Multipotent Neural Progenitor Research Articles

Notch directs telencephalic development and controls neocortical neuron fate determination by regulating microRNA levels.

The central nervous system contains a myriad of different cell types produced from multipotent neural progenitors. Neural progenitors acquire distinct cell identities depending on their spatial position, but they are also influenced by temporal cues to give rise to different cell populations over time. For instance, the progenitors of the cerebral neocortex generate different populations of excitatory projection neurons following a well-known sequence. The Notch signaling pathway plays crucial roles during this process, but the molecular mechanisms by which Notch impacts progenitor fate decisions have not been fully resolved. Here, we show that Notch signaling is essential for neocortical and hippocampal morphogenesis, and for the development of the corpus callosum and choroid plexus. Our data also indicate that, in the neocortex, Notch controls projection neuron fate determination through the regulation of two microRNA clusters that include let-7, miR-99a/100 and miR-125b. Our findings collectively suggest that balanced Notch signaling is crucial for telencephalic development and that the interplay between Notch and miRNAs is essential for the control of neocortical progenitor behaviors and neuron cell fate decisions.

Integrated transcriptome and proteome analysis reveals posttranscriptional regulation of ribosomal genes in human brain organoids.

During development of the human cerebral cortex, multipotent neural progenitors generate excitatory neurons and glial cells. Investigations of the transcriptome and epigenome have revealed important gene regulatory networks underlying this crucial developmental event. However, the posttranscriptional control of gene expression and protein abundance during human corticogenesis remains poorly understood. We addressed this issue by using human telencephalic brain organoids grown using a dual reporter cell line to isolate neural progenitors and neurons and performed cell class and developmental stage-specific transcriptome and proteome analysis. Integrating the two datasets revealed modules of gene expression during human corticogenesis. Investigation of one such module uncovered mTOR-mediated regulation of translation of the 5'TOP element-enriched translation machinery in early progenitor cells. We show that in early progenitors partial inhibition of the translation of ribosomal genes prevents precocious translation of differentiation markers. Overall, our multiomics approach proposes novel posttranscriptional regulatory mechanisms crucial for the fidelity of cortical development.

Key transcription factors influence the epigenetic landscape to regulate retinal cell differentiation.

How the diverse neural cell types emerge from multipotent neural progenitor cells during central nervous system development remains poorly understood. Recent scRNA-seq studies have delineated the developmental trajectories of individual neural cell types in many neural systems including the neural retina. Further understanding of the formation of neural cell diversity requires knowledge about how the epigenetic landscape shifts along individual cell lineages and how key transcription factors regulate these changes. In this study, we dissect the changes in the epigenetic landscape during early retinal cell differentiation by scATAC-seq and identify globally the enhancers, enriched motifs, and potential interacting transcription factors underlying the cell state/type specific gene expression in individual lineages. Using CUT&Tag, we further identify the enhancers bound directly by four key transcription factors, Otx2, Atoh7, Pou4f2and Isl1, including those dependent on Atoh7, and uncover the sequential and combinatorial interactions of these factors with the epigenetic landscape to control gene expression along individual retinal cell lineages such as retinal ganglion cells (RGCs). Our results reveal a general paradigm in which transcription factors collaborate and compete to regulate the emergence of distinct retinal cell types such as RGCs from multipotent retinal progenitor cells (RPCs).

Cerebrovasculature pumps up progenitors

Fetal human brain stem cell niches that contain multipotent neural progenitors are progressively vascularized during development. Crouch etal. (Crouch etal., 2022) report endothelial and mural lineage trajectories that build developing prenatal vascular in second trimester fetal brain. This cerebral angiogenesis in neural progenitor zones occurs simultaneously with and can promote neurogenesis.

Diversification of multipotential postmitotic mouse retinal ganglion cell precursors into discrete types.

