Biology subjects

Xie, H.

Publications and source records attributed to Xie, H..

At least 163 records · Page 9Linked to original sources

bioRxiv2019

Sensitive detection of highly fragmented cytomegalovirus nucleic acid in human cfDNA

Congenital human cytomegalovirus (CMV) infections are the leading cause of newborn hearing and central nervous system impairments worldwide. Currently, routine prenatal screening for congenital CMV is not performed in the United States and confirmation in suspected perinatal cases requires invasive sampling by amniocentesis. We hypothesized that detection of CMV from maternal cell-free DNA (cfDNA) plasma could provide a non-invasive indicator of congenital CMV infection. We analyzed sequence data from 2,208 individuals undergoing routine non-invasive prenatal aneuploidy screening at the University of Washington. CMV reads were identified in 117 (5.3%) samples. Positive samples were stratified based on CMV reads per million sample reads (RPM), resulting in ten samples being classified as strong positive (RPM > 0.3) and 107 as intermediate positive (0.01<RPM<0.3). Subsequent qPCR testing identified CMV in 9/10 strong positive samples and 2/32 intermediate positive samples. Median cfDNA insert size derived from CMV was significantly shorter than cfDNA derived from human chromosomes (103 vs 172 bp, p<0.0001), corresponding to the 3rd percentile of human cfDNA insert size. In addition, CMV cfDNA fragment lengths were distributed over a wider range than human cfDNA reads. These studies reveal the highly fragmented nature of CMV cfDNA and offer precise measurements of its length: these features likely explain discrepancies in serum CMV viral loads measurements determined by different qPCR assays, despite widespread efforts to standardize results. More work is required to determine how detection of CMV from maternal cfDNA can be best used as tool for congenital CMV screening or diagnosis.

microbiology↗

bioRxiv2019

Inherited chromosomally integrated HHV-6 demonstrates tissue-specific RNA expression in vivo that correlates with increased antibody immune response.

Human herpesvirus-6A and 6B (HHV-6A, HHV-6B) are human viruses capable of chromosomal integration. Approximately 1% of the human population carry one copy of HHV-6A/B integrated into every cell in their body, referred to as inherited chromosomally integrated human herpesvirus 6A/B (iciHHV-6A/B). Whether iciHHV-6A/B is transcriptionally active in vivo and how it shapes the immunological response is still unclear. Here, we screened DNA-Seq and RNA-Seq data for 650 individuals available through the Genotype-Tissue Expression (GTEx) project and identified 2 iciHHV-6A and 4 iciHHV-6B positive candidates. When corresponding tissue-specific gene expression signatures were analyzed, low levels HHV-6A/B gene expression was found across multiple tissues, with the highest levels of gene expression in the brain (specifically for iciHHV-6A), testis, esophagus, and adrenal gland. U90 and U100 were the most highly expressed HHV-6 genes in both iciHHV-6A and iciHHV-6B individuals. To assess whether tissue-specific gene expression from iciHHV-6A/B influences the immune response, a cohort of 15,498 subjects was screened and 85 iciHHV-6A/B+ subjects were identified. Plasma samples from iciHHV-6A/B+ and age and sex matched controls were analyzed for antibodies to control antigens (CMV, EBV, FLU) or HHV-6A/B antigens. Our results indicate that iciHHV-6A/B+ subjects have significantly more antibodies against the U90 gene product (IE1) relative to non-iciHHV-6 individuals. Antibody responses against EBV and FLU antigens or HHV-6A/B gene products either not expressed or expressed at low levels, such as U47, U57 or U72, were identical between controls and iciHHV-6A/B+ subjects. CMV seropositive individuals with iciHHV-6A/B+ have more antibodies against CMV pp150, relative to CMV seropositive controls. These results argue that spontaneous gene expression from integrated HHV-6A/B leads to an increase in antigenic burden that translates into a more robust HHV-6A/B specific antibody response.\n\nImportanceHHV-6A/B are human herpesviruses that have the unique property of being able to integrate into the subtelomeric regions of human chromosomes. Approximately 1% of the worlds population carries integrated HHV-6A/B genome in every cell of their body. Whether viral genes are transcriptionally active in these individuals is unclear. By taking advantage of a unique tissue-specific gene expression dataset, we show the majority of tissues from iciHHV-6 individuals do not show HHV-6 gene expression. Brain and testes showed the highest tissue-specific expression of HHV-6 genes in two separate datasets. Two HHV-6 genes, U90 (immediate early 1 protein) and U100 (glycoproteins Q1 and Q2), were found to be selectively and consistently expressed across several human tissues. Expression of U90 translates into an increase in antigen-specific antibody response in iciHHV-6A/B+ subjects relative to controls. Future studies will be needed to determine the mechanism of gene expression, the effects of these genes on human gene transcription networks and the pathophysiological impact of having increased viral protein expression in tissue in conjunction with increased antigen-specific antibody production.

