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Optimized inner ear organoids for efficient hair cell generation and ototoxicity response modeling

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Science China life Sciences 2025年

作者： Xuanhe Qin Liping Fu Chunying Li Xilin Tan Xiaolei Yin Institute for Regenerative Medicine State Key Laboratory of Cardiology and Medical Innovation CenterShanghai East HospitalFrontier Science Center for Stem Cell ResearchSchool of Life Sciences and TechnologyTongji University

Hair cells in the mammalian cochlea are highly vulnerable to damage from drug toxicity,noise exposure,aging,and genetic mutations,with no capacity for *** in hair cell protection research has been limited by the scarcity of cochlear tissue and suitable in vitro ***,we present a novel one-step,self-organizing inner ear organoid system optimized with small molecules,which bypasses the need for multi-step expansion and forced differentiation *** approach efficiently generates hair cells and supporting cells that recapitulate the molecular,cellular,and structural characteristics of the inner ***-cell RNA sequencing revealed the diversity and fidelity of cell populations within the *** this platform,we validated the protective effects of candidate compounds against hair cell damage,highlighting its potential as a powerful tool for drug discovery and mechanistic studies of hair cell protection.

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Altered 3D genome reorganization mediates precocious myeloid differentiation of aged hematopoietic stem cells in inflammation

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Science China life Sciences 2025年

作者： Xinyu Cui Yu Dong Qiang Zhan Yixin Huang Qianshu Zhu Zihao Zhang Guang Yang Liping Wang Shijun Shen Jia Zhao Zhiyi Lin Jiatong Sun Zhongqu Su Yihan Xiao Chuyu Zhang Yuwei Liang Lu Shen Lichen Ji Xuguang Zhang Jiqing Yin Hong Wang Zhiyang Chen Zhenyu Ju Cizhong Jiang Rongrong Le Shaorong Gao Clinical and Translational Research center of Shanghai First Maternity & Infant Hospital Frontier Science Center for Stem Cells School of Life Sciences and Technology Tongji University Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education Orthopaedic Department of Tongji Hospital School of Life Sciences and Technology Tongji University Key Laboratory of Regenerative Medicine of Ministry of Education Institute of Aging and Regenerative Medicine Department of Developmental & Regenerative Medicine College of Life Science and Technology Jinan University Shandong Key Laboratory of Animal Bioengineering and Disease Prevention College of Animal Science and Technology Shandong Agricultural University Department of Joint Surgery Shanghai East Hospital Tongji University School of Medicine Shanghai Institute of Nutrition and Health Chinese Academy of Sciences

Inflammation is a driving force of hematopoietic stem cells(HSCs) aging, causing irreversible exhaustion of functional HSCs. However, the underlying mechanism of HSCs erosion by inflammatory insult remains poorly understood. Here, we find that transient LPS exposure primes aged HSCs to undergo accelerated differentiation at the expense of self-renewal, leading to depletion of HSCs. Meanwhile, the central regulator nuclear factor kappa B(NF-κB) mediating functional impairment by inflammation insult induces differential transcriptional response in aged HSCs compared with young HSCs, with precocious activation of myeloid lineage genes. Altered compartmentalization and chromatin loop formation are associated with aging-related differential transcriptional response in HSCs upon lipopolysaccharide(LPS)stimulation. Mechanistically, enhancer and promoter regions of myeloid lineage genes in aged HSCs are more accessible and display more rapid and prominent CTCF occupancy upon LPS stimulation. Our study provides comprehensive resources for the three-dimensional(3D)genome structure of HSCs and sheds light into the ordered genome organization and the associated transcriptome signature underlying HSCs aging.

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Gender and Race Differences in Mental Health and Well-Being Among Older Americans During the COVID-19 Pandemic

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International Journal of Disaster Risk Science 2024年第2期15卷 239-250页

作者： Dongjuan Xu Nasreen Lalani Yitong Wang School of Nursing Purdue UniversityWest LafayetteIN 47907USA center on aging and the life course Purdue UniversityWest LafayetteIN 47907USA

The objectives of this study were to investigate(1) gender and race differences in mental health and psychological wellbeing among older adults during the COVID-19 pandemic and(2) whether there were significant interaction effects between gender and race. This study used the National Health and aging Trends Study(NHATS) and COVID-19 public use data files. It focused on mental health and psychological well-being, including loneliness, no time to yourself, poor sleep quality, anxiety, depression, and post-traumatic stress disorder(PTSD). The sample consisted of 2465 older adults, and multivariate logistic and linear regression models were adopted for the analysis. The results show that approximately two out of five older people(43%) experienced poor sleep, followed by loneliness(35%), anxiety(30%), depression(23%), and no time to themselves(11%). The average PTSD score was 11. Mental health and psychological well-being varied by gender and race. There were significant interaction effects on anxiety and depression between females and Black older adults. Black females reported lower levels of anxiety and depressive symptoms than Black males, although the differences were not statistically significant. Black older adults were more likely to experience PTSD but less likely to feel lonely and have poorer sleep than their White counterparts. Female older adults reported poorer mental health and psychological well-being than males, except for Black females. Black females had the lowest levels of anxiety, depression, loneliness, and highest quality of sleep among all females of different ethnic and racial origins.