The genesis of broad neuronal classes from multipotential neural progenitor cells has been extensively studied, but less is known about the diversification of a single neuronal class into multiple types. We used single-cell RNA-seq to study how newly born (postmitotic) mouse retinal ganglion cell (RGC) precursors diversify into ~45 discrete types. Computational analysis provides evidence that RGC transcriptomic type identity is not specified at mitotic exit, but acquired by gradual, asynchronous restriction of postmitotic multipotential precursors. Some types are not identifiable until a week after they are generated. Immature RGCs may be specified to project ipsilaterally or contralaterally to the rest of the brain before their type identity emerges. Optimal transport inference identifies groups of RGC precursors with largely nonoverlapping fates, distinguished by selectively expressed transcription factors that could act as fate determinants. Our study provides a framework for investigating the molecular diversification of discrete types within a neuronal class.

Maternal embryonal leucine zipper kinase immunoreactivity in atypical teratoid/rhabdoid tumors: a study of 50 cases.

Atypical teratoid/rhabdoid tumors (AT/RTs) are aggressive embryonal neoplasms of the central nervous system that correspond to WHO grade IV and have a dismal prognosis. The latest Central Brain Tumor Registry of the United States data shows that AT/RT constitutes 16.6% of all embryonal tumors in children. The molecular hallmark of this tumor is pathogenic SMARCB1 genetic alterations resulting in the loss of INI-1 immunopositivity, with fewer tumors harboring SMARCA4 (BRG1) variants. Maternal embryonal leucine zipper kinase (MELK) is a member of the Snf1/AMPK family of serine/threonine-protein kinases involved in various processes such as cell cycle regulation, self-renewal of stem cells, apoptosis, and splicing regulation. Recent studies have highlighted the involvement of MELK in AT/RT and its possible therapeutic role.The purpose of this study was to review the histological and immunohistochemical profile of AT/RT with special reference to MELK staining.In this retrospective study conducted over 6years, all diagnosed cases of AT/RT, defined by loss of INI-1 immunopositivity, were retrieved and studied. Demographic details of patients and microscopic findings were analyzed, with special attention to histological patterns and immunohistochemistry profile including MELK immunoreactivity.There were 50 cases of AT/RT diagnosed in the specified period. Of the cases operated at our institute during this period, embryonal tumors constituted 20.6% of all pediatric brain tumors with AT/RT representing 12.6% of this subset. The median age at presentation was 3.5years (range: 8months-22years) and there were three adult cases. Males outnumbered females by a ratio of 1.94:1. Tumor location was distributed equally between the supratentorial and infratentorial compartments. Characteristic rhabdoid cells were identified in 70% of cases. Areas with epithelial, mesenchymal, and undifferentiated tumor cells were seen in 8%, 20%, and 52% of cases, respectively. Cells with vacuolated cytoplasm were noted in 28% of cases. Immunohistochemistry (IHC) showed a polyimmunophenotypic profile with immunopositivity for GFAP in 70%, Vimentin in 100%, SMA in 68%, and EMA in 88% of cases, indicating the remarkable heterogeneity of the tumor cells. MELK immunopositivity was noted in 83.33% of cases.Thus,atypical teratoid/rhabdoid tumors are rare neoplasms. In line with other studies, we show that these tumors occur predominantly in very young children and display marked variability on histology and IHC with loss of INI-1. MELK is presumed to be an important molecule involved in cell cycle regulation, proliferation, and other critical functions. High expression of MELK in AT/RT may suggest its plausible role in neoplastic transformation of embryonic and postnatal multipotent neural progenitors which in turn could explain the diverse morphological and immunohistochemical characteristics observed in these tumors.

Derivation of Multipotent Neural Progenitors from Human Embryonic Stem Cells for Cell Therapy and Biomedical Applications.

