Adult Neurogenesis and the Vascular Nietzsche

AbstractAdult neurogenesis is mediated by immature neural precursors that divide within the residual germinal matrices of the brain. In the paper by Louissaint et al. (2002) in this issue of Neuron, the “cause and effect” of adult neurogenesis takes a major step forward with the description of a vascular signaling network that influences neuronal precursor migration and fate

Immune Influence on Adult Neural Stem Cell Regulation and Function

Neural stem cells (NSCs) lie at the heart of central nervous system development and repair, and deficiency or dysregulation of NSCs or their progeny can have significant consequences at any stage of life. Immune signaling is emerging as one of the influential variables that define resident NSC behavior. Perturbations in local immune signaling accompany virtually every injury or disease state, and signaling cascades that mediate immune activation, resolution, or chronic persistence influence resident stem and progenitor cells. Some aspects of immune signaling are beneficial, promoting intrinsic plasticity and cell replacement, while others appear to inhibit the very type of regenerative response that might restore or replace neural networks lost in injury or disease. Here we review known and speculative roles that immune signaling plays in the postnatal and adult brain, focusing on how environments encountered in disease or injury may influence the activity and fate of endogenous or transplanted NSCs

Human 3D cellular model of hypoxic brain injury of prematurity.

Owing to recent medical and technological advances in neonatal care, infants born extremely premature have increased survival rates1,2. After birth, these infants are at high risk of hypoxic episodes because of lung immaturity, hypotension and lack of cerebral-flow regulation, and can develop a severe condition called encephalopathy of prematurity3. Over 80% of infants born before post-conception week 25 have moderate-to-severe long-term neurodevelopmental impairments4. The susceptible cell types in the cerebral cortex and the molecular mechanisms underlying associated gray-matter defects in premature infants remain unknown. Here we used human three-dimensional brain-region-specific organoids to study the effect of oxygen deprivation on corticogenesis. We identified specific defects in intermediate progenitors, a cortical cell type associated with the expansion of the human cerebral cortex, and showed that these are related to the unfolded protein response and changes. Moreover, we verified these findings in human primary cortical tissue and demonstrated that a small-molecule modulator of the unfolded protein response pathway can prevent the reduction in intermediate progenitors following hypoxia. We anticipate that this human cellular platform will be valuable for studying the environmental and genetic factors underlying injury in the developing human brain

Enriched Monolayer Precursor Cell Cultures from Micro-Dissected Adult Mouse Dentate Gyrus Yield Functional Granule Cell-Like Neurons

BACKGROUND: Stem cell cultures are key tools of basic and applied research in Regenerative Medicine. In the adult mammalian brain, lifelong neurogenesis originating from local precursor cells occurs in the neurogenic regions of the hippocampal dentate gyrus. Despite widespread interest in adult hippocampal neurogenesis and the use of mouse models to study it, no protocol existed for adult murine long-term precursor cell cultures with hippocampus-specific differentiation potential. METHODOLOGY/PRINCIPAL FINDINGS: We describe a new strategy to obtain serum-free monolayer cultures of neural precursor cells from microdissected dentate gyrus of adult mice. Neurons generated from these adherent hippocampal precursor cell cultures expressed the characteristic markers like transcription factor Prox1 and showed the TTX-sensitive sodium currents of mature granule cells in vivo. Similar to granule cells in vivo, treatment with kainic acid or brain derived neurotrophic factor (BDNF) elicited the expression of GABAergic markers, further supporting the correspondence between the in vitro and in vivo phenotype. When plated as single cells (in individual wells) or at lowest density for two to three consecutive generations, a subset of the cells showed self-renewal and gave rise to cells with properties of neurons, astrocytes and oligodendrocytes. The precursor cell fate was sensitive to culture conditions with their phenotype highly influenced by factors within the media (sonic hedgehog, BMP, LIF) and externally applied growth factors (EGF, FGF2, BDNF, and NT3). CONCLUSIONS/SIGNIFICANCE: We report the conditions required to generate adult murine dentate gyrus precursor cell cultures and to analyze functional properties of precursor cells and their differentiated granule cell-like progeny in vitro

Cancer risk in DES daughters

We examined long-term risk of cancer in women exposed to diethylstilbestrol (DES) in utero. A total of 12,091 DES-exposed women in the Netherlands were followed prospectively from December 1992 till June 2008. Cancer incidence was assessed through linkage with the Dutch pathology database (PALGA) and the Netherlands Cancer Registry and compared with the Dutch female population. A total of 348 medically verified cancers occurred; median age at end of follow-up was 44.0 years. No overall increased risk of cancer was found (standardized incidence ratio [SIR] = 1.01; 95% confidence interval [CI] = 0.91, 1.13). The risk of clear cell adenocarcinoma of the vagina and cervix (CCA) was statistically significantly increased (SIR = 24.23; 95% CI = 8.89, 52.74); the elevated risk persisted above 40 years of age. The risk of melanoma diagnosed before age 40 was increased (SIR = 1.59; 95% CI = 1.08, 2.26). No excess risks were found for other sites, including breast cancer. Except for an elevated risk of CCA, persisting at older ages, and an increased risk of melanoma at young ages, we found no increased risk of cancer. Longer follow-up is warranted to examine cancer risk at ages when cancer occurs more frequently

