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Anti-Sca-1 antibody-functionalized vascular grafts improve vascular regeneration via selective capture of endogenous vascular stem/progenitor cells

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Bioactive Materials 2022年第10期7卷 433-450页

作者： He Wang Mengmeng Xing Weiliang Deng Meng Qian Fei Wang Kai Wang adam c.midgley Qiang Zhao State Key Laboratory of Medicinal chemical Biology Haihe Laboratory of Sustainable Chemical TransformationsKey Laboratory of Bioactive Materials(Ministry of Education)Frontiers Science Center for Cell ResponsesCollege of Life SciencesNankai UniversityTianjinChina

Small-diameter vascular grafts fabricated from synthetic biodegradable polymers exhibit beneficial mechanical properties but often face poor regenerative potential.Different tissue engineering approaches have been employed to improve tissue regeneration in vascular grafts,but there remains a requirement for a new generation of synthetic grafts that can orchestrate the host response to achieve robust vascular regeneration.Vascular stem/progenitor cells(SPcs)are mostly found in quiescent niches but can be activated in response to injury and participate in endothelium and smooth muscle regeneration during neo-artery formation.Here,we developed a functional vascular graft by surface immobilization of stem cell antigen-1(Sca-1)antibody on an electrospun poly(ε-caprolactone)graft(PcL-Sca-1 Ab).PcL-Sca-1 Ab promoted capture and retainment of Sca-1+SPcs in vitro.In rat abdominal aorta replacement models,PcL-Sca-1 Ab stimulated in vivo recruitment of Sca-1+SPcs,and drove SPcs differentiation towards vascular cell lineages.The origin of infiltrated Sca-1+SPcs was further investigated using a bone marrow transplantation mouse model,which revealed that Sca-1+SPcs originating from the resident tissues and bone marrow contributed to rapid vascular regeneration of vascular grafts.Our data indicated that PcL-Sca-1 Ab vascular grafts may serve as a useful strategy to develop next generation cell-free vascular grafts.

关键词： Small-diameter vascular grafts Surface modification Stem cell antigen-1(Sca-1)antibody Vascular stem/progenitor cells(SPcs) Tissue regeneration

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Exosome-mimicking nanovesicles derived from efficacy-potentiated stem cell membrane and secretome for regeneration of injured tissue

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Nano Research 2022年第2期15卷 1680-1690页

作者： chunxiao Qi Xiangsheng Liu Dengke Zhi Yifan Tai Yufei Liu Qiqi Sun Kai Wang Shufang Wang adam c.midgley Deling Kong Key Laboratory of Bioactive Materials Ministry of EducationCollege of Life Sciencesand State Key Laboratory of Medicinal Chemical BiologyNankai UniversityTianjin 300071China

Translation of exosome-based therapies to pharmaceutical use is hindered by difficulties in large-scale and cost-effective production of clinical-grade exosomes.The rational design of nanovesicles that mimic the functionalities and physicochemical properties of exosomes may circumvent these issues.In this study,membranes and secretome from efficacy-potentiated mesenchymal stem cells(MScs)were developed into size-controllable nanovesicles(Meseomes).MScs were primed with interferon-y(IFNy)and tumor necrosis factor-a(TNFa),harvested,and exosome-mimicking Meseomes were subsequently synthesized via one-step extrusion.Meseomes demonstrated significant enhancement of pro-angiogenic,pro-proliferative,antiinflammatory,and anti-fibrotic effects on endothelial cells,macrophages,and hepatic stellate cells in vitro.Meseomes from primed MScs benefited from an enrichment of bioactive and therapeutic molecules compared to nanovesicles from unprimed MScs,as validated by liquid chromatography-mass spectrometry(Lc-MS)proteomic analysis.Systemic administration of Meseomes to acute liver injury models resulted in the recovery of liver function,attenuated tissue necrosis.Further assessment of locally administered Meseomes in acute hindlimb ischemia models resulted in the salvage of the majority of the ischemic hindlimb(>80%),which was due to enhanced angiogenesis and M2 macrophage polarization.The versatility and therapeutic efficacy of our developed acellular Meseomes offer an appealing alternative to traditional cell or exosome therapies for regenerative and translational medicine.