Long-term neuroepithelial-like stem cells (lt-NES) derived from human embryonic stem cells are a stable self-renewing progenitor population with high neurogenic potential and phenotypic plasticity. Lt-NES are amenable to regional patterning toward neurons and glia subtypes and thus represent a valuable source of cells for many biomedical applications. For use in regenerative medicine and cell therapy, lt-NES and their progeny require derivation with high-quality culture conditions suitable for clinical use. In this chapter, we describe a robust method to derive multipotent and expandable lt-NES based on good manufacturing practice and cell therapy-grade reagents. We further describe fully defined protocols to terminally differentiate lt-NES toward GABA-ergic, dopaminergic, and motor neurons.

MAP4K4 is Involved in the Neuronal Development of Retinal Photoreceptors

Differentiated from multipotent neural progenitors, the development of retinal photoreceptors is under sophisticated programming of multiple genes. Mitogen-activated protein kinase kinase kinase kinase-4 (MAP4K4) is one of the upstream regulators in the mitogen-activated protein kinase (MAPK) signaling pathway, associated to neurodegeneration. However the role of MAP4K4 in retina—an extension of neural system—remains unknown. In the present study, we generated knockout models of C57BL/6j mice in vivo and 661W cells in vitro to unfold the mechanism of MAP4K4 during neuronal development of retinal photoreceptors. We identified the linkage between the Map4k4 ablation induced murine homozygous lethality and neural tube malformation during the embryonic phase from EM9.5 to EM10.5, providing a collateral evidence for the involvement of MAP4K4 in early stage embryonic neural formation. To further clarify the participation of MAP4K4 in neurogenesis of photoreceptors, we subjected 661W cells of both Map4k4 +/+ and Map4k4 -/- to staurosporine. Later, spatiotemporal development and remodeling of photoreceptor cells were detected. Ablation of Map4k4 leaded to vulnerability of photoreceptor nerites during induced neuronal development. By monitoring transcriptional and protein variation of MAPK signaling pathway targeted factors, we discovered the imbalanced neurogenesis factors occurring in Map4k4 -/- cells. MAP4K4 promoted jun proto-oncogene (c-JUN) phosphorylation and recruited other factors related to nerve growth, convoying the photoreceptors to robust formation of neurites. Together, MAP4K4 showed decisiveness in the programming fate of retinal photoreceptors through molecular modulations, which may be providing a new insight into the blueprint of visual formation. Funding Statement: This study was supported by the National Natural Science Foundation of China (81670874 and 81670885), the Natural Science Foundation of Gurangdong Province of China (2020A1515010144), the Fundamental Research Funds and the Open Research Funds of the State Key Laboratory of Ophthalmology. Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: All animal experiments in this study were approved by and in compliance with the guides of the Animal Experimentation Ethics Committee of State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China (Approval Number: 2017-083). All animal experiments were performed in accordance with the Association for Research in Vision and Ophthalmology (ARVO) Statement for the Use and Care of Animals in Ophthalmic and Vision Research.

Implications of TORCH Diseases in Retinal Development-Special Focus on Congenital Toxoplasmosis.

There are certain critical periods during pregnancy when the fetus is at high risk for exposure to teratogens. Some microorganisms, including Toxoplasma gondii, are known to exhibit teratogenic effects, interfering with fetal development and causing irreversible disturbances. T. gondii is an obligate intracellular parasite and the etiological agent of Toxoplasmosis, a zoonosis that affects one third of the world's population. Although congenital infection can cause severe fetal damage, the injury extension depends on the gestational period of infection, among other factors, like parasite genotype and host immunity. This parasite invades the Central Nervous System (CNS), forming tissue cysts, and can interfere with neurodevelopment, leading to frequent neurological abnormalities associated with T. gondii infection. Therefore, T. gondii is included in the TORCH complex of infectious diseases that may lead to neurological malformations (Toxoplasmosis, Others, Rubella, Cytomegalovirus, and Herpes). The retina is part of CNS, as it is derived from the diencephalon. Except for astrocytes and microglia, retinal cells originate from multipotent neural progenitors. After cell cycle exit, cells migrate to specific layers, undergo morphological and neurochemical differentiation, form synapses and establish their circuits. The retina is organized in nuclear layers intercalated by plexus, responsible for translating and preprocessing light stimuli and for sending this information to the brain visual nuclei for image perception. Ocular toxoplasmosis (OT) is a very debilitating condition and may present high severity in areas in which virulent strains are found. However, little is known about the effect of congenital infection on the biology of retinal progenitors/ immature cells and how this infection may affect the development of this tissue. In this context, this study reviews the effects that congenital infections may cause to the developing retina and the cellular and molecular aspects of these diseases, with special focus on congenital OT.

