Current Molecular Medicine (v.13, #9)

Editorial: Exciting Progresses in Stem Cell and Neural Stem Cell Research by Jialin C. Zheng,, Zenghan Tong (1409-1411).

Road to Future: iPSC Clinical Application in Parkinsonµs Disease Treatment by L. Xu, Y. -Y. Tan, L. Wu, L -L. Wang, H. Li, J.-Q. Ding, S.-D. Chen (1412-1418).
Cell-replacement therapy using Parkinson's disease (PD) specific induced pluripotent stem cell(iPSC) holds great promise in treating PD. However, the problem of iPSC safety and efficiency restrict itsclinical application. Meanwhile the requirement of skin biopsy for fibroblast will increase the risk ofcomplication. In the past few years, the advances of iPSC technology in efficiency, cell resource, safety andcell culture have made it possible to use the derivatives of iPSCs to clinical PD treatment. This review willsummarize these progresses of iPSC technique in this fast-moving community.

Subretinal Transplantation of Rat MSCs and Erythropoietin Gene Modified Rat MSCs for Protecting and Rescuing Degenerative Retina in Rats by Y. Guan, L. Cui, Z. Qu, L. Lu, F. Wang, Y. Wu, J. Zhang, F. Gao, H. Tian, L. Xu, G. Xu, W. Li, Y. Jin, G. -T. Xu (1419-1431).
For degenerative retinal diseases, like the acquired form exemplified by age-related maculardegeneration (AMD), there is currently no cure. This study was to explore a stem cell therapy and a stem cellbasedgene therapy for sodium iodate (SI)-induced retinal degeneration in rats. Three cell types, i.e., ratmesenchymal stem cells (rMSCs) alone, erythropoietin (EPO) gene modified rMSCs (EPO-rMSCs) ordoxycycline (DOX) inducible EPO expression rMSCs (Tet-on EPO-rMSCs), were transplanted into thesubretinal spaces of SI-treated rats. The rMSCs were prepared for transplantation after 3 to 5 passages ormodified with EPO gene. During the 8 weeks after the transplantation, the rats treated with rMSCs alone orwith two types of EPO-rMSCs were all monitored with fundus examination, fundus fluorescein angiography(FFA) and electroretinogram. The transplantation efficiency of donor cells was examined for their survival,integration and differentiation. Following the transplantation, labeled donor cells were observed in subretinalspace and adopted RPE morphology. EPO concentration in vitreous and retina of SI-treated rats which weretransplanted with EPO-rMSCs or Tet-on EPO-rMSCs was markedly increased, in parallel with the improvementof retinal morphology and function. These findings suggest that rMSCs transplantation could be a new therapyfor degenerative retinal diseases since it can protect and rescue RPE and retinal neurons, while EPO genemodification to rMSCs could be an even better option.

Novel Cerebellum-Enriched miR-592 May Play a Role in Neural Progenitor Cell Differentiation and Neuronal Maturation Through Regulating Lrrc4c and Nfasc in Rat by J. Zhang, J. Zhang, Y. Zhou, Y. -J. Wu, L. Ma, R. -J. Wang, S. -Q. Huang, R. -R. Gao, L. -H. Liu, Z. -H. Shao, H. -J. Shi, L. -M. Cheng, L. Yu (1432-1445).
MicroRNAs (miRNAs) are a class of small non-encoding RNAs that regulate gene expression at theposttranscriptional level. MiRNAs may characterize not only specific stages of the development of the neuralcell population in CNS, but also distinct types of neural cells. However, the common pathways of the neuralenriched miRNAs involved in neurogenesis of specific cell lineages remain poorly understood. In this report, inorder to get insights into the common role of the miRNAs shared by cerebellum and forebrain, we studied theregulatory mechanism of neural enriched-miRNA in neural progenitor cell (NPCs) differentiation. Here, weidentified a new cerebellum-enriched rno-miR-592 in rat cerebellum. It showed that rno-miR-592 was a neuralenrichedmiRNA and may play an important role in rat embryonic neurogenesis or/and astrogliogenesis. Weused both gain-of -function and loss-of -function approaches to demonstrate that rno-miR-592 could changethe balance between neuron- and astrocyte- like differentiation and neuronal morphology. We observed thatmiR-592 could induce astrogliogenesis differentiation arrest or/and enhance neurogenesis in vitro. Meanwhile,silencing of miR-592 was not beneficial for neuronal maturation. We also identified Lrrc4c and Nfasc as miR-592 target genes, and miR-592 could affect the changes of Lrrc4c and Nfasc expression levels, suggestingthat these two target genes may be involved in miR-592 regulative function in NPCs differentiation andneuronal maturation. Thus, we conclude that rno-miR-592 may affect the neural lineage differentiation viareducing astrogliogenesis or/and enhancing neurogenesis at least in part through regulating its target genesLrrc4c and Nfasc in vitro. Together, we report here for the first time the important role of miR-592 in rat NPCsdifferentiation and neuronal maturation.