关键词： acellular therapy biomimetic nanovesicles acute liver injury hindlimb ischemia regenerative medicine

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Functionalization of in vivo tissue-engineered living biotubes enhance patency and endothelization without the requirement of systemic anticoagulant administration

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Bioactive Materials 2023年第8期26卷 292-305页

作者： Hongyu Yan Quhan cheng Jianghua Si Songdi Wang Ye Wan Xin Kong Ting Wang Wenting Zheng Muhammad Rafique Xiaofeng Li Ju He adam c.midgley Yi Zhu Kai Wang Deling Kong a a Key Laboratory of Bioactive Materials for the Ministry of Education College of Life SciencesNankai UniversityTianjin300071China Department of Ultrasound in Medicine Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai200233China Tianjin Key Laboratory of Urban Transport Emission Research College of Environmental Science and EngineeringNankai UniversityTianjin300071China State Key Laboratory of Experimental Hematology National Clinical Research Center for Blood DiseasesChinese Academy of Medical Sciences&Peking Union Medical CollegeTianjin300020China Department of Vascular Surgery Tianjin First Central HospitalNankai UniversityTianjin300192China Department of Physiology and Pathophysiology Tianjin Medical UniversityTianjin300070China

Vascular regeneration and patency maintenance,without anticoagulant administration,represent key developmental trends to enhance small-diameter vascular grafts(SDVG)performance.In vivo engineered autologous biotubes have emerged as SDVG candidates with pro-regenerative properties.However,mechanical failure coupled with thrombus formation hinder translational prospects of biotubes as SDVGs.Previously fabricated poly(ε-caprolactone)skeleton-reinforced biotubes(PBs)circumvented mechanical issues and achieved vascular regeneration,but orally administered anticoagulants were required.Here,highly efficient and biocompatible functional modifications were introduced to living cells on PB lumens.The 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(DMPE)-PEG-conjugated anti-coagulant bivalirudin(DPB)and DMPE-PEG-conjugated endothelial progenitor cell(EPc)-binding TPS-peptide(DPT)modifications possessed functionality conducive to promoting vascular graft patency.co-modification of DPB and DPT swiftly attained luminal saturation without influencing cell viability.DPB repellent of non-specific proteins,DPB inhibition of thrombus formation,and DPB protection against functional masking of DPT’s EPc-capture by blood components,which promoted patency and rapid endothelialization in rat and canine artery implantation models without anticoagulant administration.This strategy offers a safe,facile,and fast technical approach to convey additional functionalization to living cells within tissue-engineered constructs.

关键词： In vivo tissue-engineering Biotube Living tissue modification Anticoagulation Rapid endothelialization

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Micro-nanofiber composite biomimetic conduits promote long-gap peripheral nerve regeneration in canine models

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Bioactive Materials 2023年第12期30卷 98-115页

作者： Xianhao Dong Yueyue Yang Zheheng Bao adam c.midgley Feiyi Li Shuxin Dai Zhuangzhuang Yang Jin Wang Lihua Liu Wenlei Li Yayuan Zheng Siyang Liu Yang Liu Weijian Yu Jun Liu Meng Fan Meifeng Zhu Zhongyang Shen Gu Xiaosong Deling Kong State Key Laboratory of Medicinal chemical Biology The Key Laboratory of Bioactive MaterialsMinistry of EducationCollege of Life ScienceNankai UniversityTianjinChina Department of Orthopaedics Tianjin First Central HospitalSchool of MedicineNankai UniversityTianjinChina Department of Radiology Tianjin First Central HospitalTianjin Medical Imaging InstituteSchool of MedicineNankai UniversityTianjinChina Institute of Transplantation Medicine NHC Key Laboratory for Critical Care MedicineTianjin First Central HospitalSchool of MedicineNankai UniversityTianjinChina Haihe Laboratory of Sustainable chemical Transformations Keyan West RoadTianjin300192China Jiangsu Key Laboratory of Neuroregeneration Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury RepairCo-innovation Center ofNeuroregenerationNMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology ProductsNantong UniversityNantongChina Outpatient Department Tianjin First Central HospitalSchool of MedicineNankai UniversityTianjinChina clinical School/college of Orthopedics Tianjin Medical UniversityTianjinChina Department of Joint Tianjin HospitalTianjinChina