genomics↗

bioRxiv2019

Enhancing single-cell cellular state inference by incorporating molecular network features

In biological systems, genes function in conjunction rather than in isolation. However, traditional single-cell RNA-seq (scRNA-seq) analyses heavily rely on the transcriptional similarity of individual genes, ignoring the inherent gene-gene interactions. Here, we present SCORE, a network-based method, which incorporates the validated molecular network features to infer cellular states. Using real scRNA-seq datasets, SCORE outperforms existing methods in accuracy, robustness, scalability, data integration and removal of batch effect. When applying SCORE to a newly generated human ileal scRNA-seq dataset, we identified several novel stem/progenitor clusters, including a Cripto-1+ cluster. Moreover, two distinct groups of goblet cells were identified and only one of them tended to secrete mucus. Besides, we found that the recently identified BEST4+OTOP2+ microfold cells also highly expressed CFTR, which is different from their colonic counterparts. In summary, SCORE enhances cellular state inference by simulating the dynamic changes of molecular networks, providing more biological insights beyond statistical interpretations.

bioinformatics↗

bioRxiv2019

Detecting Transcriptomic Structural Variants in Heterogeneous Contexts via the Multiple Compatible Arrangements Problem

Transcriptomic structural variants (TSVs) -- structural variants that affect expressed regions -- are common, especially in cancer. Detecting TSVs is a challenging computational problem. Sample heterogeneity (including differences between alleles in diploid organisms) is a critical confounding factor when identifying TSVs. To improve TSV detection in heterogeneous RNA-seq samples, we introduce the MO_SCPCAPULTIPLEC_SCPCAP CO_SCPCAPOMPATIBLEC_SCPCAP AO_SCPCAPRRANGEMENTC_SCPCAP PO_SCPCAPROBLEMC_SCPCAP (MCAP), which seeks k genome rearrangements to maximize the number of reads that are concordant with at least one rearrangement. This directly models the situation of a heterogeneous or diploid sample. We prove that MCAP is NP-hard and provide a [Formula]-approximation algorithm for k = 1 and a [Formula]-approximation algorithm for the diploid case (k = 2) assuming an oracle for k = 1. Combining these, we obtain a [Formula]-approximation algorithm for MCAP when k = 2 (without an oracle). We also present an integer linear programming formulation for general k. We completely characterize the graph structures that require k > 1 to satisfy all edges and show such structures are prevalent in cancer samples. We evaluate our algorithms on 381 TCGA samples and 2 cancer cell lines and show improved performance compared to the state-of-the-art TSV-calling tool, SQUID.

bioinformatics↗

bioRxiv2019

Evaluation of deep-learning-based lncRNA identification tools

Long non-coding RNAs (lncRNAs, length above 200 nt) exert crucial biological roles and have been implicated in cancers1,2. To characterize newly discovered transcripts, one major issue is to distinguish lncRNAs from mRNAs. Since experimental methods are time-consuming and costly, computational methods are preferred for large-scale lncRNA identification. In a recent study, Amin et al.3 evaluated three deep-learning-based lncRNA identification tools (i.e., lncRNAnet4, LncADeep5, and lncFinder6) and concluded \"The LncADeep PR (precision recall) curve is just above the no-skill model and LncADeep showed poor overall performance\". This surprising conclusion is based on the authors use of a non-default setting of LncADeep. Actually, LncADeep has two models, one for full-length transcripts, and the other for transcripts including partial-length. Being aware of the difficulty of assembling full-length transcripts from RNA-seq dataset, LncADeeps default model is for transcripts including partial-length. However, according to the results posted on Amin et al.s website, the authors used LncADeep with full-length model, while they claimed to use the default setting of LncADeep, to identify lncRNAs from GENCODE dataset, which is composed of full- and partial-length transcripts. Thus, in their evaluation, the performance of LncADeep was underestimated. In this correspondence, we have tested LncADeeps default setting (i.e., model for transcripts including partial-length) on the datasets used in Amin et al.3, and LncADeep achieved overall the best performance compared with the other tools results reported by Amin et al.

