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Engineered stem cells by emerging biomedical stratagems

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Science Bulletin 2024年第2期69卷 248-279页

作者： Jinglin Wang Xiaoxuan Zhang Hanxu Chen Haozhen Ren Min Zhou Yuanjin Zhao Department of Vascular Surgery.Nanjing Drum Tower hospital Affliated Hospital of Medical SchoolNanjing UniversityNanjing 210008China Division of Hepatobiliary Surgery and Transplantation Surgery Department of General SurgeryNanjing Drum Tower HospitalSchool of Biological Science and Medical EngineeringSoutheast UniversityNanjing 210096China Shenzhen research institute Southeast UniversityShenzhen 518038China

Stem cell therapy holds immense potential as a viable treatment for a widespread range of intractable disorders.As the safety of stem cell transplantation having been demonstrated in numerous clinical trials,various kinds of stem cells are currently utilized in medical applications.Despite the achievements,the therapeutic benefits of stem cells for diseases are limited,and the data of clinical researches are unstable.To optimize tthe effectiveness of stem cells,engineering approaches have been developed to enhance their inherent abilities and impart them with new functionalities,paving the way for the next generation of stem cell therapies.This review offers a detailed analysis of engineered stem cells,including their clinical applications and potential for future development.We begin by briefly introducing the recent advances in the production of stem cells(induced pluripotent stem cells(ipsCs),embryonic stem cells(ESCs),mesenchymal stem cells(MSCs)and hematopoietic stem cells(HSCs).Furthermore,we present the latest developments of engineered strategies in stem cells,including engineered methods in molecular biology and biomaterial fields,and their application in biomedical research.Finally,we summarize the current obstacles and suggest future prospects for engineered stem cells in clinical translations and biomedical applications.

关键词： Stem cells Genetic modification Biomaterials Microfluidics Organ-on-a-chip Bioprinting

AKT2^(S128)/CCTα^(S315/319/323)-positive cancer-associated fibroblasts (CAFs) mediate focal adhesion kinase (FAK) inhibitors resistance via secreting phosphatidylcholines (PCs)

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Signal Transduction and Targeted Therapy 2024年第2期9卷 782-796页

作者： Jie Chen Lingyuan Zhang Yuheng Zhu Di Zhao Jing Zhang Yanmeng Zhu Jingyuan Pang Yuanfan Xiao Qingnan Wu Yan Wang Qimin Zhan Key Laboratory of Carcinogenesis and Translational research(Ministry of Education/Beijing) Laboratory of Molecular OncologyPeking University Cancer Hospital&Institute100142 BeijingChina Peking University International Cancer institute Peking University100191 BeijingChina research Unit of Molecular Cancer research Chinese Academy of Medical SciencesBeijingChina Soochow University Cancer institute Suzhou 215000China institute of Cancer research Shenzhen Bay LaboratoryShenzhen 518107China

Abnormal metabolism is regarded as an oncogenic hallmark related to tumor progression and therapeutic resistance.Present study employed multi-omics,including phosphoproteomics,untargeted metabolomics and lipidomics,to demonstrate that the pAKT2 Ser128 and pCCTαSer315/319/323-positive cancer-associated fibroblasts(CAFs)substantially release phosphatidylcholines(PCs),contributing to the resistance of focal adhesion kinase(FAK)inhibitors in esophageal squamous cell carcinoma(ESCC)treatment.Additionally,we observed extremely low levels of FAK Tyr397 expression in CAFs,potentially offering no available target for FAK inhibitors playing their anti-growth role in CAFs.Consequently,FAK inhibitor increased the intracellular concentration of Ca2+in CAFs,promoting the formation of AKT2/CCTαcomplex,leading to phosphorylation of CCTαSer315/319/323 sites and eventually enhancing stromal PC production.This activation could stimulate the intratumoral Janus kinase 2(JAK2)/Signal transducer and activator of transcription 3(STAT3)pathway,triggering resistance to FAK inhibition.Analysis of clinical samples demonstrated that stromal pAKT2 Ser128 and pCCTαSer315/319/323 are related to the tumor malignancy and reduced patient survival.Pseudo-targeted lipidomics and further validation cohort quantitatively showed that plasma PCs enable to distinguish the malignant extent of ESCC patients.In conclusion,inhibition of stroma-derived PCs and related pathway could be possible therapeutic strategies for tumor therapy.