关键词： COVID-19 Gender Mental health Older adults Psychological well-being Race and ethnicity United States

Single-cell technologies: current and near future

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Science China(life Sciences) 2025年第1期68卷 1-4页

作者： Chenfei Wang Qi Liu Xiaohui Fan Tieliu Shi KeyLaboratory of Spine and Spinal CordInjury Repairand Regeneration Ministry of EducationOrthopedics DepartmentTongji HospitalBioinformatics DepartmentSchoolofLifeSciencesandTechnologyTongji UniversityShanghai 200082China Frontier Science center for Stem Cells School of Life Sciences and TechnologyTongji UniversityShanghai 200092China Translational Medical center for Stem Cell Therapy and Institute for Regenerative Medicine Shanghai East HospitalBioinformatics DepartmentSchool of Life Sciences and TechnologyTongji UniversityShanghai 200082China Research Institute of Intelligent Computing Zhejiang LabHangzhou 311121China Pharmaceutical Informatics Institute College of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China National Key Laboratory of Chinese Medicine Modernization Innovation Center of Yangtze River DeltaZhejiang UniversityJiaxing 314103China center for Bioinformatics and Computational Biology Shanghai Key Laboratory of Regulatory Biologythe Institute of Biomedical Sciences and School of Life SciencesEast China Normal UniversityShanghai 200241China Key Laboratory of Advanced Theory and Application in Statistics and Data Science(MOE) School of StatisticsEast China Normal UniversityShanghai 200062China

Single-cell technologies enable the indepth exploration of multiple biological hierarchies at the scale of individual cells,which have deepened our knowledge of cellular diversity,tissue organization,and overall organism function(Sun et al.,2024).In 2009,single-cell RNA sequencing(scRNA-seq)was first developed as a powerful tool to dissect gene expression and uncover transcriptional *** the rapid advancement of technology,single-cell approaches have expanded to encompass other omics,such as genomics,epigenomics,proteomics,and ***,multimodal technologies including spatially resolved transcriptomics and clustered regularly interspaced short palindromic repeats(CRISPR)screening at the single-cell level further advanced our ability to comprehensively understand cellular ***-cell methods provide deeper insights into disease mechanisms across various conditions,including cancer,developmental disorders,and aging-associated *** this issue,we focus on topics related to single-cell methods,covering the following four aspects:(i)single-cell multi-omic sequencing technology;(ii)single-cell spatial technology;(iii)singlecell CRISPR screening technology;(iv)applications of single-cell technology.

关键词： expanded enable insight

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Tauroursodeoxycholic acid targets HSP90 to promote protein homeostasis and extends healthy lifespan

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Science China(life Sciences) 2025年第2期68卷 416-430页

作者： Jia-Yu Liu Yao Wang Yue Guo Run-Qi Zheng Yun-Ying Wang Yan-Yan Shen Yan-Hong Liu Ai-Ping Cao Rui-Bo Wang Bo-Yang Xie Shuai Jiang Qiu-Ying Han Jing Chen Fang-Ting Dong Kun He Na Wang Xin Pan Tao Li Tao Zhou Ai-Ling Li Qing Xia Wei-Na Zhang Nanhu Laboratory National Center of Biomedical AnalysisBeijing 100850China

As the elderly population expands,the pursuit of therapeutics to reduce morbidity and extend lifespan has become increasingly *** an FDA-approved drug for chronic cholestatic liver diseases,tauroursodeoxycholic acid(TUDCA),a natural bile acid,offers additional health benefits beyond liver ***,we show that TUDCA extends the lifespan and healthspan of ***,oral supplementation of TUDCA improves fitness in old mice,including clinically relevant phenotypes,exercise capacity and cognitive ***,TUDCA treatment drives broad transcriptional changes correlated with anti-aging ***,we discover that TUDCA targets the chaperone HSP90 to promote its protein refolding *** collaboration further alleviates aging-induced endoplasmic reticulum(ER)stress and facilitates protein homeostasis,thus offering resistance to *** summary,our findings uncover new molecular links between an endogenous metabolite and protein homeostasis,and propose a novel anti-aging strategy that could improve both lifespan and healthspan.

