The dentate gyrus of the mammalian hippocampus continuously generates new neurons during adulthood. These adult-born neurons become functionally active and are thought to contribute to learning and ...memory, especially during their maturation phase, when they have extraordinary plasticity. In this Review, we discuss the molecular machinery involved in the generation of new neurons from a pool of adult neural stem cells and their integration into functional hippocampal circuits. We also summarize the potential functions of these newborn neurons in the adult brain, their contribution to behavior, and their relevance to disease.
The dentate gyrus of the mammalian hippocampus continuously generates new neurons during adulthood. Understanding the molecular mechanisms underlying the generation, integration, and functions of these newborn neurons in the adult brain may help design future regenerative approaches for treating neurological disease.
Noncoding genetic variation is a major driver of phenotypic diversity, but functional interpretation is challenging. To better understand common genetic variation associated with brain diseases, we ...defined noncoding regulatory regions for major cell types of the human brain. Whereas psychiatric disorders were primarily associated with variants in transcriptional enhancers and promoters in neurons, sporadic Alzheimer's disease (AD) variants were largely confined to microglia enhancers. Interactome maps connecting disease-risk variants in cell-type-specific enhancers to promoters revealed an extended microglia gene network in AD. Deletion of a microglia-specific enhancer harboring AD-risk variants ablated
expression in microglia, but not in neurons or astrocytes. These findings revise and expand the list of genes likely to be influenced by noncoding variants in AD and suggest the probable cell types in which they function.
Sepsis is now operationally defined as life-threatening organ dysfunction caused by an infection, identified by an acute change in SOFA-Score of at least two points, including clinical chemistry such ...as creatinine or bilirubin concentrations. However, little knowledge exists about organ-specific microRNAs as potentially new biomarkers. Accordingly, we tested the hypotheses that micro-RNA-122, the foremost liver-related micro-RNA (miR), 1) discriminates between sepsis and infection, 2) is an early predictor for mortality, and 3) improves the prognostic value of the SOFA-score.
We analyzed 108 patients with sepsis (infection + increase SOFA-Score ≥2) within the first 24h of ICU admission and as controls 20 patients with infections without sepsis (infection + SOFA-Score ≤1). Total circulating miR was isolated from serum and relative miR-122 expression was measured (using spiked-in cel-miR-54) and associated with 30-day survival.
30-day survival of the sepsis patients was 63%. miR-122 expression was 40-fold higher in non-survivors (p = 0.001) and increased almost 6-fold in survivors (p = 0.013) compared to controls. miR-122 serum-expression discriminated both between sepsis vs. infection (AUC 0.760, sensitivity 58.3%, specificity 95%) and survivors vs. non-survivors (AUC 0.728, sensitivity 42.5%, specificity 94%). Multivariate Cox-regression analysis revealed miR-122 (HR 4.3; 95%-CI 2.0-8.9, p<0.001) as independent prognostic factor for 30-day mortality. Furthermore, the predictive value for 30-day mortality of the SOFA-Score (AUC 0.668) was improved by adding miR-122 (AUC 0.743; net reclassification improvement 0.37, p<0.001; integrated discrimination improvement 0.07, p = 0.007).
Increased miR-122 serum concentration supports the discrimination between infection and sepsis, is an early and independent risk factor for 30-day mortality, and improves the prognostic value of the SOFA-Score, suggesting a potential role for miR-122 in sepsis-related prediction models.
Altered microRNA profiles have been implicated in human brain disorders. However, the functional contribution of individual microRNAs to neuronal development and function is largely unknown. Here, we ...report biological functions for miR-19 in adult neurogenesis. We determined that miR-19 is enriched in neural progenitor cells (NPCs) and downregulated during neuronal development in the adult hippocampus. By manipulating miR-19 in NPCs for gain- and loss-of-function studies, we discovered that miR-19 regulates cell migration by directly targeting Rapgef2. Concordantly, dysregulation of miR-19 in NPCs alters the positioning of newborn neurons in the adult brain. Furthermore, we found abnormal expression of miR-19 in human NPCs generated from schizophrenic patient-derived induced pluripotent stem cells (iPSCs) that have been described as displaying aberrant migration. Our study demonstrates the significance of posttranscriptional gene regulation by miR-19 in preventing the irregular migration of adult-born neurons that may contribute to the etiology of schizophrenia.
•miR-19 is highly expressed in adult NPCs and decreases during neuronal development•miR-19 governs migration of newborn neurons in the adult brain•Rapgef2 is a direct target of miR-19, and it controls migration of adult-born neurons•miR-19 is dysregulated in human NPCs derived from iPSCs of schizophrenic patients
Proper neuronal migration is critical for brain development and function. Han et al. found that miR-19 controls migration of adult-born neurons by suppressing Rapgef2, and that miR-19 expression is dysregulated in a subset of schizophrenic patient-derived NPCs.