Identity and lineage fate of proteolipid protein 1 gene (Plp1)-expressing cells in the embryonic murine spinal cord.

The proteolipid protein (PLP) is the most abundant protein in the myelin sheath of the central nervous system (CNS). The gene coding PLP, proteolipid protein 1 (Plp1) is highly expressed in oligodendrocytes, the myelin-forming cells in the CNS. Previous studies demonstrate that Plp1 gene is expressed in the embryonic CNS much earlier before the generation of oligodendrocytes. However, the progenitor identity and the fate of Plp1-expressing cells are still elusive. We employed genetic approaches to permanently label Plp1-expressing cells with the reporter enhanced yellow fluorescence protein (EYFP) and used multicolored immunohistochemistry to characterize their identity and lineage fate. We found that Plp1-expressing cells were initially present without spatial restrictions and later confined to the ventral progenitor domains of the embryonic spinal cord. Our fate-mapping results showed that Plp1-expressing cells during early embryogenesis were multipotent neural progenitor cells that gave rise to not only neurons but also glial progenitor cells whereas they were bipotent glial progenitor cells during later neural development stages and generated oligodendroglial and astroglial lineage cells but not neurons. Intriguingly, postnatal astrocytes generated from embryonic Plp1-expressing glial progenitor cells were present only in the ventral spinal cord. Our study reveals that Plp1-expressing cells during embryonic neural development display dynamic cellular identities and have a broader lineage fate than oligodendroglial lineage.

The Paf1 complex and P-TEFb have reciprocal and antagonist roles in maintaining multipotent neural crest progenitors.

Multipotent progenitor populations are necessary for generating diverse tissue types during embryogenesis. We show the RNA polymerase-associated factor 1 complex (Paf1C) is required to maintain multipotent progenitors of the neural crest (NC) lineage in zebrafish. Mutations affecting each Paf1C component result in near-identical NC phenotypes; alyron mutant embryos carrying a null mutation in paf1 were analyzed in detail. In the absence of zygotic paf1 function, definitive premigratory NC progenitors arise but fail to maintain expression of the sox10 specification gene. The mutant NC progenitors migrate aberrantly and fail to differentiate appropriately. Blood and germ cell progenitor development is affected similarly. Development of mutant NC could be rescued by additional loss of positive transcription elongation factor b (P-TEFb) activity, a key factor in promoting transcription elongation. Consistent with the interpretation that inhibiting/delaying expression of some genes is essential for maintaining progenitors, mutant embryos lacking the CDK9 kinase component of P-TEFb exhibit a surfeit of NC progenitors and their derivatives. We propose Paf1C and P-TEFb act antagonistically to regulate the timing of the expression of genes needed for NC development.

Born this way: Hippocampal neurogenesis across the lifespan.

The capability of the mammalian brain to generate new neurons through the lifespan has gained much attention for the promise of new therapeutic possibilities especially for the aging brain. One of the brain regions that maintains a neurogenesis‐permissive environment is the dentate gyrus of the hippocampus. Here, new neurons are generated from a pool of multipotent neural progenitor cells to become fully functional neurons that are integrated into the brain circuitry. A growing body of evidence points to the fact that neurogenesis in the adult hippocampus is necessary for certain memory processes, and in mood regulation, while alterations in hippocampal neurogenesis have been associated with a myriad of neurological and psychiatric disorders. More recently, evidence has come to light that new neurons may differ in their vulnerability to environmental and disease‐related influences depending on the time during the life course at which they are exposed. Thus, it has been the topic of intense research in recent years. In this review, we will discuss the complex process and associated functional relevance of hippocampal neurogenesis during the embryonic/postnatal period and in adulthood. We consider the implications of hippocampal neurogenesis during the developmentally critical periods of adolescence and older age. We will further consider the literature surrounding hippocampal neurogenesis and its functional role during these critical periods with a view to providing insight into the potential of harnessing neurogenesis for health and therapeutic benefit.