bioinformatics↗

bioRxiv2019

Enhancer-dependence of gene expression increases with developmental age

How overall principles of gene regulation (the \"logic\") may change during ontogeny is largely unexplored. We compared transcriptomic, epigenomic and topological profiles in embryonic (EryP) and adult (EryD) erythroblasts. Despite reduced chromatin accessibility compared to EryP, distal chromatin of EryD is enriched in H3K27ac, Gata1 and Myb occupancy. In contrast to EryP-specific genes, which exhibit promoter-centric regulation through Gata1, EryD-specific genes employ distal enhancers for long-range regulation through enhancer-promoter looping, confirmed by Gata1 HiChIP. Genome editing demonstrated distal enhancers are required for gene expression in EryD but not in EryP. Applying a metric for enhancer-dependence of transcription, we observed a progressive reliance on enhancer control with increasing age of ontogeny among diverse primary cells and tissues of mouse and human origin. Our findings highlight fundamental and conserved differences in regulatory logic at distinct developmental stages, characterized by simpler promoter-centric regulation in embryonic cells and combinatorial enhancer-driven control in adult cells.\n\nHighlightsO_LIRegulation of embryonic-specific erythroid genes is promoter-centric through Gata1\nC_LIO_LIAdult-specific control is combinatorial enhancer-driven and requires Myb\nC_LIO_LIAdult specific genes have increased enhancer-promoter chromatin interactions\nC_LIO_LIEnhancer-dependence increases progressively with increasing developmental age\nC_LI

molecular biology↗

bioRxiv2019

3D observation of large-scale subcellular dynamics in vivo at the millisecond scale

Observing large-scale three-dimensional (3D) subcellular dynamics in vivo at high spatiotemporal resolution has long been a pursuit for biology. However, both the signal-to-noise ratio and resolution degradation in multicellular organisms pose great challenges. Here, we propose a method, termed Digital Adaptive Optics Scanning Lightfield Mutual Iterative Tomography (DAOSLIMIT), featuring both 3D incoherent synthetic aperture and tiled wavefront correction in post-processing. We achieve aberration-free fluorescence imaging in vivo over a 150 x 150 x 16 m3 field-of-view with the spatiotemporal resolution up to 250 nm laterally and 320 nm axially at 100 Hz, corresponding to a huge data throughput of over 15 Giga-voxels per second. Various fast subcellular processes are observed, including mitochondrial dynamics in cultured neurons, membrane dynamics in zebrafish embryos, and calcium propagation in cardiac cells, human cerebral organoids, and Drosophila larval neurons, enabling simultaneous in vivo studies of morphological and functional dynamics in 3D.

cell biology↗

bioRxiv2019

Multimodal memory components and their long-term dynamics identified in cortical layers II/III but not layer Vb

Activity patterns of cerebral cortical regions represent the present environment in which animals receive multi-modal inputs. They are also shaped by the history of previous activity that reflects learned information on past multimodal exposures. We studied the long-term dynamics of cortical activity patterns during the formation of multimodal memories by analysing in vivo high-resolution 2-photon mouse brain imaging of Immediate Early Gene expression, resolved by cortical layers. Strikingly, in layers II/III, the patterns showed similar dynamics across functional distinct cortical areas and the consistency of dynamic patterns lasts for one to several days. In contrast, in layer Vb, the activity dynamics varied across functional distinct areas, and the present activities are sensitive to the previous activities at different time depending on the cortical locations, indicating that the information stored in the cortex at different time points is distributed across different cortical areas. These results suggest different roles of layer II/III and layer Vb neurons in the long-term multimodal perception of the environment.

neuroscience↗

bioRxiv2019

Mice with GNAO1 R209H Movement Disorder Variant Display Hyperlocomotion Alleviated by Risperidone