Peripheral nerve injuries may result in severe long-gap interruptions that are challenging to repair.Autografting is the gold standard surgical approach for repairing long-gap nerve injuries but can result in prominent donor-site complications.Instead,imitating the native neural microarchitecture using synthetic conduits is expected to offer an alternative strategy for improving nerve regeneration.Here,we designed nerve conduits composed of high-resolution anisotropic microfiber grid-cordes with randomly organized nanofiber sheaths to interrogate the positive effects of these biomimetic structures on peripheral nerve regeneration.Anisotropic microfiber-grids demonstrated the capacity to directionally guide Schwann cells and neurites.Nanofiber sheaths conveyed adequate elasticity and permeability,whilst exhibiting a barrier function against the infiltration of fibroblasts.We then used the composite nerve conduits bridge 30-mm long sciatic nerve defects in canine models.At 12 months post-implant,the morphometric and histological recovery,gait recovery,electrophysiological function,and degree of muscle atrophy were assessed.The newly regenerated nerve tissue that formed within the composite nerve conduits showed restored neurological functions that were superior compared to sheaths-only scaffolds and Neurolac nerve conduit controls.Our findings demonstrate the feasibility of using synthetic biophysical cues to effectively bridge long-gap peripheral nerve injuries and indicates the promising clinical application prospects of biomimetic composite nerve conduits.

关键词： composite fiber injuries

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A modular microfluidic platform to study how fluid shear stress alters estrogen receptor phenotype in ER+breast cancer cells

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Microsystems & Nanoengineering 2024年第1期10卷 287-299页

作者： Braulio Andrés Ortega Quesada Jonathan cuccia Rachael coates Blake Nassar Ethan Littlefield Elizabeth c.Martin adam T.Melvin cain Department of chemical Engineering Louisiana State UniversityBaton RougeLA 70803USA Department of chemical and Biological Engineering Clemson UniversityClemsonSC 29634USA Biological and Agricultural Engineering Louisiana State UniversityBaton RougeLA 70803USA Department Medicine Section Hematology and Medical OncologyTulane UniversityNew OrleansLA 70118USA

Metastatic breast cancer leads to poor prognoses and worse outcomes in patients due to its invasive behavior and poor response to therapy.It is still unclear what biophysical and biochemical factors drive this more aggressive phenotype in metastatic cancer;however recent studies have suggested that exposure to fluid shear stress in the vasculature could cause this.In this study a modular microfluidic platform capable of mimicking the magnitude of fluid shear stress(FSS)found in human vasculature was designed and fabricated.This device provides a platform to evaluate the effects of FSS on McF-7 cell line,an estrogen receptor positive(ER+)breast cancer cell line,during circulation in the vessels.Elucidation of the effects of FSS on McF-7 cells was carried out utilizing two approaches:single cell analysis and bulk analysis.For single cell analysis,cells were trapped in a microarray after exiting the serpentine channel and followed by immunostaining on the device(on-chip).Bulk analysis was performed after cells were collected in a microtube at the outlet of the microfluidic serpentine channel for western blotting(off-chip).It was found that cells exposed to an FSS magnitude of 10 dyn/cm^(2) with a residence time of 60 s enhanced expression of the proliferation marker Ki67 in the McF-7 cell line at a single cell level.To understand possible mechanisms for enhanced Ki67 expression,on-chip and off-chip analyses were performed for pro-growth and survival pathways ERK,AKT,and JAK/STAT.Results demonstrated that after shearing the cells phosphorylation of p-AKT,p-mTOR,and p-STAT3 were observed.However,there was no change in p-ERK1/2.AKT is a mediator of ER rapid signaling,analysis of phosphorylated ERαwas carried out and no significant differences between sheared and non-sheared populations were observed.Taken together these results demonstrate that FSS can increase phosphorylation of proteins associated with a more aggressive phenotype in circulating cancer cells.These findings provide additional information that may help

关键词： fluid breast estrogen

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人工血管组织再生的细胞来源

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中国科学：生命科学 2019年第9期49卷 1100-1108页