关键词： CAFs metabolism resistance

Neuroprotective effects of chaperone-mediated autophagy in neurodegenerative diseases

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Neural Regeneration research 2024年第6期19卷 1291-1298页

作者： Qi Jia Jin Li Xiaofeng Guo Yi Li You Wu Yuliang Peng Zongping Fang Xijing Zhang Department of Anesthesiology and Perioperative Medicine and Department of Intensive Care Unit Xijing Hospital The Fourth Military Medical University Department of Critical Care Medicine Translational research institute of Brain and Brain-Like Intelligence Shanghai Fourth People's Hospital School of Medicine Tongji University

Chaperone-mediated autophagy is one of three types of autophagy and is characterized by the selective degradation of proteins. Chaperone-mediated autophagy contributes to energy balance and helps maintain cellular homeostasis, while providing nutrients and support for cell survival. Chaperone-mediated autophagy activity can be detected in almost all cells, including neurons. Owing to the extreme sensitivity of neurons to their environmental changes, maintaining neuronal homeostasis is critical for neuronal growth and survival. Chaperone-mediated autophagy dysfunction is closely related to central nervous system diseases. It has been shown that neuronal damage and cell death are accompanied by chaperone-mediated autophagy dysfunction. Under certain conditions, regulation of chaperone-mediated autophagy activity attenuates neurotoxicity. In this paper, we review the changes in chaperone-mediated autophagy in neurodegenerative diseases, brain injury, glioma, and autoimmune diseases. We also summarize the most recent research progress on chaperone-mediated autophagy regulation and discuss the potential of chaperone-mediated autophagy as a therapeutic target for central nervous system diseases.

关键词： chaperone-mediated autophagy neurodegenerative disease neuronal homeostasis neuroprotection

Unveiling DNA methylation in Alzheimer’s disease:a review of array-based human brain studies

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Neural Regeneration research 2024年第11期19卷 2365-2376页

作者： Victoria Cunha Alves Eva Carro Joana Figueiro-Silva Neurodegenerative Diseases Group Hospital Universitario 12 de Octubre Research Institute(imas12)MadridSpain Network Center for Biomedical research Neurodegenerative Diseases(CIBERNED)MadridSpain PhD Program in Neuroscience Autonoma de Madrid UniversityMadridSpain Neurotraumatology and Subarachnoid Hemorrhage Group Hospital Universitario 12 de Octubre Research Institute(imas12)MadridSpain Neurobiology of Alzheimer’s Disease Unit Functional Unit for Research Into Chronic DiseasesInstituto de Salud Carlos IIIMadridSpain institute of Medical Genetics University of ZurichZurichSwitzerland Department of Molecular Life Science University of ZurichZurichSwitzerland

The intricacies of Alzheimer’s disease pathogenesis are being increasingly illuminated by the exploration of epigenetic mechanisms,particularly DNA methylation.This review comprehensively surveys recent human-centered studies that investigate whole genome DNA methylation in Alzheimer’s disease neuropathology.The examination of various brain regions reveals distinctive DNA methylation patterns that associate with the Braak stage and Alzheimer’s disease progression.The entorhinal cortex emerges as a focal point due to its early histological alterations and subsequent impact on downstream regions like the hippocampus.Notably,ANK1 hypermethylation,a protein implicated in neurofibrillary tangle formation,was recurrently identified in the entorhinal cortex.Further,the middle temporal gyrus and prefrontal cortex were shown to exhibit significant hypermethylation of genes like HOXA3,RHBDF2,and MCF2L,potentially influencing neuroinflammatory processes.The complex role of BIN1 in late-onset Alzheimer’s disease is underscored by its association with altered methylation patterns.Despite the disparities across studies,these findings highlight the intricate interplay between epigenetic modifications and Alzheimer’s disease pathology.Future research efforts should address methodological variations,incorporate diverse cohorts,and consider environmental factors to unravel the nuanced epigenetic landscape underlying Alzheimer’s disease progression.

