SummaryHere, we show that the lysophosphatidic acid receptor 1 (LPA1) is expressed by a defined population of type 1 stem cells and type 2a precursor cells in the adult mouse dentate gyrus. LPA1, in contrast to Nestin, also marks the quiescent stem cell population. Combining LPA1-GFP with EGFR and prominin-1 expression, we have enabled the prospective separation of both proliferative and non-proliferative precursor cell populations. Transcriptional profiling of the isolated proliferative precursor cells suggested immune mechanisms and cytokine signaling as molecular regulators of adult hippocampal precursor cell proliferation. In addition to LPA1 being a marker of this important stem cell population, we also show that the corresponding ligand LPA is directly involved in the regulation of adult hippocampal precursor cell proliferation and neurogenesis, an effect that can be attributed to LPA signaling via the AKT and MAPK pathways.

2D mussel-inspired polydopamine (PDA) nanosheets are prepared and exploited as a functional surface for grafting various polymer brushes. The PDA nanosheet and its polymer-brush derivatives show lateral integrity and are robust; therefore, they can be detached from their substrates. Cell-adhesion tests show that the PDA nanosheet promotes cell growth and attachment, while a PDA-based poly(3-sulfopropyl methacrylate) carpet exhibits nonfouling behavior.

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Background: In the adult hippocampus, the granule cell layer of the dentate gyrus is a heterogeneous structure formed by neurons of different ages, morphologies and electrophysiological properties. Retroviral vectors have been extensively used to transduce cells of the granule cell layer and study their inherent properties in an intact brain environment. In addition, lentivirus-based vectors have been used to deliver transgenes to replicative and non-replicative cells as well, such as post mitotic neurons of the CNS. However, only few studies have been dedicated to address the applicability of these widespread used vectors to hippocampal cells in vivo. Therefore, the aim of this study was to extensively characterize the cell types that are effectively transduced in vivo by VSVg-pseudotyped lentivirus-based vectors in the hippocampus dentate gyrus.

Resveratrol (RVTL) is a flavonoid found in red wine and has been publicized heavily as an anti-aging compound. Indeed, basic research confirms that although there is much hype in the promotion of RVTL, flavonoids such as RVTL have a wide range of biological effects. We here investigated the effects of RVTL treatment on hippocampal plasticity and memory performance in female Balb/C mice, a strain with low baseline levels of adult neurogenesis. Two weeks of treatment with RVTL (40 mg/kg) induced the production of new neurons in vivo by increasing cell survival and possibly precursor cell proliferation. In addition, RVTL decreased the number of apoptotic cells. The number of doublecortin (DCX)-expressing intermediate cells was increased. RVTL stimulated neuronal differentiation in vitro without effects on proliferation. In the dentate gyrus, RVTL promoted the formation and maturation of spines on granule cell dendrites. RVTL also improved performance in the step down passive avoidance test. The RVTL-treated mice showed increase in the levels of two key signaling proteins, phospho-Akt and phospho-PKC, suggesting the involvement of these signaling pathways. Our results support the vision that flavonoids such as resveratrol deserve further examination as plasticity-inducing compounds in the context of successful cognitive aging.

We asked whether cell-cycle associated protein p27kip1 might be involved in the transition of precursor cells to postmitotic maturation in adult hippocampal neurogenesis. p27kip1 was expressed throughout the dentate gyrus with a strong nuclear expression in early postmitotic, calretinin-positive neurons and neuronally determined progenitor cells (type-3 and some type2b), lower or absent expression in radial glia-like precursor cells (type-1) and type-2a cells and essentially no expression in granule cells. This suggested a transitory role in late proliferative and early postmitotic phases of neurogenesis. Inconsistent with a role limited to cell cycle arrest the acute stimuli, voluntary wheel running (RUN), environmental enrichment (ENR) and kainate-induced seizures increased p27kip1 expressing cells. Sequential short-term combination of RUN and ENR yielded more p27kip1 cells than either stimulus alone, indicating an additive effect. In vitro, p27kip1 was lowly expressed by proliferating precursor cells but increased upon differentiation. In p27kip12/2 mice neurogenesis was reduced in vivo, whereas the number of proliferating cells was increased. Accordingly, the microdissected dentate gyrus of p27kip12/2 mice generated more colonies in the neurosphere assay and an increased number of larger spheres with the differentiation potential unchanged. In p27kip12/2 monolayer cultures, proliferation was increased and cell cycle genes were upregulated. In the Morris water maze p27kip12/2 mice learned the task but were specifically impaired in the reversal phase explainable by the decrease in adult neurogenesis. We conclude that p27kip1 is involved in the decisive step around cell-cycle exit and plays an important role in activity-regulated and functionally relevant adult hippocampal neurogenesis. STEM CELLS 2017;35:787-799 SIGNIFICANCE STATEMENTThe cell cycle associated factor p27kip1 has multiple roles in adult hippocampal neurogenesis, including the control of cell cycle exit. A p27kip1 knockout mouse shows increased proliferation of precursor cells, but (as shown in the study) reduced net neurogenesis: p27kip1 is required for controlled cell cycle exit.

