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immunomodulation of adipose-derived mesenchymal stem cells on peripheral blood mononuclear cells in colorectal cancer patients with COVID-19

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World Journal of Gastrointestinal Oncology 2024年第5期16卷 2113-2122页

作者： Jun-Feng Wang Xiao-Xia Yang Jian Zhang Yan Zheng Fu-Qing Zhang Xiao-Feng Shi Yu-Liang Wang Department of Colorectal Oncology Tianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerTianjin’s Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjin 300060China Department of Neurology Tianjin First Center HospitalTianjin 300192China Prosthodontics Studio Tianjin Stomatological HospitalTianjin 300041China Department of Clinical Laboratory Medicine Tianjin Institute of UrologyThe Second Hospital of Tianjin Medical UniversityTianjin 300211China Department of Emergency Tianjin First Central HospitalTianjin 300192China

BACKGROUND Accumulating evidence has shown that adipose tissue-derived mesenchymal stem cells(ADSCs)are an effective therapeutic approach for managing coronavirus disease 2019(COVID-19);however,further elucidation is required to determine their underlying immunomodulatory effect on the mRNA expression of T helper cell-related transcription factors(TFs)and cytokine release in peripheral blood mononuclear cells(PBMCs).AIM To investigate the impact of ADSCs on the mRNA expression of TFs and cytokine release in PBMCs from colorectal cancer(CRC)patients with severe COVID-19(CRC^(+)patients).METHODS PBMCs from CRC^(+)patients(PBMCs-C+)and age-matched CRC patients(PBMCs-C)were stimulated and cultured in the presence/absence of ADSCs.The mRNA levels of T-box TF TBX21(T-bet),GATA binding protein 3(GATA-3),RAR-related orphan receptor C(RORC),and forkhead box P3(FoxP3)in the PBMCs were determined by reverse transcriptase-polymerase chain reaction.Culture supernatants were evaluated for levels of interferon gamma(IFN-γ),interleukin 4(IL-4),IL-17A,and transforming growth factor beta 1(TGF-β1)using an enzyme-linked immunosorbent assay.RESULTS Compared with PBMCs-C,PBMCs-C+exhibited higher mRNA levels of T-bet and RORC,and increased levels of IFN-γ and IL-17A.Additionally,a significant decrease in FoxP3 mRNA and TGF-β1,as well as an increase in Tbet/GATA-3,RORC/FoxP3,IFN-γ/IL-4,and IL-17A/TGF-β1 ratios were observed in PBMCs-C+.Furthermore,ADSCs significantly induced a functional regulatory T cell(Treg)subset,as evidenced by an increase in FoxP3 mRNA and TGF-β1 release levels.This was accompanied by a significant decrease in the mRNA levels of T-bet and RORC,release of IFN-γ and IL-17A,and T-bet/GATA-3,RORC/FoxP3,IFN-γ/IL-4,and IL-17A/TGF-β1 ratios,compared with the PBMCs-C+alone.CONCLUSION The present in vitro studies showed that ADSCs contributed to the immunosuppressive effects on PBMCs-C+,favoring Treg responses.Thus,ADSC-based cell therapy could be a beneficial approach for patients with severe COVID-19 who fail to respond

关键词： Colorectal cancer COVID-19 Adipose-derived mesenchymal stem cells T helper cell immunomodulation

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immunomodulation of Proton-activated G Protein-coupled Receptors in Inflammation

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Current Medical Science 2024年第3期44卷 475-484页

作者： Min-shan LI Xiang-hong WANG Heng WANG Department of Otolaryngology-Head and Neck Surgery Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China Institute of Allergy and Clinical Immunology Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China Hubei Clinical Research Center for Nasal Inflammatory Diseases Wuhan430030China

Proton-activated G protein-coupled receptors(GPCRs),initially discovered by Ludwig in 2003,are widely distributed in various tissues.These receptors have been found to modulate the immune system in several inflammatory diseases,including inflammatory bowel disease,atopic dermatitis,and asthma.Proton-activated GPCRs belong to the G protein-coupled receptor family and can detect alternations in extracellular pH.This detection triggers downstream signaling pathways within the cells,ultimately influencing the function of immune cells.In this review,we specifically focused on investigating the immune response of proton-activated GPCRs under inflammatory conditions.