Human brain organoids are 3-dimensional cell aggregates that are generated from pluripotent stem cells and recapitulate features of the early developing human brain. Brain organoids mainly consist of ...cells from the neural lineage, such as neural progenitor cells, neurons, and astrocytes. However, current brain organoid systems lack functional vasculature as well as other non-neuronal cells that are indispensable for oxygen and nutrient supply to the organoids, causing cell stress and formation of a necrotic center. Attempts to utilize intracerebral transplantation approaches have demonstrated successful vascularization of brain organoids and robust neurodifferentiation. In this review, we summarize recent progress and discuss ethical considerations in the field of brain organoid transplantation.
Brain organoids are three-dimensional neural aggregates derived from pluripotent stem cells through self-organization and recapitulate architectural and cellular aspects of certain brain regions. ...Brain organoids are currently a highly exciting area of research that includes the study of human brain development, function, and dysfunction in unprecedented ways. In this Review, we discuss recent discoveries related to the generation of brain organoids that resemble diverse brain regions. We provide an overview of the strategies to complement these primarily neuroectodermal models with cell types of non-neuronal origin, such as vasculature and immune cells. Recent transplantation approaches aiming to achieve higher cellular complexity and long-term survival of these models will then be discussed. We conclude by highlighting unresolved key questions and future directions in this exciting area of human brain organogenesis.
Autism spectrum disorder (ASD) is thought to emerge during early cortical development. However, the exact developmental stages and associated molecular networks that prime disease propensity are ...elusive. To profile early neurodevelopmental alterations in ASD with macrocephaly, we monitored subject-derived induced pluripotent stem cells (iPSCs) throughout the recapitulation of cortical development. Our analysis revealed ASD-associated changes in the maturational sequence of early neuron development, involving temporal dysregulation of specific gene networks and morphological growth acceleration. The observed changes tracked back to a pathologically primed stage in neural stem cells (NSCs), reflected by altered chromatin accessibility. Concerted over-representation of network factors in control NSCs was sufficient to trigger ASD-like features, and circumventing the NSC stage by direct conversion of ASD iPSCs into induced neurons abolished ASD-associated phenotypes. Our findings identify heterochronic dynamics of a gene network that, while established earlier in development, contributes to subsequent neurodevelopmental aberrations in ASD.
Microglia are specialized brain-resident macrophages that play crucial roles in brain development, homeostasis, and disease. However, until now, the ability to model interactions between the human ...brain environment and microglia has been severely limited. To overcome these limitations, we developed an in vivo xenotransplantation approach that allows us to study functionally mature human microglia (hMGs) that operate within a physiologically relevant, vascularized immunocompetent human brain organoid (iHBO) model. Our data show that organoid-resident hMGs gain human-specific transcriptomic signatures that closely resemble their in vivo counterparts. In vivo two-photon imaging reveals that hMGs actively engage in surveilling the human brain environment, react to local injuries, and respond to systemic inflammatory cues. Finally, we demonstrate that the transplanted iHBOs developed here offer the unprecedented opportunity to study functional human microglia phenotypes in health and disease and provide experimental evidence for a brain-environment-induced immune response in a patient-specific model of autism with macrocephaly.
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•Xenotransplanted brain organoids as in vivo platform for studying human microglia (hMGs)•hMGs gain human-specific transcriptomic signatures and assume in-vivo-like identities•hMGs engage in surveilling the human brain environment and react to perturbations•A patient-derived model reveals a brain-environment-induced immune response in autism
Schafer et al. present an organoid-based xenotransplantation platform to study human brain-environment-dependent and disease-associated microglia phenotypes under in vivo conditions.
Sporadic Alzheimer’s disease (AD) exclusively affects elderly people. Using direct conversion of AD patient fibroblasts into induced neurons (iNs), we generated an age-equivalent neuronal model. AD ...patient-derived iNs exhibit strong neuronal transcriptome signatures characterized by downregulation of mature neuronal properties and upregulation of immature and progenitor-like signaling pathways. Mapping iNs to longitudinal neuronal differentiation trajectory data demonstrated that AD iNs reflect a hypo-mature neuronal identity characterized by markers of stress, cell cycle, and de-differentiation. Epigenetic landscape profiling revealed an underlying aberrant neuronal state that shares similarities with malignant transformation and age-dependent epigenetic erosion. To probe for the involvement of aging, we generated rejuvenated iPSC-derived neurons that showed no significant disease-related transcriptome signatures, a feature that is consistent with epigenetic clock and brain ontogenesis mapping, which indicate that fibroblast-derived iNs more closely reflect old adult brain stages. Our findings identify AD-related neuronal changes as age-dependent cellular programs that impair neuronal identity.
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•Alzheimer's patients’ induced neurons (iNs) show transcriptional and cellular defects•Alzheimer's iNs activate de-differentiation pathways and markers of neuronal fate loss•Epigenetic erosion underlies the pathogenic hypo-mature state of Alzheimer's iNs•Rejuvenated iPSC neurons show only very mild transcriptomic disease signatures
Mertens et al. generated directly induced neurons (iNs) from Alzheimer's patients’ fibroblasts that show neuronal defects and activate immature and de-differentiation signaling pathways. Aging- and cancer-associated epigenetic changes promote the underlying pathogenic hypo-mature neuronal state, and iPSC rejuvenation largely rescued the age-dependent disease phenotype.
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