BACKGROUND:Type 2 Diabetes Mellitus is one of the most common metabolic diseases worldwide. The most common complication of DM is diabetic neuropathy (DN), especially diabetic polyneuropathy (DPN). Vitamin D plays an important role in the pathogenesis of DN, thus affecting its severity which can be assessed using nerve conduction study (NCS).AIM:This study aimed to develop a predictive model of DPN severity based on vitamin D level.METHODS:This was a prospective cohort study involving 50 subjects with DM which was conducted in Haji Adam Malik General Hospital Medan. All subjects were fulfilling inclusion criteria underwent laboratory examination to determine HbA1c and 25 (OH) D levels. Predictive variables were sex, age, duration of DM, smoking status, type and number of anti-diabetic drugs, the presence of metabolic syndrome, HbA1c and vitamin D levels. A scoring system was developed to determine a predictive model. The DPN severity was assessed using NCS and was re-evaluated after 3 months.RESULTS:Most of the subjects were female (60%), belonged to ≥ 50 years old age-group (88%), with DM duration < 5 years (56%), were non-smoker (90%), we’re using one anti-diabetic drug (60%), were using insulin (50%), had metabolic syndrome (68%), had HbA1c level > 6.5% (94%), and had vitamin D level < 20 ng/ml (56%). A score of > 4 on this predictive model of DPN severity had a relative risk (RR) of 2.70. The predictive model had a sensitivity of 82.8% and specificity of 61.9%.CONCLUSION:A score of higher than 4 on this predictive model showed a 2.7 times higher risk of severe DPN. A predictive model of DPN severity based on vitamin D level had high sensitivity and specificity.

In much animal research, genetic variation is rather avoided than used as a powerful tool to identify key regulatory genes in complex phenotypes. Adult hippocampal neurogenesis is one such highly complex polygenic trait, for which the understanding of the molecular basis is fragmented and incomplete, and for which novel genetic approaches are needed. In this study, we aimed at marrying the power of the BXD panel, a mouse genetic reference population, with the flexibility of a cell culture model of adult neural precursor proliferation and differentiation. We established adult-derived hippocampal precursor cell cultures from 20 strains of the BXD panel, including the parental strains C57BL/6J and DBA/2J. The rates of cell proliferation and neuronal differentiation were measured, and transcriptional profiles were obtained from proliferating cultures. Together with the published genotypes of all lines, these data allowed a novel systems genetics analysis combining quantitative trait locus analysis with transcript expression correlation at a cellular level to identify genes linked with the differences in proliferation. In a proof-of-principle analysis, we identified Lrp6, the gene encoding the coreceptor to Frizzled in the Wnt pathway, as a potential negative regulator of precursor proliferation. Overexpression and siRNA silencing confirmed the regulatory role of Lrp6. As well as adding to our knowledge of the pathway surrounding Wnt in adult hippocampal neurogenesis, this finding allows the new appreciation of a negative regulator within this system. In addition, the resource and associated methodology will allow the integration of regulatory mechanisms at a systems level. STEM CELLS 2016;34:674-684 SIGNIFICANCE STATEMENTNeural stem cells from the hippocampus of adult mice can be grown in culture where they are amenable to experimental manipulation. The proliferation of these cells, and their differentiation into mature cell types, is under complex genetic control. To discover genes regulating stem and precursor cell proliferation, we have established cultures from different strains of mice. We measured proliferation rates and transcript expression in each cell line and mapped these to existing genotypes. Using a novel systems genetics approach, we identified the Wnt pathway gene Lrp6 as a novel negative regulator of proliferation in these cells.