关键词： Alzheimer’s disease ANK1 BIN1 DNA methylation epigenome-wide association studies HOXA3 MCF2L RHBDF2

Characteristics and quality of clinical practice guidelines for diabetic kidney disease: a systematic review

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Journal of Traditional Chinese Medicine 2024年第3期44卷 609-619页

作者： WANG Yuhuang ZHANG Le ZHANG Zhengshan YAO Zhi LI Xiyao SUN Luying LIAO Xing Department of Nephropathy and Endocrine Dongzhimen HospitalBeijing University of Chinese Medicine Centre for Evidence-Based Chinese Medicine Institute of Basic Research in Clinical MedicineChina Academy of Chinese Medical Sciences Department of Endocrine One Zone Fangshan HospitalBeijing University of Chinese Medicine

OBJECTIVE: To assess the quality of Clinical practice guidelines(CPGs) in the context of diabetic kidney disease(DKD) and determine whether any factors affect the quality. METHODS: We searched eight databases along with five international and national organizations to develop or archive guidelines from their inception to July 2023, with an additional search of ***. And the authoritative organizations related to nephrology. CPGs and consensus statements created using direct differential diagnosis or therapy for DKD were included without language restrictions. Their quality was evaluated by four reviewers using the Appraisal of Guidelines for research and Evaluation Ⅱ(AGREE Ⅱ) instrument. Along with the item and domain scores, the guideline was also allocated an overall quality score, which ranged from 1(lowest possible quality) to 7(highest possible quality). Moreover, an overall recommendation for use was also assigned(“recommended”, “recommended with modifications” or “not recommended”). RESULTS: A total of 16 CPGs were included, of which 14 were from Asia and the remaining two from Europe. These two CPGs were updated in the third version. Six CPGs were recommended for use because their primary domains scored in the medium or high category. Furthermore, five CPGs were recommended with modifications as the stakeholder involvement, applicability, and editorial independence domains were evaluated as low categories. In all domains, the lowest average score was for rigour of development(33%), followed by application(36%), and stakeholder involvement(51%). The highest average score was for scope and purpose(79%), followed by clarity of presentation(75%). None of the CPGs considered the patient's viewpoint, and six of 16 CPGs did not use any grading system to translate the evidence into recommendations. Additionally, only three of 16 CPGs shared search strategy, and eight of 16 CPGs did not declare a funding source. CONCLUSIONS: According to the AGREE II evaluation, more than one in four CPGs for DKD had poor methodolo

关键词： appraisal of guidelines for research and evaluation II diabetic nephropathies practice guideline quality assessment systematic review

Association of cardiometabolic multimorbidity with all-cause and cardiovascular disease mortality among Chinese hypertensive patients

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Journal of Geriatric Cardiology 2024年第2期21卷 211-218页

作者： Luo-Xi XIAO Zi-Yu WANG Jiang-Tao LI Hai-Mei WANG Yi-Ming HAO Pan ZHOU Yu-Lin HUANG Qiu-Ju DENG Yong-Chen HAO Na YANG Li-Zhen HAN Zhao YANG Ping-Ping JIA Yue QI Jing LIU Center for Clinical and Epidemiologic research Beijing Anzhen HospitalCapital Medical UniversityBeijing Institute of HeartLung and Blood Vessel DiseasesBeijing Municipal Key Laboratory of Clinical EpidemiologyBeijingChina

BACKGROUND Hypertension usually clusters with multiple comorbidities.However,the association between cardiometabolic multimorbidity(CMM)and mortality in hypertensive patients is unclear.This study aimed to investigate the association between CMM and all-cause and cardiovascular disease(CVD)mortality in Chinese patients with hypertension.METHODS The data used in this study were from the China National Survey for Determinants of Detection and Treatment Status of Hypertensive Patients with Multiple Risk Factors(CONSIDER),which comprised 5006 participants aged 19–91 years.CMM was defined as the presence of one or more of the following morbidities:diabetes mellitus,dyslipidemia,chronic kidney disease,coronary heart disease,and stroke.Cox proportional hazard models were used to calculate the hazard ratios(HR)with 95%CI to determine the association between the number of CMMs and both all-cause and CVD mortality.RESULTS Among 5006 participants[mean age:58.6±10.4 years,50%women(2509 participants)],76.4%of participants had at least one comorbidity.The mortality rate was 4.57,4.76,8.48,and 16.04 deaths per 1000 person-years in hypertensive patients without any comorbidity and with one,two,and three or more morbidities,respectively.In the fully adjusted model,hypertensive participants with two cardiometabolic diseases(HR=1.52,95%CI:1.09–2.13)and those with three or more cardiometabolic diseases(HR=2.44,95%CI:1.71–3.48)had a significantly elevated risk of all-cause mortality.The findings were similar for CVD mortality but with a greater increase in risk magnitude.CONCLUSIONS In this study,three-fourths of hypertensive patients had CMM.Clustering with two or more comorbidities was associated with a significant increase in the risk of all-cause and cardiovascular mortality among hypertensive patients,suggesting more intensive treatment and control in this high-risk patient group.

