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. Disclosure of potential conflicts of interest is found at the end of this article.

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-a, 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.

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.

SummaryPrenatal 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.

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.

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Male homosexual preference (MHP) is an evolutionary enigma because it is partially heritable and imposes a fertility cost. In occidental societies, homosexual men are feminized at various levels and they have more older brothers than heterosexual men. To evaluate whether femininity and the fraternal birth order (FBO) effect are universal features of MHP or not, we collected original data from homosexual men, heterosexual men, and heterosexual women from Java (Indonesia). Facial photographs were used to test whether homosexual faces are feminized when compared with heterosexual ones. We found that faces manipulated to resemble the average face of homosexual men are perceived as facially feminized, suggesting that homosexual men are facially feminized compared to heterosexual men, although a higher facial femininity was not captured by morphological analyses. Then, family data were used to detect differences in siblings’ composition between homosexuals and heterosexuals. Homosexual men displayed a higher number of older brothers than heterosexual men, even when sibship size was controlled for, suggesting that the FBO effect exists in Indonesian populations. Independent of sexual orientation, men with older brothers seem more feminized than those without older brothers, consistent with the immune origin of the FBO effect. In conclusion, MHP in Indonesia is partially feminized and they have more older brothers. Such features are also associated with MHP in other cultural contexts, suggesting a cross-cultural effect of men homosexual preference. An evolutionary explanation is available for the feminizing effect, although the FBO effect remains unexplained even if proximal mechanisms start to be identified.