Neurodevelopmental disorder with involuntary movements (NEDIM, OMIM: 617493) is a severe, early onset neurological condition characterized by a delay in psychomotor development, hypotonia, and hyperkinetic involuntary movements. Heterozygous de novo mutations in the GNAO1 gene cause NEDIM. Go, the gene product of GNAO1, is the alpha subunit of Go, a member of the heterotrimeric Gi/o family of G-proteins. Go is found abundantly throughout the brain but the pathophysiological mechanisms linking Go functions to clinical manifestations of GNAO1-related disorders are still poorly understood. One of the most common mutant alleles among the GNAO1 encephalopathies is the c.626G>A or p.Arg209His (R209H) mutation. We developed heterozygous knock-in Gnao1+/R209H mutant mice using CRISPR/Cas9 methodology to assess whether a mouse model could replicate aspects of the NEDIM clinical pattern. Mice carrying the R209H mutation exhibited increased locomotor activity and a modest gait abnormality at 8-12 weeks. In contrast to mice carrying other mutations in Gnao1, the Gnao1+/R209H mice did not show enhanced seizure susceptibility. Levels of protein expression in multiple brain regions were unchanged from WT mice but the nucleotide exchange rate of mutant R209H Go was 9 times faster than WT. The atypical neuroleptic risperidone has shown efficacy in a patient with the R209H mutation. It also alleviated the hyperlocomotion phenotype observed in our mouse model but suppressed locomotion in WT mice as well. In this study, we show that Gnao1+/R209H mice mirror elements of the patient phenotype and respond to an approved pharmacological agent.

neuroscience↗

bioRxiv2019

FcγRIIB I232T polymorphic change allosterically suppresses ligand binding

Fc{gamma}RIIB bindings to its ligand suppress immune cell activation. A single-nucleotide polymorphic (SNP) change, I232T, in the transmembrane (TM) domain of Fc{gamma}RIIB loses its suppression function, which clinically associates with systemic lupus erythematosus (SLE). Previously, we reported that I232T tilts Fc{gamma}RIIBs TM domain. In this study, combining with molecular dynamics simulations and single-cell FRET assay, we further revealed that such tilting by I232T unexpectedly bends the Fc{gamma}RIIBs ectodomain towards plasma membrane to allosterically impede Fc{gamma}RIIBs ligand association. We then used single-cell biomechanical assay to further find out that I232T also reduces two-dimensional in-situ binding affinities and association rates of Fc{gamma}RIIB interacting with its ligands by three-folds. This allosteric regulation by a SNP provides an intrinsic molecular mechanism for functional loss of Fc{gamma}RIIB-I232T in SLE patients.

immunology↗

bioRxiv2018

A novel polyphasic identification system for genus Trichoderma

As the rapid-changing in Trichoderma taxonomy, an efficient identification of Trichoderma species is an urgent issue for Trichoderma-based research. In this study, based on the current taxonomy of Trichoderma, we constructed curated databases including 338 ITS sequences, 435 TEF1 sequences, 415 RPB2 sequences and 28 phenotypic characters. In addition, a polyphasic identification system (PIST) was developed. Within PIST, the resolution ability of molecular and phenotype characters could be combined for species identification in a step-by-step way. Compared with other identification systems, the involved Trichoderma species were extended from 88 to 252 species and 175 from 188 tested Trichoderma species could be identified within PIST. In most tested cases, three nucleotide markers and phenotypic characters showed improved identification performance. The TEF1 sequences have superior resolution than other characters.\n\nImportanceThe genus Trichoderma is important to human society with a wide application in industry, agriculture and environment bio-remediation. Thus, a quick and accurate identification of Trichoderma spp. is paramount since it is usually the first step to conduct a Trichoderma-based scientific research and is an obstruction especially for those researchers as nematologist, chemists, nutritionist and the like, lacking of taxonomic knowledge of fungi.

microbiology↗

bioRxiv2018

The impact of interspecies recombination on human herpes simplex virus evolution and host immune recognition

Among the most ubiquitous of human pathogens, HSV-1 and HSV-2 are distinct viral species that diverged about six million years ago. At least four ancient HSV-1 x HSV-2 interspecies recombination events have affected the HSV-2 genome, with recombinants and non-recombinants at each locus circulating today. Though interspecies recombination has occurred in the past, its importance in HSV evolution remains incompletely defined. Using 255 newly-sequenced and 219 existing HSV genome sequences, we comprehensively assessed interspecies recombination in HSV. The novel recombinants we identify demonstrate that the sizes and locations of interspecies recombination events in HSV-2 are more variable than previously appreciated. One novel recombinant arose in its current host, showing for the first time that interspecies recombination occurs in contemporary HSV populations. We also demonstrate that interspecies recombination affects T-cell recognition of HSV. Our findings indicate that interspecies recombination can significantly influence genetic variation in and host immunologic response to HSV-2.

genomics↗

bioRxiv2018

Discrimination of the hierarchical structure of cortical layers in 2-photon microscopy data by combined unsupervised and supervised machine learning

