Berry Juliandi

Treatment of a Mouse Model of Spinal Cord Injury by Transplantation of Human Induced Pluripotent Stem Cell-Derived Long-Term Self-Renewing Neuroepithelial-Like Stem Cells†‡§

Because of their ability to self‐renew, to differentiate into multiple lineages, and to migrate toward a damaged site, neural stem cells (NSCs), which can be derived from various sources such as fetal tissues and embryonic stem cells, are currently considered to be promising components of cell replacement strategies aimed at treating injuries of the central nervous system, including the spinal cord. Despite their efficiency in promoting functional recovery, these NSCs are not homogeneous and possess variable characteristics depending on their derivation protocols. The advent of induced pluripotent stem (iPS) cells has provided new prospects for regenerative medicine. We used a recently developed robust and stable protocol for the generation of long‐term, self‐renewing, neuroepithelial‐like stem cells from human iPS cells (hiPS‐lt‐NES cells), which can provide a homogeneous and well‐defined population of NSCs for standardized analysis. Here, we show that transplanted hiPS‐lt‐NES cells differentiate into neural lineages in the mouse model of spinal cord injury (SCI) and promote functional recovery of hind limb motor function. Furthermore, using two different neuronal tracers and ablation of the transplanted cells, we revealed that transplanted hiPS‐lt‐NES cell‐derived neurons, together with the surviving endogenous neurons, contributed to restored motor function. Both types of neurons reconstructed the corticospinal tract by forming synaptic connections and integrating neuronal circuits. Our findings indicate that hiPS‐lt‐NES transplantation represents a promising avenue for effective cell‐based treatment of SCI. STEM CELLS2012;30:1163–1173

Epigenetic regulation in neural stem cell differentiation

The central nervous system (CNS) is composed of three major cell types – neurons, astrocytes, and oligodendrocytes – which differentiate from common multipotent neural stem cells (NSCs). This differentiation process is regulated spatiotemporally during the course of mammalian development. It is becoming apparent that epigenetic regulation is an important cell‐intrinsic program, which can interact with transcription factors and environmental cues to modulate the differentiation of NSCs. This knowledge is important given the potential of NSCs to produce specific CNS cell types that will be beneficial for clinical applications. Here we review recent findings that address molecular mechanisms of epigenetic and transcription factor‐mediated regulation that specify NSC fate during CNS development, with a particular focus on the developing mammalian forebrain.

Chromatin remodeling in neural stem cell differentiation.

Chromatin remodeling is a dynamic alteration of chromatin structure that regulates several important biological processes. It is brought about by enzymatic activities that catalyze covalent modifications of histone tail or movement of nucleosomes along the DNA, and these activities often require multisubunit protein complexes for its proper functions. In concert with DNA methylation and noncoding RNA-mediated processes, histone modification such as acetylation and methylation regulates gene expression epigenetically, without affecting DNA sequence. Recent advances have revealed that this intrinsic regulation, together with protein complexes such as RE1 silencer of transcription/neuron-restrictive silencer factor (REST/NRSF) and switch/sucrose nonfermentable (SWI/SNF), play critical roles in neural stem cell fate determination.

Epigenetic regulation of neural stem cell fate during corticogenesis

The cerebral cortex comprises over three quarters of the brain, and serves as structural basis for the sophisticated perceptual and cognitive functions. It develops from common multipotent neural stem cells (NSCs) that line the neural tube. Development of the NSCs encompasses sequential phases of progenitor expansion, neurogenesis, and gliogenesis along with the progression of developmental stages. Interestingly, NSCs steadfastly march through all of these phases and give rise to specific neural cell types in a temporally defined and highly predictable manner. Herein, we delineate the intrinsic and extrinsic factors that dictate the progression and tempo of NSC differentiation during cerebral cortex development, and how epigenetic modifications contribute to the dynamic properties of NSCs.

TLR9 signalling in microglia attenuates seizure-induced aberrant neurogenesis in the adult hippocampus

Pathological conditions such as epilepsy cause misregulation of adult neural stem/progenitor populations in the adult hippocampus in mice, and the resulting abnormal neurogenesis leads to impairment in learning and memory. However, how animals cope with abnormal neurogenesis remains unknown. Here we show that microglia in the mouse hippocampus attenuate convulsive seizure-mediated aberrant neurogenesis through the activation of Toll-like receptor 9 (TLR9), an innate immune sensor known to recognize microbial DNA and trigger inflammatory responses. We found that microglia sense self-DNA from degenerating neurons following seizure, and secrete tumour necrosis factor-α, resulting in attenuation of aberrant neurogenesis. Furthermore, TLR9 deficiency exacerbated seizure-induced cognitive decline and recurrent seizure severity. Our findings thus suggest the existence of bidirectional communication between the innate immune and nervous systems for the maintenance of adult brain integrity.

Induction of superficial cortical layer neurons from mouse embryonic stem cells by valproic acid

Within the developing mammalian cortex, neural progenitors first generate deep-layer neurons and subsequently more superficial-layer neurons, in an inside-out manner. It has been reported recently that mouse embryonic stem cells (mESCs) can, to some extent, recapitulate cortical development in vitro, with the sequential appearance of neurogenesis markers resembling that in the developing cortex. However, mESCs can only recapitulate early corticogenesis; superficial-layer neurons, which are normally produced in later developmental periods in vivo, are under-represented. This failure of mESCs to reproduce later corticogenesis in vitro implies the existence of crucial factor(s) that are absent or uninduced in existing culture systems. Here we show that mESCs can give rise to superficial-layer neurons efficiently when treated with valproic acid (VPA), a histone deacetylase inhibitor. VPA treatment increased the production of Cux1-positive superficial-layer neurons, and decreased that of Ctip2-positive deep-layer neurons. These results shed new light on the mechanisms of later corticogenesis.