作者：吴依璠智登科 adam c.midgley 赵强孔德领王恺南开大学生命科学学院生物活性材料教育部重点实验室

小口径人工血管的研发已成为近些年来的研究热点.理想的人工血管能够募集自体细胞参与血管组织再生,以实现小口径人工血管的长期通畅.基于小口径人工血管的国内外研究动态,本文详述了参与血管再生的细胞来源以及细胞种类.目前,公认的细... 详细信息

小口径人工血管的研发已成为近些年来的研究热点.理想的人工血管能够募集自体细胞参与血管组织再生,以实现小口径人工血管的长期通畅.基于小口径人工血管的国内外研究动态,本文详述了参与血管再生的细胞来源以及细胞种类.目前,公认的细胞来源主要包括吻合端天然血管、循环血液中的细胞和人工血管外围/外周组织;参与血管再生的细胞种类主要包括血管细胞、干/祖细胞、炎症细胞和外源种植细胞等.最后对募集宿主细胞的技术手段以及目前研究的局限性进行了讨论.

关键词：小口径人工血管组织再生细胞来源

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Degradation and resynthesis of chlorophyll during increased oxidative stress and prolonged darkness differ between annual and perennial flax(Linum L.)

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Oil crop Science 2024年第2期9卷 121-130页

作者： Kenyon J. Nisbett Abida Alokozai Su Hyun Elizabeth Ko G. adam Mott Jason c.L. Browna Department of Biological Sciences University of Toronto ScarboroughTorontoONCanada Department of cell&Systems Biology University of TorontoTorontoONCanada centre for the Analysis of Genome Evolution&Function University of TorontoTorontoONCanada

Among plants,there is considerable variation in lifespan:annuals live less than one year,whereas perennials live for several years,with the longest-living perennial having survived 43,600 years.As proposed by the Disposable Soma Theory,this lifespan variation among plants likely reflects differential investment of limited energy and nutrient resources,with perennials investing more energy and nutrients into biomolecular maintenance compared to annuals in order to ensure persistence over multiple seasons.Such differential investment may be particularly important during periods of exogenous stress,which are known to accelerate biomolecular damage.The present study evaluated this hypothesis using annual and perennial flax(Linum L.)subjected to two exogenous stressors—increased oxidative stress(i.e.,foliar H2O2spraying)and complete prolonged darkness.As chlorophyll has been shown to exhibit degradation in response to changes in environmental conditions,we utilized changes in chlorophyll levels during and after periods of exogenous stress to evaluate our hypotheses.We predicted that i)perennials would exhibit a slower rate of chlorophyll degradation during exposure to exogenous stressors compared to annuals,and ii)perennials would exhibit a faster rate of chlorophyll resynthesis following such exposure compared to annuals.chlorophyll levels before,during,and after exposure to both exogenous stressors were measured in two separate trails,once using image colour analysis and once using spectrophotometry.While chlorophyll degradation rates in response to oxidative stress did not differ between annuals and perennials,contrary to our predictions,chlorophyll resynthesis rates following such exposure were significantly higher in perennials,as predicted.When plants were subjected to complete prolonged darkness,chlorophyll degradation rates were significantly lower in perennials than annuals,as predicted;however,when plants were subsequently reintroduced to natural photoperiod,chlorophyll resynthesis rates did not consistently

关键词： Ageing Life history Maximum lifespan Oxidative stress Somatic maintenance

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Unsynchronized butyrophilin molecules dictate cancer cell evasion of Vγ9Vδ2 T-cell killing

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cellular & Molecular Immunology 2024年第4期21卷 362-373页

作者： Zeguang Wu Qiezhong Lamao Meichao Gu Xuanxuan Jin Ying Liu Feng Tian Ying Yu Pengfei Yuan Shuaixin Gao Thomas S.Fulford adam P.Uldrich catherine c.L Wong Wensheng Wei Biomedical Pioneering Innovation center Peking-Tsinghua Center for Life SciencesPeking University Genome Editing Research CenterState Key Laboratory of Protein and Plant Gene ResearchSchool of Life SciencesPeking University100871BeijingChina EdiGene Inc. Life Science ParkChangping District102206BeijingChina center for Precision Medicine Multi-Omics Research Peking University Health Science CenterPeking University100191BeijingChina Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity The University of MelbourneParkvilleVIC3010Australia cancer Immunology Program Peter MacCallum Cancer CentreMelbourneVICAustralia State Key Laboratory for complex Severe and Rare DiseasesClinical Research InstitutePeking Union Medical College HospitalChinese Academy of Medical Science&Peking Union Medical CollegePeking-Tsinghua Center for Life Sciences100871BeijingChina