SNCA Triplication Parkinson's Patient's iPSC-derived DA Neurons Accumulate α-Synuclein and Are Susceptible to Oxidative Stress

Parkinson's disease (PD) is an incurable age-related neurodegenerative disorder affecting both the central and peripheral nervous systems. Although common, the etiology of PD remains poorly understood. Genetic studies infer that the disease results from a complex interaction between genetics and environment and there is growing evidence that PD may represent a constellation of diseases with overlapping yet distinct underlying mechanisms. Novel clinical approaches will require a better understanding of the mechanisms at work within an individual as well as methods to identify the specific array of mechanisms that have contributed to the disease. Induced pluripotent stem cell (iPSC) strategies provide an opportunity to directly study the affected neuronal subtypes in a given patient. Here we report the generation of iPSC-derived midbrain dopaminergic neurons from a patient with a triplication in the α-synuclein gene (SNCA). We observed that the iPSCs readily differentiated into functional neurons. Importantly, the PD-affected line exhibited disease-related phenotypes in culture: accumulation of α-synuclein, inherent overexpression of markers of oxidative stress, and sensitivity to peroxide induced oxidative stress. These findings show that the dominantly-acting PD mutation is intrinsically capable of perturbing normal cell function in culture and confirm that these features reflect, at least in part, a cell autonomous disease process that is independent of exposure to the entire complexity of the diseased brain

Prox1 Is Required for Granule Cell Maturation and Intermediate Progenitor Maintenance During Brain Neurogenesis

The transcription factor Prox1 plays a crucial role in intermediate progenitor maintenance and hippocampal neuron differentiation during adult neurogenesis in the dentate gyrus region of the hippocampus

Sea-level change in the Dutch Wadden Sea

Rising sea levels due to climate change can have severe consequences for coastal populations and ecosystems all around the world. Understanding and projecting sea-level rise is especially important for low-lying countries such as the Netherlands. It is of specific interest for vulnerable ecological and morphodynamic regions, such as the Wadden Sea UNESCO World Heritage region. Here we provide an overview of sea-level projections for the 21st century for the Wadden Sea region and a condensed review of the scientific data, understanding and uncertainties underpinning the projections. The sea-level projections are formulated in the framework of the geological history of the Wadden Sea region and are based on the regional sea-level projections published in the Fifth Assessment Report of the Intergovernmental Panel on Climate Change (IPCC AR5). These IPCC AR5 projections are compared against updates derived from more recent literature and evaluated for the Wadden Sea region. The projections are further put into perspective by including interannual variability based on long-term tide-gauge records from observing stations at Den Helder and Delfzijl. We consider three climate scenarios, following the Representative Concentration Pathways (RCPs), as defined in IPCC AR5: the RCP2.6 scenario assumes that greenhouse gas (GHG) emissions decline after 2020; the RCP4.5 scenario assumes that GHG emissions peak at 2040 and decline thereafter; and the RCP8.5 scenario represents a continued rise of GHG emissions throughout the 21st century. For RCP8.5, we also evaluate several scenarios from recent literature where the mass loss in Antarctica accelerates at rates exceeding those presented in IPCC AR5. For the Dutch Wadden Sea, the IPCC AR5-based projected sea-level rise is 0.07±0.06m for the RCP4.5 scenario for the period 2018–30 (uncertainties representing 5–95%), with the RCP2.6 and RCP8.5 scenarios projecting 0.01m less and more, respectively. The projected rates of sea-level change in 2030 range between 2.6mma−1 for the 5th percentile of the RCP2.6 scenario to 9.1mma−1 for the 95th percentile of the RCP8.5 scenario. For the period 2018–50, the differences between the scenarios increase, with projected changes of 0.16±0.12m for RCP2.6, 0.19±0.11m for RCP4.5 and 0.23±0.12m for RCP8.5. The accompanying rates of change range between 2.3 and 12.4mma−1 in 2050. The differences between the scenarios amplify for the 2018–2100 period, with projected total changes of 0.41±0.25m for RCP2.6, 0.52±0.27m for RCP4.5 and 0.76±0.36m for RCP8.5. The projections for the RCP8.5 scenario are larger than the high-end projections presented in the 2008 Delta Commission Report (0.74m for 1990–2100) when the differences in time period are considered. The sea-level change rates range from 2.2 to 18.3mma−1 for the year 2100. We also assess the effect of accelerated ice mass loss on the sea-level projections under the RCP8.5 scenario, as recent literature suggests that there may be a larger contribution from Antarctica than presented in IPCC AR5 (potentially exceeding 1m in 2100). Changes in episodic extreme events, such as storm surges, and periodic (tidal) contributions on (sub-)daily timescales, have not been included in these sea-level projections. However, the potential impacts of these processes on sea-level change rates have been assessed in the report