Sevoflurane Inhibits Neurogenesis and the Wnt-Catenin Signaling Pathway in Mouse Neural Progenitor Cells by Y. Zhang, Y. Dong, H. Zheng, V. Shie, H. Wang, J. J. Busscher, Y. Yue, Z. Xu, Z. Xie (1446-1454).
Recent population studies suggest that children who receive anesthesia and surgery could be at anincreased risk for developing learning disabilities. The underlying reason for this clinical observation is largelyunknown. Whether undergoing anesthesia contributes to learning disability development, or if the need foranesthesia and surgery is a marker for other unidentified factors that contribute to the development of learningdisabilities, remains to be determined. Neurogenesis, regulated by the Wnt-catenin signaling pathway, hasbeen shown to be involved in learning and memory, and sevoflurane is the most commonly used inhalationanesthetic in children. We therefore set out to determine the effects of sevoflurane on neurogenesis and theWnt-catenin signaling pathway in mouse neural progenitor cells (NPCs) using immunofluorescence andWestern blot analysis. Here we show for the first time that 4.1%, but not 2.0%, sevoflurane reduced mouseNPC proliferation, increased Glycogen synthase kinase-3β(GSK-3β) levels, and decreased levels of β-Cateninin mouse NPCs. The GSK-3β inhibitor Lithium attenuated the sevoflurane-induced reduction in mouse NPCproliferation. The data suggest that sevoflurane may reduce neurogenesis through the Wnt-catenin signalingpathway. These findings would promote further studies to investigate the effects of anesthesia onneurogenesis and function of learning and memory, as well as the underlying mechanisms in vitro and in vivo.Ultimately these efforts would lead to safer anesthesia care and better postoperative outcomes in children.

Roles of Nicotinic Acetylcholine Receptors in Stem Cell Survival/Apoptosis, Proliferation and Differentiation by J. -X. Shen, D. Qin, H. Wang, C. Wu, F. -D. Shi, J. Wu (1455-1464).
The potential of stem cells in regenerative medicine, developmental biology, and drug discovery hasbeen well documented. For example, stem cells have the extraordinary ability of self-renewal, and also giverise to many specialized cells. It is clear that stem cell technology has revolutionized our understanding ofmodern biology and medicine and provided new insights into the mechanisms controlling basic cell biology andvarious diseases. Nicotinic acetylcholine receptors (nAChRs) are prototypical members of the ligand-gated ionchannel super family of neurotransmitter receptors that play many critical roles in brain and body function. Ithas been demonstrated that in addition to mediation of classical excitatory neurotransmission at some loci andmodulation of release of neurotransmitters in some cases, nAChRs also play important roles in influencingsynaptic architecture and plasticity as well as neuronal survival/death. Recently, emerging lines of evidencehave suggested that nAChRs express on stem cells, where they likely mediate crucial effects of cholinergicsignaling on stem cell survival/apoptosis, proliferation, differentiation and maturation. In this review, wesummarize current development in cholinergic modulations of stem cell survival/apoptosis, proliferation anddifferentiation in order to evaluate the impact of nAChRs in stem cell biology and pathology.

Transgenic Overproduction of Omega-3 Polyunsaturated Fatty Acids Provides Neuroprotection and Enhances Endogenous Neurogenesis After Stroke by X. Hu, F. Zhang, R. K. Leak, W. Zhang, M. Iwai, R. A. Stetler, Y. Dai, A. Zhao, Y. Gao, J. Chen (1465-1473).
Strokes are devastating as there are no current therapies to prevent the long term neurologicaldeficits that they cause. Soon after ischemic stroke, there is proliferation and differentiation of neuralstem/progenitor cells as an important mechanism for neuronal restoration. However, endogenousneurogenesis by itself is insufficient for effective brain repair after stroke as most newborn neurons do notsurvive. One fascinating strategy for stroke treatment would thus be maintaining the survival and/or promotingthe differentiation of endogenous neural stem/progenitor cells. Using transgenic (Tg) mice over-expressing theC. elegans fat-1 gene encoding an enzyme that converts endogenous omega-6 to omega-3 polyunsaturatedfatty acids (n-3 PUFAs), we showed that fat-1 Tg mice with chronically elevated brain levels of n-3 PUFAsexhibited less brain damage and significantly improved long-term neurological performance compared to wildtype littermates. Importantly, post-stroke neurogenesis occurred more robustly in fat-1 Tg mice after focalischemia. This was manifested by enhanced neural stem cell proliferation/differentiation and increasedmigration of neuroblasts to the ischemic sites where neuroblasts matured into resident neurons. Moreover,these neurogenic effects were accompanied by significantly increased oligodendrogenesis. Our resultssuggest that n-3 PUFA supplementation is a potential neurogenic and oligodendrogenic treatment to naturallyimprove post-stroke brain repair and long-term functional recovery.

A Novel Role of the STAT3 Pathway in Brain Inflammation-induced Human Neural Progenitor Cell Differentiation by E. Chen, D. Xu, X. Lan, B. Jia, L. Sun, J. C. Zheng, H. Peng (1474-1484).
Brain inflammation is a primary pathological driving force of many neurodegenerative disorders. Inthe destructive process, pro-inflammatory cytokines (IL-1β and TNF-α), are robustly released, affecting normalneural progenitor cell (NPC) differentiation, and resulting in a vast number of astrocytes and a diminishedneural population. A counteractive mechanism is still unknown. In this study, we have identified a link betweenbrain inflammation and the signal transducer and activator of transcription 3 (STAT3) pathway: IL-1β and TNF-α induce STAT3 activation in NPCs. Then to investigate STAT3's effects on NPC fate, we observed that aninhibition of STAT3 expression by siRNA inhibited astrocytic differentiation and increased neuronaldifferentiation of human NPCs in fetal bovine serum (FBS)-induced astrocyte differentiation condition.Furthermore, STAT3-targeting siRNA abrogated IL-1β and TNF-α-induced astrocyte differentiation and partiallyrestored neuronal differentiation. Elimination of STAT3 expression also countered IL-1β and TNF-α-inducedinhibition of proneural bHLH genes, mammalian achaete-schute homologue-1 (Mash1), Neurogenin1 (Ngn1),and Neurogenin2 (Ngn2). These data suggest that a suppression of STAT3 during brain inflammation wouldinhibit astrogliogenesis and promote neurogenesis. Thus, STAT3 could be a potential target of drug therapy forneurodegenerative disorders.