Current Molecular Medicine - Volume 13, Issue 9, 2013

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 its clinical application. Meanwhile the requirement of skin biopsy for fibroblast will increase the risk of complication. In the past few years, the advances of iPSC technology in efficiency, cell resource, safety and cell culture have made it possible to use the derivatives of iPSCs to clinical PD treatment. This review will summarize these progresses of iPSC technique in this fast-moving community.

For degenerative retinal diseases, like the acquired form exemplified by age-related macular degeneration (AMD), there is currently no cure. This study was to explore a stem cell therapy and a stem cellbased gene therapy for sodium iodate (SI)-induced retinal degeneration in rats. Three cell types, i.e., rat mesenchymal stem cells (rMSCs) alone, erythropoietin (EPO) gene modified rMSCs (EPO-rMSCs) or doxycycline (DOX) inducible EPO expression rMSCs (Tet-on EPO-rMSCs), were transplanted into the subretinal spaces of SI-treated rats. The rMSCs were prepared for transplantation after 3 to 5 passages or modified with EPO gene. During the 8 weeks after the transplantation, the rats treated with rMSCs alone or with 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 subretinal space and adopted RPE morphology. EPO concentration in vitreous and retina of SI-treated rats which were transplanted with EPO-rMSCs or Tet-on EPO-rMSCs was markedly increased, in parallel with the improvement of retinal morphology and function. These findings suggest that rMSCs transplantation could be a new therapy for degenerative retinal diseases since it can protect and rescue RPE and retinal neurons, while EPO gene modification to rMSCs could be an even better option.

MicroRNAs (miRNAs) are a class of small non-encoding RNAs that regulate gene expression at the posttranscriptional level. MiRNAs may characterize not only specific stages of the development of the neural cell population in CNS, but also distinct types of neural cells. However, the common pathways of the neural enriched miRNAs involved in neurogenesis of specific cell lineages remain poorly understood. In this report, in order to get insights into the common role of the miRNAs shared by cerebellum and forebrain, we studied the regulatory mechanism of neural enriched-miRNA in neural progenitor cell (NPCs) differentiation. Here, we identified a new cerebellum-enriched rno-miR-592 in rat cerebellum. It showed that rno-miR-592 was a neuralenriched miRNA and may play an important role in rat embryonic neurogenesis or/and astrogliogenesis. We used both gain-of -function and loss-of -function approaches to demonstrate that rno-miR-592 could change the balance between neuron- and astrocyte- like differentiation and neuronal morphology. We observed that miR-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, suggesting that these two target genes may be involved in miR-592 regulative function in NPCs differentiation and neuronal maturation. Thus, we conclude that rno-miR-592 may affect the neural lineage differentiation via reducing astrogliogenesis or/and enhancing neurogenesis at least in part through regulating its target genes Lrrc4c and Nfasc in vitro. Together, we report here for the first time the important role of miR-592 in rat NPCs differentiation and neuronal maturation.

Recent population studies suggest that children who receive anesthesia and surgery could be at an increased risk for developing learning disabilities. The underlying reason for this clinical observation is largely unknown. Whether undergoing anesthesia contributes to learning disability development, or if the need for anesthesia and surgery is a marker for other unidentified factors that contribute to the development of learning disabilities, remains to be determined. Neurogenesis, regulated by the Wnt-catenin signaling pathway, has been shown to be involved in learning and memory, and sevoflurane is the most commonly used inhalation anesthetic in children. We therefore set out to determine the effects of sevoflurane on neurogenesis and the Wnt-catenin signaling pathway in mouse neural progenitor cells (NPCs) using immunofluorescence and Western blot analysis. Here we show for the first time that 4.1%, but not 2.0%, sevoflurane reduced mouse NPC proliferation, increased Glycogen synthase kinase-3β(GSK-3β) levels, and decreased levels of β-Catenin in mouse NPCs. The GSK-3β inhibitor Lithium attenuated the sevoflurane-induced reduction in mouse NPC proliferation. The data suggest that sevoflurane may reduce neurogenesis through the Wnt-catenin signaling pathway. These findings would promote further studies to investigate the effects of anesthesia on neurogenesis 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.

The potential of stem cells in regenerative medicine, developmental biology, and drug discovery has been well documented. For example, stem cells have the extraordinary ability of self-renewal, and also give rise to many specialized cells. It is clear that stem cell technology has revolutionized our understanding of modern biology and medicine and provided new insights into the mechanisms controlling basic cell biology and various diseases. Nicotinic acetylcholine receptors (nAChRs) are prototypical members of the ligand-gated ion channel super family of neurotransmitter receptors that play many critical roles in brain and body function. It has been demonstrated that in addition to mediation of classical excitatory neurotransmission at some loci and modulation of release of neurotransmitters in some cases, nAChRs also play important roles in influencing synaptic architecture and plasticity as well as neuronal survival/death. Recently, emerging lines of evidence have suggested that nAChRs express on stem cells, where they likely mediate crucial effects of cholinergic signaling on stem cell survival/apoptosis, proliferation, differentiation and maturation. In this review, we summarize current development in cholinergic modulations of stem cell survival/apoptosis, proliferation and differentiation in order to evaluate the impact of nAChRs in stem cell biology and pathology.

Strokes are devastating as there are no current therapies to prevent the long term neurological deficits that they cause. Soon after ischemic stroke, there is proliferation and differentiation of neural stem/progenitor cells as an important mechanism for neuronal restoration. However, endogenous neurogenesis by itself is insufficient for effective brain repair after stroke as most newborn neurons do not survive. One fascinating strategy for stroke treatment would thus be maintaining the survival and/or promoting the differentiation of endogenous neural stem/progenitor cells. Using transgenic (Tg) mice over-expressing the C. elegans fat-1 gene encoding an enzyme that converts endogenous omega-6 to omega-3 polyunsaturated fatty acids (n-3 PUFAs), we showed that fat-1 Tg mice with chronically elevated brain levels of n-3 PUFAs exhibited less brain damage and significantly improved long-term neurological performance compared to wild type littermates. Importantly, post-stroke neurogenesis occurred more robustly in fat-1 Tg mice after focal ischemia. This was manifested by enhanced neural stem cell proliferation/differentiation and increased migration of neuroblasts to the ischemic sites where neuroblasts matured into resident neurons. Moreover, these neurogenic effects were accompanied by significantly increased oligodendrogenesis. Our results suggest that n-3 PUFA supplementation is a potential neurogenic and oligodendrogenic treatment to naturally improve post-stroke brain repair and long-term functional recovery.

Brain inflammation is a primary pathological driving force of many neurodegenerative disorders. In the destructive process, pro-inflammatory cytokines (IL-1β and TNF-α), are robustly released, affecting normal neural progenitor cell (NPC) differentiation, and resulting in a vast number of astrocytes and a diminished neural population. A counteractive mechanism is still unknown. In this study, we have identified a link between brain 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 an inhibition of STAT3 expression by siRNA inhibited astrocytic differentiation and increased neuronal differentiation 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 partially restored neuronal differentiation. Elimination of STAT3 expression also countered IL-1β and TNF-α-induced inhibition 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 would inhibit astrogliogenesis and promote neurogenesis. Thus, STAT3 could be a potential target of drug therapy for neurodegenerative disorders.