes, and down-regulate the expression of Oct4 and Sox2 genesIn vitro[184]
Scutellariacalensis Georgi, Phellodendronchinense Schneid, Ligusticumwallichii FranchNSCs and NPCsPromote the proliferation of NSCs and NPCsModulate HPA axis and increase the content of corticosteroneIn vivo and in vitro[23]
Table 3  Effects of single herb and compound Chinese medicinal preparations on NSC proliferation and differentiation.
Effective components of Chinese herbsOriginCategories of Chinese herbsAffected cell typeEffectsUnderlying mechanismsIn vivo or in vitro

Ginsenoside Rg1
Panax ginseng C. A. MeyTonifying Qi herbsNSCs and NSPCsPromote the differentiation of NSCs and NSPCsIncrease the expression of SOX-2 and decrease the expression of IL-1β, IL-6 and TNF-α; Enhance the role of anti-inflammatory and antioxidantIn vivo[186, 187]

Ginsenoside Rd
Panax ginseng C. A. MeyTonifying Qi herbsNSCsPromote the proliferation of NSCsRegulate the expression of neurotrophic factor 3 and activate the expression of iNOS and NMDA receptorsIn vivo and in vitro[188]
Oleanolic acidLigustrum lucidum AitTonifying Yin herbsNSCs and NPCsPromote the self-renewal and differentiation of NSCs; Promote the neurogenesis in hippocampusIncrease the expression of tubulin and the ratio of tubulin /DAPIIn vivo and in vitro[24]
Stilbene glucosideFallopia multiflora (Thunb.) HaraldTonifying blood herbsNSCsPromote the self-renewal and differentiation of NSCsIncrease the expression of tubulin and the ratio of tubulin /DAPIIn vitro[24]
ResveratrolFructus MoriTonifying Yin herbsNSCsPromote the survival and proliferation of NSCsUp-regulate the expression of Ptch-1, Smo, Gli-1 protein and RNAIn vitro[25, 158]
(+)-Cholesten-3-oneChinemys reevesii (Gray)Tonifying Yin herbsNSCsInduce NSCs into dopaminergic neuronsActivate BMP signal; Improve the expression of TH and BMPR-IBIn vitro[189]
PsoralenPsoralea corylifolia L.Tonifying kidney herbsNSCsIncrease the expression of GFAP protein in NSCs in vitroIncrease the expression of GFAP proteinIn vitro[190]
IcariinEpimediumgrandiflorum MorrTonifying kidney herbsNSCsPromote the self-renewal and differentiation of NSCsMediate the related kinase signal transduction pathwaysIn vitro[191]
Salvianolic acid BSalvia miltiorrhiza BgeHuoxuehuayu herbsNSCs and NSPCsMaintain the self-renewal of NSCs/NSPCs Promote the proliferation of NSCsRegulate PI3K/Akt signaling pathway; Improve the expression of tau mRNA; Down-regulate the expression of mRNA GFAPIn vivo and in vitro[192, 193]
TMPLigusticum wallichii FranchHuoxuehuayu herbsNSCsPromote the proliferation and differentiation of NSCsIncrease the phosphorylation of erk1/2; Reduce the phosphorylation of p38In vitro[194, 195]
PNSPanax Notoginseng (Burk.) F.H. ChenHuoxuehuayu herbsNSCsPromote the self-renewal, proliferation, and differentiation of NSCsImprove the expression of tuj-1, vimentin, and nestin mRNAIn vitro[196]
BilobalideGinkgo bilobaHuoxuehuayu herbsNSCsPromote the proliferation of NSCsIncrease the phosphorylation of CREB and the level of the neurotrophic factorIn vivo[197]
BerberineCoptis chinensis FranchQingrejiedu herbsNSCsInhibit cell cycle arrest
Promote the survival and differentiation of NSCs
Improve the activity of cell viability-dependent NMDAIn vivo and in vitro[198]
BaicaleinScutellaria baicalensis GeorgiQingrejiedu herbsNSCs and NPCsPromote the differentiation of NPCs into neurons;
Inhibit the apoptosis and promote the proliferation of NSCs
Increase the expression of presynaptic protein, synapsin I, and PSD95In vivo[199, 200]
BaicalinScutellaria baicalensis GeorgiQingrejiedu herbsNSCs and NSPCsDetermine the fate of NSCs; Promote the differentiation of NSCs and NSPCsReduce the expression of p-STAT3 and Hes1; Increase the expression of NeuroD1 and Mash1; Regulate the expressionof p-stat3 and bHLH protein familyIn vivo and in vitro[201, 202]
PaeoniflorinPaeonia lactiflora Pall, Paeonia suffruticosaQingrejiedu herbsNSCs and NSPCsPromote the proliferation of nerve cells and inhibit the apoptosis of cellsActivate the PI3k/Akt-1 signaling pathwayIn vitro[203]
Table 4  Effects of active components of Chinese herbs on NSC proliferation and differentiation.
Figure 1.  Structures of Chinese herbal monomers
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