Reduced Adult Hippocampal Neurogenesis and Cognitive Impairments following Prenatal Treatment of the Antiepileptic Drug Valproic Acid

Summary Prenatal exposure to valproic acid (VPA), an established antiepileptic drug, has been reported to impair postnatal cognitive function in children born to VPA-treated epileptic mothers. However, how these defects arise and how they can be overcome remain unknown. Using mice, we found that comparable postnatal cognitive functional impairment is very likely correlated to the untimely enhancement of embryonic neurogenesis, which led to depletion of the neural precursor cell pool and consequently a decreased level of adult neurogenesis in the hippocampus. Moreover, hippocampal neurons in the offspring of VPA-treated mice showed abnormal morphology and activity. Surprisingly, these impairments could be ameliorated by voluntary running. Our study suggests that although prenatal exposure to antiepileptic drugs such as VPA may have detrimental effects that persist until adulthood, these effects may be offset by a simple physical activity such as running.

Prenatal exposure to suberoylanilide hydroxamic acid perturbs corticogenesis

Suberoylanilide hydroxamic acid (SAHA) is one of the epidrugs developed for cancer treatment that works epigenetically by inhibiting histone deacetylases (HDACs). SAHA has been reported to diffuse across the placenta and found in fetal plasma in preclinical study, implying that it can influence fetus if taken by pregnant cancer patients. However, report regarding this aspect and the study of in utero HDAC inhibition by SAHA especially on fate specification of neural stem/progenitor cells within the developing mammalian cortex, is yet unavailable. Here we show that transient exposure of SAHA to mouse embryos during prominent neurogenic period resulted in an enhancement of cortical neurogenesis, which is accompanied by an increased expression of proneuronal transcription factor Neurog1. Neurogenesis was enhanced due to the increase number of proliferating Tbr2+ intermediate progenitor cells following SAHA exposure. In this relation, we observed that SAHA perturbed neonatal cortical lamination because of the increased production of Cux1+ and Satb2+ upper-layer neurons, and decreased that of Ctip2+ deep-layer neurons. Furthermore, an upper-layer neuronal lineage determinant Satb2 was also up-regulated, whereas those of deep-layer ones Fezf2 and Ctip2 were down-regulated by SAHA treatment. Taken together, our study suggests that proper regulation of HDACs is important for precise embryonic corticogenesis.

Biodiversity and Distribution of Horseshoe Crabs in Northern Coast of Java and Southern Coast of Madura

Horseshoe crab is an important component of macro-benthos communities in the fine sand or mud substrate in coastal waters, both in the tropical and temperate region. This primitive animal consists of four species in the world, and three species can be found di Asian region, including Indonesia, namely Tachypleus tridentatus, T. gigas, and Carcinoscorpius rotundicauda. Scientific information about species distribution of three Asian horseshoe crab in Indonesia is limited, also about morphometric characters. This study aims to determine the morphometric characters and species distribution of three Asian horseshoe crab in north coast of Java and south coast of Madura Island. This study was conducted on July-August 2016. The total number of three Asian horseshoe crab obtained in this study was 260 individuals, distributed along north coast of Java and south coast of Madura Island, respectively 176 individuals of C. rotundicauda, 35 individuals of T. tridentatus, and 49 individuals of T. gigas. Tachypleus gigas has the largest size and widest class interval among three Asian horseshoe crab species. Morphometric characters is differences among three Asian horseshoe crab species. Carapace width and telson length were not significantly different among sampling locations only in T. tridentatus.

The ischial callosities of Sulawesi macaques

Sulawesi island has a high level of endemism, including the seven species of monkey from the genus Macaca (macaques). These monkeys have a pair of sitting pads, termed ischial callosities that have diverse shapes and previously were described verbally only. Although useful, these verbal descriptions cannot fully describe shape variation and are somewhat subjective, and cannot directly be used to analyze relationships among species. Here, we report a quantitative analysis of shape of Sulawesi macaque ischial callosities using geometric morphometric tools to optimally describe shape variation and objectively reconstruct general pattern of callosity shapes. By quantification of shape variation, we compare the relationships of each Sulawesi macaque species with each other and with the two geographically neighboring macaque species, M. nemestrina and M. fascicularis, by consensus coordinates of the callosity outlines. The Sulawesi macaques have a wider degree of variation compared with M. fascicularis and M. nemestrina; variation exists in the dorsal part and in the bending of the callosity. There are three general types of callosity shape in Sulawesi macaques: oval without bending (M. tonkeana and M. maurus), oval with outward bending (M. ochreata and M. brunnescens), and oval or reniform with inward bending (M. hecki, M. nigrescens, and M. nigra). These types are congruent with their geographical distribution. The pathway of shape change may have started from oval without bending in the center and the southern peninsula, to outward bending in the southeastern species, and to oval or reniform with inward bending in the northern species. Am. J. Primatol. 71:1021–1031, 2009.