The laminar organization of the cerebral cortex is a fundamental characteristic of the brain, with essential implications for cortical function. Due to the rapidly growing amount of high-resolution brain imaging data, a great demand arises for automated and flexible methods for discriminating the laminar texture of the cortex. Here, we propose a combined approach of unsupervised and supervised machine learning to discriminate the hierarchical cortical laminar organization in high-resolution 2-photon microscopic neural image data without observer bias, that is, without the prerequisite of manually labeled training data. For local cortical foci, we modify an unsupervised clustering approach to identify and represent the laminar cortical structure. Subsequently, supervised machine learning is applied to transfer the resulting layer labels across different locations and image data, to ensure the existence of a consistent layer label system. By using neurobiologically meaningful features, the discrimination results are shown to be consistent with the layer classification of the classical Brodmann scheme, and provide additional insight into the structure of the cerebral cortex and its hierarchical organization. Thus, our work paves a new way for studying the anatomical organization of the cerebral cortex, and potentially its functional organization.

neuroscience↗

bioRxiv2018

Neuraminidase Inhibition Contributes to Influenza A Virus Neutralization by Anti-Hemagglutinin Stem Antibodies

Broadly neutralizing antibodies (Abs) that bind the influenza virus hemagglutinin (HA) stem may enable universal influenza vaccination. Here, we show that anti-stem Abs sterically inhibit viral neuraminidase activity against large substrates, with activity inversely proportional to the length of the fibrous NA stalk that supports the enzymatic domain. By modulating NA stalk length in recombinant IAVs, we show that anti-stem Abs inhibit virus release from infected cells by blocking NA, accounting for their in vitro neutralization activity. NA inhibition contributes to anti-stem Ab protection in influenza infected mice, likely due at least in part to NA-mediated inhibition of Fc{gamma}R dependent activation of innate immune cells by antibody bound to virions. FDA approved NA inhibitors enhance anti-stem based Fc{gamma} dependent immune cell activation, raising the possibility of therapeutic synergy between NA inhibitors and anti-stem mAb treatment in humans.

microbiology↗

bioRxiv2018

Determining the Mutation Bias of Favipiravir in Influenza Using Next-generation Sequencing

AbstractFavipiravir is a broad spectrum antiviral drug that may be used to treat influenza. Previous research has identified that favipiravir likely acts as a mutagen but the precise mutation bias that favipiravir induces in influenza virus RNAs has not been described. Here, we use next-generation sequencing (NGS) with barcoding of individual RNA molecules to accurately and quantitatively detect favipiravir-induced mutations and to sample orders of magnitude more mutations than would be possible through Sanger sequencing. We demonstrate that favipiravir causes mutations and show that favipiravir primarily acts as a guanine analogue and secondarily as an adenine analogue resulting in the accumulation of transition mutations. We also use a standard NGS pipeline to show that the mutagenic effect of favipiravir can be measured by whole genome sequencing of virus.\n\nImportanceNew antiviral drugs are needed as a first line of defence in the event of a novel influenza pandemic. Favipiravir is a broad-spectrum antiviral which is effective against influenza. The exact mechanism of how favipiravir works to inhibit influenza is still unclear. We used next-generation sequencing (NGS) to demonstrate that favipiravir causes mutations in influenza RNA. The greater depth of NGS sequence information over traditional sequencing methods allowed us to precisely determine the bias of particular mutations caused by favipiravir. NGS can also be used in a standard diagnostic pipeline to show that favipiravir is acting on the virus by revealing the mutation bias pattern typical to the drug. Our work will aid in testing whether viruses are resistant to favipiravir and may help demonstrate the effect of favipiravir on viruses in a clinical setting. This will be important if favipiravir is used during a future influenza pandemic.

microbiology↗

bioRxiv2018

Mouse Models of GNAO1-Associated Movement Disorder: Allele- and sex-specific differences in phenotypes