关键词： tauroursodeoxycholic acid lifespan healthspan protein homeostasis

Neuroprotective effects of human bone marrow mesenchymal stem cells against cerebral ischemia are mediated in part by an anti-apoptotic mechanism

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Neural Regeneration Research 2019年第4期14卷 597-604页

作者： Yuyang Zhang Seongjin Yu Julian P.Tuazon Jea-Young Lee Sydney Corey Lauren Kvederis Chase Kingsbury Yuji Kaneko Cesar V.Borlongan Department of Neurosurgery and Brain Repair Center of Excellence for Aging and Brain Repair University of South Florida Department of Pharmacology/School of life Science and Biopharmaceutical Science Shenyang Pharmaceutical University

Transplantation of human bone marrow mesenchymal stem cells(hMSCs) stands as a potent stroke therapy, but its exact mechanism remains unknown. This study investigated the anti-apoptotic mechanisms by which hMSCs exert neuroprotective effects on cerebral ischemia. Primary mixed cultures of rat neurons and astrocytes were cultured and exposed to oxygen-glucose deprivation. A two-hour period of "reperfusion" in standard medium and normoxic conditions was allowed and immediately followed by hMSCs and/or Bcl-2 antibody treatment. Cell viability of primary rat neurons and astrocytes was determined by 3-(4,5-dimethylthianol-2-yl)-2,5 diphenyl tetrazolium bromide and trypan blue exclusion methods. hMSC survival and differentiation were characterized by immunocytochemistry, while the concentration of Bcl-2 in the supernatant was measured by enzyme-linked immunosorbent assay to reveal the secretory anti-apoptotic function of hMSCs. Cultured hMSCs expressed embryonic-like stem cell phenotypic markers CXCR4, Oct4, SSEA4, and Nanog, as well as immature neural phenotypic marker Nestin. Primary rat neurons and astrocytes were protected from oxygen-glucose deprivation by hMSCs, which was antagonized by the Bcl-2 antibody. However, Bcl-2 levels in the supernatants did not differ between hMSCand non-treated cells exposed to oxygen-glucose deprivation. Neuroprotective effects of hMSCs against cerebral ischemia were partially mediated by the anti-apoptotic mechanisms. However, further studies are warranted to fully elucidate this pathway.

关键词： apoptosis Bcl-2 antibody human mesenchymal stem cells ischemia neuroprotection oxygen glucose deprivation

REVA as A Well-curated Database for Human Expressionmodulating Variants

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Genomics, Proteomics & Bioinformatics 2021年第4期19卷 590-601页

作者： Yu Wang Fang-Yuan Shi Yu Liang Ge Gao State Key Laboratory of Protein and Plant Gene Research School of Life SciencesBiomedical Pioneering Innovation Center(BIOPIC)&Beijing Advanced Innovation Center for Genomics(ICG)Center for Bioinformatics(CBI)Peking UniversityBeijing 100871China Human aging Research Institute School of Life SciencesNanchang UniversityNanchang 330031.China

More than 90%of disease-and trait-associated human variants are *** systematically screening multiple large-scale studies,we compiled REVA,a manually curated database for over 11.8 million experimentally tested noncoding variants with expression-modulating *** provided 2424 functional annotations that could be used to pinpoint the plausible regulatory mechanism of these *** further benchmarked multiple state-of-the-art computational tools and found that their limited sensitivity remains a serious challenge for effective large-scale *** provides high-quality experimentally tested expression-modulating variants with extensive functional annotations,which will be useful for users in the noncoding variant *** is freely available at http://***.

关键词： Noncoding variant Expression-modulating variant Massively parallel reporter assay Database Benchmark

OTOTOXIC EFFECTS OF CARBOPLATIN IN ORGANOTYPIC CULTURES IN CHINCHILLAS AND RATS

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Journal of Otology 2012年第2期7卷 92-101页

作者： DING Dalian JIANG Haiyan FU Yong Richard SALVI Shinichi SOMEYA Masaru TANOKURA center for Hearing and Deafness State University of New York at Buffalo Graduate School of Agricultural and life Sciences University of Tokyo Departments of aging and Geriatric Research Division of Biology of Aging University of Florida