Vγ9Vδ2 T cells are specialized effector cells that have gained prominence as immunotherapy agents due to their ability to target and kill cells with altered pyrophosphate metabolites.In our effort to understand how cancer cells evade the cell-killing activity of Vγ9Vδ2 T cells,we performed a comprehensive genome-scale cRISPR screening of cancer cells.We found that four molecules belonging to the butyrophilin(BTN)family,specifically BTN2A1,BTN3A1,BTN3A2,and BTN3A3,are critically important and play unique,nonoverlapping roles in facilitating the destruction of cancer cells by primary Vγ9Vδ2 T cells.The coordinated function of these BTN molecules was driven by synchronized gene expression,which was regulated by IFN-γsignaling and the RFX complex.Additionally,an enzyme called QPcTL was shown to play a key role in modifying the N-terminal glutamine of these BTN proteins and was found to be a crucial factor in Vγ9Vδ2 T cell killing of cancer cells.Through our research,we offer a detailed overview of the functional genomic mechanisms that underlie how cancer cells escape Vγ9Vδ2 T cells.Moreover,our findings shed light on the importance of the harmonized expression and function of gene family members in modulating T-cell activity.

关键词： Butyrophilin Vγ9Vδ2 T-cell cancer-specific immune evasion Glutaminyl-peptide cyclotransferase-like Pyrophosphate metabolite Immunotherapy

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Exercise immunology:Novel insights

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Journal of Sport and Health Science 2024年第3期13卷 277-279,I0001页

作者： David c.Nieman Human Performance Laboratory Appalachian State UniversityNorth Carolina Research CampusKannapolisNC 28081USA

The coronavirus disease 2019(cOVID-19)pandemic heightened worldwide attention on the influence of exercise on the immune system.Questions were raised about whether regular moderate-to-vigorous physical activity(MVPA)could help prevent cOVID-19 or mitigate symptoms when ill.could MVPA bolster immunity among those most prone to cOVID-19 including the elderly,obese,and immunocompromised patients?Does regular MVPA dampen systemic inflammation,thereby lessening the cOVID-19 cytokine storm?

关键词： immunity inflammation thereby

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The value of the INFEcTIONS scoring system in identifying bacterial infections among patients presenting at the emergency department of a middle-income country:A pilot study

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chinese Journal of Traumatology 2024年第2期27卷 77-82页

作者： Dooshanveer c.Nuckchady Department of Internal Medicine Victoria HospitalCandosMauritius

Purpose:To investigate which scoring system is the most accurate tool in predicting mortality among the infected patients who present to the emergency department in a middle-income country,and to validate a new scoring system to predict bacterial infections.Methods:This was a retrospective,single-center study among patients who were admitted via the emergency department of a public hospital.All patients who were started on antibiotics were included in the study,while patients agedcluded.Data collected includeding patients'demographics,vital signs and basic laboratory parameters like white blood cell count and creatinine.The sensitivity and specificity of different scoring systems were calculated as well as their negative and positive predictive values.Logistic regression was used to derive a novel early warning system for bacterial infections.The area under the receiver operating characteristic(AUROc)was computed for each scoring model.Results:In total,109 patients were included in this study.The quick sequential organ failure assessment(qSOFA),search out severity and rapid acute physiology score had the highest AUROc(≥0.89)for predicting mortality,while qSOFA and universal vital assessment were the simplest scoring systems with an AUROc>0.85;however,these scoring systems failed to predict whether patients were truly infected.The INFEcTIONS(short for impaired mental status,not conscious,fast heart rate,elevated creatinine,high temperature,on inotrope,low oxygen,high neutrophils and high sugar)model reached an AUROc of 0.88 to more accurately predict the infectious state of a patient.conclusions:Middle-income countries should use the qSOFA or universal vital assessment score to identify the sickest patients in emergency department.The INFEcTIONS score may help recognize patients with bacterial infections,but it should be further validated in multiple countries prior to widely use.

关键词： Prognosis Mortality Bacterial infection INFEcTIONS scoring system Sequential organ failure assessment Prediction

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