Background\n\nInfants and children with dominant de novo mutations in GNAO1 exhibit movement disorders, epilepsy, or both. Children with loss-of-function (LOF) mutations exhibit Epileptiform Encephalopathy 17 (EIEE17). Gain-of-function (GOF) mutations or those with normal function are found in patients with Neurodevelopmental Disorder with Involuntary Movements (NEDIM). There is no animal model with a human mutant GNAO1 allele.\n\nObjectives\n\nHere we develop a mouse model carrying a human GNAO1 mutation and determine whether clinical features of the GNAO1 mutation including movement disorder would be evident in the mouse model.\n\nMethods\n\nA mouse Gnao1 knock-in GOF mutation (G203R) was created by CRISPR/Cas9 methods. The resulting offspring and littermate controls were subjected to a battery of behavioral tests. A previously reported GOF mutant mouse knock-in (Gnao1+/G184S) was also studied for comparison.\n\nResults\n\nGnao1+/G203R mutant mice are viable and gain weight comparably to controls. Homozygotes are non-viable. Grip strength was decreased in both males and females. Male Gnao1+/G203R mice were strongly affected in movement assays (RotaRod and DigiGait) while females were not. Male Gnao1+/G203R mice also showed enhanced seizure propensity in the pentylenetetrazole kindling test. Mice with a G184S GOF knock-in also showed movement-related behavioral phenotypes but females were more strongly affected than males.\n\nConclusions\n\nGnao1+/G203R mice phenocopy children with heterozygous GNAO1 G203R mutations, showing both movement disorder and a relatively mild epilepsy pattern. This mouse model should be useful in mechanistic and preclinical studies of GNAO1-related movement disorders.

animal behavior and cognition↗

bioRxiv2018

Ultrasensitive capture of human herpes simplex virus genomes directly from clinical samples reveals extraordinarily limited evolution in cell culture

Herpes simplex viruses (HSV) are difficult to sequence due to their large DNA genome, high GC content, and the presence of repeats. To date, most HSV genomes have been recovered from culture isolates, raising concern that these genomes may not accurately represent circulating clinical strains. We report the development and validation of a DNA oligonucleotide hybridization panel to recover near complete HSV genomes at abundances up to 50,000-fold lower than previously reported. Using copy number information on herpesvirus and host DNA background via quantitative PCR, we developed a protocol for pooling for cost-effective recovery of more than 50 HSV-1 or HSV-2 genomes per MiSeq run. We demonstrate the ability to recover >99% of the HSV genome at >100X coverage in 72 hours at viral loads that allow whole genome recovery from latently-infected ganglia. We also report a new computational pipeline for rapid HSV genome assembly and annotation. Using the above tools and a series of 17 HSV-1-positive clinical swabs sent to our laboratory for viral isolation, we show limited evolution of HSV-1 during viral isolation in human fibroblast cells compared to the original clinical samples. Our data indicate that previous studies using low passage clinical isolates of herpes simplex viruses are reflective of the viral sequences present in the lesion and thus can be used in phylogenetic analyses. We also detect superinfection within a single sample with unrelated HSV-1 strains recovered from separate oral lesions in an immunosuppressed patient during a 2.5-week period, illustrating the power of direct-from-specimen sequencing of HSV.\n\nImportanceHerpes simplex viruses affect more than 4 billion people across the globe, constituting a large burden of disease. Understanding global diversity of herpes simplex viruses is important for diagnostics and therapeutics as well as cure research and tracking transmission among humans. To date, most HSV genomics has been performed on culture isolates and DNA swabs with high quantities of virus. We describe the development of wet-lab and computational tools that enable the accurate sequencing of near-complete genomes of HSV-1 and HSV-2 directly from clinical specimens at abundances >50,000-fold lower than previously sequenced and at significantly reduced cost. We use these tools to profile circulating HSV-1 strains in the community and illustrate limited changes to the viral genome during the viral isolation process. These techniques enable cost-effective, rapid sequencing of HSV-1 and HSV-2 genomes that will help enable improved detection, surveillance, and control of this human pathogen.

genomics↗

bioRxiv2018

In vivo Chemical Reprogramming of Astrocytes into Functional Neurons

Mammals lack robust regenerative abilities. Lost cells in impaired tissue could potentially be compensated by converting nearby cells in situ through in vivo reprogramming. Small molecule-induced reprogramming is a spatiotemporally flexible and non-integrative strategy for altering cell fate, which is, in principle, favorable for the in vivo reprogramming in organs with poor regenerative abilities, such as the brain. Here, we demonstrate that in the adult mouse brain, small molecules can reprogram resident astrocytes into functional neurons. The in situ chemically induced neurons (CiNs) resemble endogenous neurons in terms of neuron-specific marker expression and electrophysiological properties. Importantly, these CiNs can integrate into the mouse brain. Our study, for the first time, demonstrates in vivo chemical reprogramming in the adult brain, which could be a novel path for generating desired cells in situ for regenerative medicine.

cell biology↗