Progressive divisions of multipotent neural progenitors generate late-born chandelier cells in the neocortex

Diverse γ-aminobutyric acid (GABA)-ergic interneurons provide different modes of inhibition to support circuit operation in the neocortex. However, the cellular and molecular mechanisms underlying the systematic generation of assorted neocortical interneurons remain largely unclear. Here we show that NKX2.1-expressing radial glial progenitors (RGPs) in the mouse embryonic ventral telencephalon divide progressively to generate distinct groups of interneurons, which occupy the neocortex in a time-dependent, early inside-out and late outside-in, manner. Notably, the late-born chandelier cells, one of the morphologically and physiologically highly distinguishable GABAergic interneurons, arise reliably from continuously dividing RGPs that produce non-chandelier cells initially. Selective removal of Partition defective 3, an evolutionarily conserved cell polarity protein, impairs RGP asymmetric cell division, resulting in premature depletion of RGPs towards the late embryonic stages and a consequent loss of chandelier cells. These results suggest that consecutive asymmetric divisions of multipotent RGPs generate diverse neocortical interneurons in a progressive manner.

FGF8 and Shh promote the survival and maintenance of multipotent neural crest progenitors

The developmental mechanisms that control the building of the complex head of vertebrates and particularly, facial skeletogenesis, remain poorly known. Progenitor cells derived from the embryonic neural crest (NC) are the major constituents and players of facial tissue development. Deciphering the cellular and molecular machinery that controls NC cell (NCC) differentiation into bone, cartilage, fat and other mesenchymal tissues, is thus a main issue for understanding vertebrate facial variations. In this work, we investigated the effects of fibroblast growth factor 8 (FGF8) and Sonic Hedgehog (Shh), two signaling molecules essential for craniofacial development, on the in vitro differentiation and multipotentiality of mesencephalic NCCs (MNCCs) isolated from the quail embryo. Comparison of distinct temporal treatments with FGF8 and/or Shh showed that both promoted chondrogenesis of MNCCs by increasing the amount and size of cartilage nodules. Higher rates of chondrogenesis were observed when MNCCs were treated with FGF8 during the migration phase, thus mimicking the in vivo exposure of migrating NCCs to FGF8 secreted by the isthmic brain signaling center. An in vitro cell cloning assay revealed that, after concomitant treatment with FGF8 and Shh, about 80% of NC progenitors displayed chondrogenic potential, while in untreated cultures, only 18% exhibited this potential. In addition, colony analysis showed for the first time the existence of a highly multipotent progenitor able to clonally give rise to adipocytes in addition to other cephalic NC phenotypes (i.e. glial cells, neurons, melanocytes, smooth muscle cells and chondrocytes) (GNMFCA progenitor). This progenitor was observed only when clonal cultures were treated with both FGF8 and Shh. Several other types of multipotent cells, which generated four, five or six distinct phenotypes, accounted for 55% of the progenitors in FGF8 and Shh treated cultures, versus 13,5% in the untreated ones. Together, these data reveal an essential role for both FGF8 and Shh together in maintenance of MNCC multipotentiality by favoring the development of NC progenitors endowed with a broad array of mesectodermal potentials.