Carboplatin, a second-generation platinum chemotherapeutic drug, is considerably less ototoxic than cisplatin. While common laboratory species such as mice, guinea pigs and rats are highly resistant to carboplatin ototoxicity, the chinchilla stands out as highly susceptible. Moreover, carboplatin causes an unusual gradient of cell death in chinchillas. Moderate doses selectively damage type I spiral ganglion neurons (SGN) and inner hair cells (IHC) and the lesion tends to be relatively uniform along the length of the cochlea. Higher doses eventually damage outer hair cells (OHC), but the lesion follows the traditional gradient in which damage is more severe in the base than the apex. While carboplatin ototoxicity has been well documented in adult animals in vivo, little is known about its in vitro toxicity. To elucidate the ototoxic effects of carboplatin in vitro, we prepared cochlear and vestibular organotypic cultures from postnatal day 3 rats and adult chinchillas. Chinchilla cochlear and vestibular cultures were treated with carboplatin concentrations ranging from 50 μM to 10 mM for 48 h. Consistent with in vivo data, carboplatin selectively damaged IHC at low concentrations (50-100 μM). Surprisingly, IHC loss decreased at higher doses and IHC were intact at doses exceeding 500 μM. The mechanisms underlying this nonlinear response are unclear but could be related to a decrease in carboplatin uptake via active transport mechanisms (e.g., copper). Unlike the cochlea, the carboplatin dose-response function increased with dose with the highest dose destroying all chinchilla vestibular hair cells. Cochlear hair cells and auditory nerve fibers in rat cochlear organotypic cultures were unaffected by carboplatin concentrations <10 μM; however, the damage in OHC were more severe than IHC once the dose reached 100 μM. A dose at 500 μM destroyed all the cochlear hair cells, but hair cell loss decreased at high concentrations and nearly all the cochlear hair cells were pre

关键词： Carboplatin ototoxicity organotypic culture

Skeletal muscle-specific Bambi deletion induces hypertrophy and oxidative switching coupling with adipocyte thermogenesis against metabolic disorders

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Science China life Sciences 2025年

作者： Xiangping Yao Xudong Mai Ye Tian Yifan Liu Guanghui Jin Ze Li Shujie Chen Xiaoshuang Dai Liujing Huang Zijing Fan Guihua Pan Xiaohan Pan Xiangmin Li Michael C Yu Jia Sun Jingxing Ou Hong Chen Liwei Xie College of life and Health Sciences Guangdong Industry Polytechnic Department of Endocrinology and Metabolism Zhujiang Hospital Southern Medical University State Key Laboratory of Applied Microbiology Southern China Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application Guangdong Open Laboratory of Applied MicrobiologyInstitute of Microbiology Guangdong Academy of Sciences Institute of aging Research Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics School of Medical Technology Guangdong Medical University Department of Hepatic Surgery and Liver transplantation center of the Third Affiliated Hospital Organ Transplantation Institute Sun Yat-sen University Organ Transplantation Research Center of Guangdong ProvinceGuangdong province engineering laboratory for transplantation medicine Guangdong Provincial Key Laboratory of Liver Disease Research School of Public Health Xinxiang Medical University BGI Institute of Applied Agriculture BGI-Shenzhen Department of Applied Biology and Chemical Technology The Hong Kong Polytechnic University Department of Biological Sciences State University of New York at Buffalo Department of Internal Medicine Shunde Women and Children's Hospital (Maternity and Child Healthcare Hospital of Shunde Foshan) Guangdong Medical University

Skeletal muscle plays a significant role in both local and systemic energy metabolism. The current investigation aims to explore the role of the Bambi gene in skeletal muscle, focusing on its implications for muscle hypertrophy and systemic metabolism. We hypothesize that skeletal muscle-specific deletion of Bambi induces muscle hypertrophy, improves metabolic performance, and activates thermogenic adipocytes via the reprogramming of progenitor of i WAT, offering potential therapeutic strategies for metabolic syndromes. Leveraging the Chromatin immunoprecipitation(ChIP)-seq and bioinformatics analysis, Bambi gene is shown to be a direct target of HIF2α, which is further confirmed by ChIP-qPCR and promoter luciferase assay. Skeletal muscle-specific Bambi deletion led to significant muscle hypertrophy and improved metabolic parameters, even under high-fat diet conditions. This deletion induced metabolic reprogramming of stromal vascular fractions(SVFs) into thermogenic adipocytes, contributing to systemic metabolic improvements, potentially through the secretory ***, mice with skeletal muscle-specific Bambi deletion demonstrate resistance to high-fat diet-induced metabolic disorders, highlighting a potential therapeutic pathway for metabolic syndrome management. Thus, skeletal muscle-specific deletion of Bambi triggers muscle growth, enhances metabolic performance, and activates thermogenic adipocytes. These findings suggest Bambi as a novel therapeutic target for metabolic syndromes, providing new insights into the interaction between muscle hypertrophy and systemic metabolic improvement. The study underscores the potential of manipulating muscle physiology to regulate whole-body metabolism, offering a novel perspective on treating metabolic disorders.

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