关键词： hypertensive patients morbidity

Current assessment and management of measurable residual disease in patients with acute lymphoblastic leukemia in the setting of CAR-T-cell therapy

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Chinese Medical Journal 2024年第2期137卷 140-151页

作者： Minghao Lin Xiaosu Zhao Yingjun Chang Xiangyu Zhao Peking University People’s hospital Peking University Institute of HematologyNational Clinical Research Center for Hematologic DiseaseBeijing Key Laboratory of Hematopoietic Stem Cell TransplantationBeijing 100044China

Chimeric antigen receptor(CAR)-modified T-cell therapy has achieved remarkable success in the treatment of acute lymphoblastic leukemia(ALL).Measurable/minimal residual disease(MRD)monitoring plays a significant role in the prognostication and management of patients undergoing CAR-T-cell therapy.Common MRD detection methods include flow cytometry(FCM),polymerase chain reaction(PCR),and next-generation sequencing(NGS),and each method has advantages and limitations.It has been well documented that MRD positivity predicts a poor prognosis and even disease relapse.Thus,how to perform prognostic evaluations,stratify risk based on MRD status,and apply MRD monitoring to guide individual therapeutic decisions have important implications in clinical practice.This review assesses the common and novel MRD assessment methods.In addition,we emphasize the critical role of MRD as a prognostic biomarker and summarize the latest studies regarding MRD-directed combination therapy with CAR-T-cell therapy and allogeneic hematopoietic stem cell transplantation(allo-HSCT),as well as other therapeutic strategies to improve treatment effect.Furthermore,this review discusses current challenges and strategies for MRD detection in the setting of disease relapse after targeted therapy.

关键词： Measurable/minimal residual disease Acute lymphoblastic leukemia Chimeric antigen receptor-modified T-cell therapy Allogeneic hematopoietic stem cell transplantation Relapse

Optimal transcorneal electrical stimulation parameters for preserving photoreceptors in a mouse model of retinitis pigmentosa

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Neural Regeneration research 2024年第11期19卷 2543-2552页

作者： Sam Enayati Karen Chang Anton Lennikov Menglu Yang Cherin Lee Ajay Ashok Farris Elzaridi Christina Yen Kasim Gunes Jia Xie Kin-Sang Cho Tor Paaske Utheim Dong Feng Chen Schepens Eye research institute of Massachusetts Eye and Ear Department of OphthalmologyHarvard Medical SchoolBostonMAUSA institute of clinical medicine Faculty of MedicineUniversity of OsloOsloNorway Department of Medical Biochemistry Oslo University HospitalUniversity of OsloOsloNorway Department of Ophthalmology Drammen HospitalVestre Viken Hospital TrustDrammenNorway Department of Histology and Embryology School of MedicineMarmara UniversityIstanbulTurkiye

Retinitis pigmentosa is a hereditary retinal disease that affects rod and cone photoreceptors,leading to progressive photoreceptor loss.Previous research supports the beneficial effect of electrical stimulation on photoreceptor survival.This study aims to identify the most effective electrical stimulation parameters and functional advantages of transcorneal electrical stimulation(tcES)in mice affected by inherited retinal degeneration.Additionally,the study seeked to analyze the electric field that reaches the retina in both eyes in mice and post-mortem humans.In this study,we recorded waveforms and voltages directed to the retina during transcorneal electrical stimulation in C57BL/6J mice using an intraocular needle probe with rectangular,sine,and ramp waveforms.To investigate the functional effects of electrical stimulation on photoreceptors,we used human retinal explant cultures and rhodopsin knockout(Rho^(-/-))mice,demonstrating progressive photoreceptor degeneration with age.Human retinal explants isolated from the donors’eyes were then subjected to electrical stimulation and cultured for 48 hours to simulate the neurodegenerative environment in vitro.Photoreceptor density was evaluated by rhodopsin immunolabeling.In vivo Rho^(-/-)mice were subjected to two 5-day series of daily transcorneal electrical stimulation using rectangular and ramp waveforms.Retinal function and visual perception of mice were evaluated by electroretinography and optomotor response(OMR),respectively.Immunolabeling was used to assess the morphological and biochemical changes of the photoreceptor and bipolar cells in mouse retinas.Oscilloscope recordings indicated effective delivery of rectangular,sine,and ramp waveforms to the retina by transcorneal electrical stimulation,of which the ramp waveform required the lowest voltage.Evaluation of the total conductive resistance of the post-mortem human compared to the mouse eyes indicated higher cornea-to-retina resistance in human eyes.The temperature recordings during and after electrical