Epigenetic modifiers promote mitochondrial biogenesis and oxidative metabolism leading to enhanced differentiation of neuroprogenitor cells

During neural development, epigenetic modulation of chromatin acetylation is part of a dynamic, sequential and critical process to steer the fate of multipotent neural progenitors toward a specific lineage. Pan-HDAC inhibitors (HDCis) trigger neuronal differentiation by generating an “acetylation” signature and promoting the expression of neurogenic bHLH transcription factors. Our studies and others have revealed a link between neuronal differentiation and increase of mitochondrial mass. However, the neuronal regulation of mitochondrial biogenesis has remained largely unexplored. Here, we show that the HDACi, sodium butyrate (NaBt), promotes mitochondrial biogenesis via the NRF-1/Tfam axis in embryonic hippocampal progenitor cells and neuroprogenitor-like PC12-NeuroD6 cells, thereby enhancing their neuronal differentiation competency. Increased mitochondrial DNA replication by several pan-HDACis indicates a common mechanism by which they regulate mitochondrial biogenesis. NaBt also induces coordinates mitochondrial ultrastructural changes and enhanced OXPHOS metabolism, thereby increasing key mitochondrial bioenergetics parameters in neural progenitor cells. NaBt also endows the neuronal cells with increased mitochondrial spare capacity to confer resistance to oxidative stress associated with neuronal differentiation. We demonstrate that mitochondrial biogenesis is under HDAC-mediated epigenetic regulation, the timing of which is consistent with its integrative role during neuronal differentiation. Thus, our findings add a new facet to our mechanistic understanding of how pan-HDACis induce differentiation of neuronal progenitor cells. Our results reveal the concept that epigenetic modulation of the mitochondrial pool prior to neurotrophic signaling dictates the efficiency of initiation of neuronal differentiation during the transition from progenitor to differentiating neuronal cells. The histone acetyltransferase CREB-binding protein plays a key role in regulating the mitochondrial biomass. By ChIP-seq analysis, we show that NaBt confers an H3K27ac epigenetic signature in several interconnected nodes of nuclear genes vital for neuronal differentiation and mitochondrial reprogramming. Collectively, our study reports a novel developmental epigenetic layer that couples mitochondrial biogenesis to neuronal differentiation.

Regulation of neural stem cell proliferation and differentiation by Kinesin family member 2a

In the developing neocortex, cells in the ventricular/subventricular zone are largely multipotent neural stem cells and neural progenitor cells. These cells undergo self-renewal at the early stage of embryonic development to amplify the progenitor pool and subsequently differentiate into neurons. It is thus of considerable interest to investigate mechanisms controlling the switch from neural stem cells or neural progenitor cells to neurons. Here, we present evidence that Kif2a, a member of the Kinesin-13 family, plays a role in regulating the proliferation and differentiation of neural stem cells or neural progenitor cells at embryonic day 13.5. Silencing Kif2a by use of in utero electroporation of Kif2a shRNA reduced neural stem cells proliferation or self-renewal but increased neuronal differentiation. We further found that knockdown of Kif2a decreased the protein level of β-catenin, which is a critical molecule for neocortical neurogenesis. Together, these results reveal an important function of Kif2a in embryonic neocortical neurogenesis.

YY1 and CTCF orchestrate a 3D chromatin looping switch during early neural lineage commitment.

CTCF is an architectural protein with a critical role in connecting higher-order chromatin folding in pluripotent stem cells. Recent reports have suggested that CTCF binding is more dynamic during development than previously appreciated. Here, we set out to understand the extent to which shifts in genome-wide CTCF occupancy contribute to the 3D reconfiguration of fine-scale chromatin folding during early neural lineage commitment. Unexpectedly, we observe a sharp decrease in CTCF occupancy during the transition from naïve/primed pluripotency to multipotent primary neural progenitor cells (NPCs). Many pluripotency gene-enhancer interactions are anchored by CTCF, and its occupancy is lost in parallel with loop decommissioning during differentiation. Conversely, CTCF binding sites in NPCs are largely preexisting in pluripotent stem cells. Only a small number of CTCF sites arise de novo in NPCs. We identify another zinc finger protein, Yin Yang 1 (YY1), at the base of looping interactions between NPC-specific genes and enhancers. Putative NPC-specific enhancers exhibit strong YY1 signal when engaged in 3D contacts and negligible YY1 signal when not in loops. Moreover, siRNA knockdown of Yy1 specifically disrupts interactions between key NPC enhancers and their target genes. YY1-mediated interactions between NPC regulatory elements are often nested within constitutive loops anchored by CTCF. Together, our results support a model in which YY1 acts as an architectural protein to connect developmentally regulated looping interactions; the location of YY1-mediated interactions may be demarcated in development by a preexisting topological framework created by constitutive CTCF-mediated interactions.

Isolation, characterization, and differentiation of multipotent neural progenitor cells from human cerebrospinal fluid in fetal cystic myelomeningocele

Despite benefits of prenatal in utero repair of myelomeningocele, a severe type of spina bifida aperta, many of these patients will still suffer mild to severe impairment. One potential source of stem cells for new regenerative medicine-based therapeutic approaches for spinal cord injury repair is neural progenitor cells (NPCs) in cerebrospinal fluid (CSF). To this aim, we extracted CSF from the cyst surrounding the exposed neural placode during the surgical repair of myelomeningocele in 6 fetuses (20 to 26weeks of gestation). In primary cultured CSF-derived cells, neurogenic properties were confirmed by in vitro differentiation into various neural lineage cell types, and NPC markers expression (TBR2, CD15, SOX2) were detected by immunofluorescence and RT-PCR analysis. Differentiation into three neural lineages was corroborated by arbitrary differentiation (depletion of growths factors) or explicit differentiation as neuronal, astrocyte, or oligodendrocyte cell types using specific induction mediums. Differentiated cells showed the specific expression of neural differentiation markers (βIII-tubulin, GFAP, CNPase, oligo-O1). In myelomeningocele patients, CSF-derived cells could become a potential source of NPCs with neurogenic capacity. Our findings support the development of innovative stem-cell-based therapeutics by autologous transplantation of CSF-derived NPCs in damaged spinal cords, such as myelomeningocele, thus promoting neural tissue regeneration in fetuses.

Electric field stimulation induced neuronal differentiation of filum terminale derived neural progenitor cells

Adult filum terminale (FT) is an atypical region from where multipotent neural progenitor cells (NPCs) have been isolated. However, poor neuronal differentiation rate of FT-NPCs currently limits their clinical applications. Using custom-designed electric fields (EFs), this study sets up a method to significantly improve neuronal differentiation rate of rat FT-NPCs in vitro. We investigated the influence of EF strength on rat FT-NPCs differentiation. By adding reasonable strength of EF to FT-NPCs, our data shows a significant increase in neuronal differentiation rate. The present innovation provides a novel method of directional differentiation and efficient production of neurons from FT-NPCs in vitro. This improved approach for inducing neuronal differentiation can be applied to future research on autoplastic transplantation.

The Dynamic Epigenetic Landscape of the Retina During Development, Reprogramming, and Tumorigenesis

SUMMARYIn the developing retina, multipotent neural progenitors undergo unidirectional differentiation in a precise spatiotemporal order. Here we profile the epigenetic and transcriptional changes that occur during retinogenesis in mice and humans. Although some progenitor genes and cell cycle genes were epigenetically silenced during retinogenesis, the most dramatic change was derepression of cell type–specific differentiation programs. We identified developmental stage–specific super-enhancers and showed that most epigenetic changes are conserved in humans and mice. To determine how the epigenome changes during tumorigenesis and reprogramming, we performed integrated epigenetic analysis of murine and human retinoblastomas and induced pluripotent stem cells (iPSCs) derived from murine rod photoreceptors. The retinoblastoma epigenome mapped to the developmental stage when retinal progenitors switch from neurogenic to a terminal patterns of cell division. The epigenome of retinoblastomas was more similar to that of normal retina than was that of retina-derived iPSCs, and we identified retina-specific epigenetic memory.