关键词： bipolar cells electrical stimulation neuroprotection photoreceptor degeneration retina retinal explants retinitis pigmentosa transcorneal electrical stimulation waveform

Cell softness reveals tumorigenic potential via ITGB8/AKT/glycolysis signaling in a mice model of orthotopic bladder cancer

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Chinese Medical Journal 2024年第2期137卷 209-221页

作者： Shi Qiu Yaqi Qiu Linghui Deng Ling Nie Liming Ge Xiaonan Zheng Di Jin Kun Jin Xianghong Zhou Xingyang Su Boyu Cai Jiakun Li Xiang Tu Lina Gong Liangren Liu Zhenhua Liu Yige Bao Jianzhong Ai Tianhai Lin Lu Yang Qiang Wei Department of Urology Institute of UrologyNational Clinical Research Center for Geriatrics and Center of Biomedical Big DataWest China Hospital of Sichuan UniversityChengduSichuan 610041China Department of Molecular Oncology Institute of Oncology Research(IOR)Oncology Institute of Southern Switzerland(IOSI)Bellinzona 6500Switzerland Department of Science and Drug Technology University of TurinTurinItaly National Clinical research Center of Geriatrics The Center of Gerontology and GeriatricsWest China HospitalSichuan UniversityChengduSichuan 610000China Department of Pathology West China HospitalSichuan UniversityChengduSichuan 610041China Department of Pharmaceutics and Bioengineering School of Chemical EngineeringSichuan UniversityChengduSichuan 610000China

Background:Bladder cancer,characterized by a high potential of tumor recurrence,has high lifelong monitoring and treatment costs.To date,tumor cells with intrinsic softness have been identified to function as cancer stem cells in several cancer types.Nonetheless,the existence of soft tumor cells in bladder tumors remains elusive.Thus,our study aimed to develop a microbarrier microfluidic chip to efficiently isolate deformable tumor cells from distinct types of bladder cancer cells.Methods:The stiffness of bladder cancer cells was determined by atomic force microscopy(AFM).The modified microfluidic chip was utilized to separate soft cells,and the 3D Matrigel culture system was to maintain the softness of tumor cells.Expression patterns of integrinβ8(ITGB8),protein kinase B(AKT),and mammalian target of rapamycin(mTOR)were determined by Western blotting.Double immunostaining was conducted to examine the interaction between F-actin and tripartite motif containing 59(TRIM59).The stem-cell-like characteristics of soft cells were explored by colony formation assay and in vivo studies upon xenografted tumor models.Results:Using our newly designed microfluidic approach,we identified a small fraction of soft tumor cells in bladder cancer cells.More importantly,the existence of soft tumor cells was confirmed in clinical human bladder cancer specimens,in which the number of soft tumor cells was associated with tumor relapse.Furthermore,we demonstrated that the biomechanical stimuli arising from 3D Matrigel activated the F-actin/ITGB8/TRIM59/AKT/mTOR/glycolysis pathways to enhance the softness and tumorigenic capacity of tumor cells.Simultaneously,we detected a remarkable up-regulation in ITGB8,TRIM59,and phospho-AKT in clinical bladder recurrent tumors compared with their non-recurrent counterparts.Conclusions:The ITGB8/TRIM59/AKT/mTOR/glycolysis axis plays a crucial role in modulating tumor softness and stemness.Meanwhile,the soft tumor cells become more sensitive to chemotherapy after stiffening,that offers new insights fo

关键词： Soft tumor cells 3D Matrigel Stemness Non-muscle invasive bladder neoplasms Microfluidic analytical techniques