关键词： proton-activated G protein-coupled receptors inflammation immunomodulation disease

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dECM restores macrophage immune homeostasis and alleviates iron overload to promote DTPI healing

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Regenerative Biomaterials 2024年第2期3卷 100-113页

作者： Ju Zhang Ruijuan Si Yu Gao Hui Shan Qi Su Zujian Feng Pingsheng Huang Deling Kong Weiwei Wang Tianjin Key Laboratory of Biomaterial Research Institute of Biomedical EngineeringChinese Academy of Medical Sciences and Peking Union Medical CollegeTianjin300192China School of Nursing Qingdao UniversityNingde RoadShinan DistrictQingdaoShandong266071China Cancer Hospital of Tianjin Medical University North Huanhu West RoadTianjinChina The Affliated Hospital of Qingdao University 16 Jjiangsu RoadShinan DistrictQingdaoChina 5NankaiUniver aniin300071.China

Due to its highly insidious and rapid progression,deep tissue pressure injury(DTPI)is a clinical challenge.Our previous study found that DTPI may be a skeletal muscle injury dominated by macrophage immune dysfunction due to excessive iron accu-mulation.Decellularized extracellular matrix(dECM)hydrogel promotes skeletal muscle injury repair.However,its role in po-larizing macrophages and regulating iron metabolism in DTPI remains unclear.Here,porcine dECM hydrogel was prepared,and its therapeutic function and mechanism in repairing DTPI were investigated.The stimulus of dECM hydrogel toward RAW264.7 cells resulted in a significantly higher percentage of CD2o6+macrophages and notably decreased intracellular divalent iron levels.In mice DTPI model,dECM hydrogel treatment promoted M1 to M2 macrophage conversion,improved iron metabolism and reduced oxidative stress in the early stage of DTPI.In the remodeling phase,the dECM hydrogel remarkably enhanced revascularization and accelerated skeletal muscle repair.Furthermore,the immunomodulation of dEcM hydrogels in vivo was mainly involved in the P13k/Akt signaling pathway,as revealed by GO and KEGG pathway analysis,which may ameliorate the iron deposition and promote the healing of DTPI.Our findings indicate that dECM hydrogel is promising in skeletal muscle repair,inflammation resolution and tissue injury healing by effectively restoring macrophage immune homeostasis and normalizing iron metabolism.

关键词： Deep tissue pressure injury hydrogel immunomodulation tissue repair

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The marriage of immunomodulatory,angiogenic,and osteogenic capabilities in a piezoelectric hydrogel tissue engineering scafold for military medicine

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Military Medical Research 2024年第3期11卷 323-344页

作者： Ping Wu Lin Shen Hui-Fan Liu Xiang-Hui Zou Juan Zhao Yu Huang Yu-Fan Zhu Zhao-Yu Li Chao Xu Li-Hua Luo Zhi-Qiang Luo Min-Hao Wu Lin Cai Xiao-Kun Li Zhou-Guang Wang Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research the Fifth Affiliated Hospital of Wenzhou Medical UniversityLishui 323000ZhejiangChina Oujiang Laboratory(Zhejiang Lab for Regenerative Medicine Vision and Brain Health)School of Pharmaceutical ScienceWenzhou Medical UniversityWenzhou 325000ZhejiangChina Department of Spine Surgery and Musculoskeletal Tumor Zhongnan Hospital of Wuhan UniversityWuhan 430071China National Engineering Research Center for Nanomedicine College of Life Science and TechnologyHuazhong University of Science and TechnologyWuhan 430074China Department of Overseas Education College Jimei UniversityXiamen 361021FujianChina School and Hospital of Stomatology Wenzhou Medical UniversityWenzhou 325035ZhejiangChina

Background:Most bone-related injuries to grassroots troops are caused by training or accidental injuries.To establish preventive measures to reduce all kinds of trauma and improve the combat effectiveness of grassroots troops,it is imperative to develop new strategies and scafolds to promote bone regeneration.Methods:In this study,a porous piezoelectric hydrogel bone scafold was fabricated by incorporating polydopamine(PDA)-modified ceramic hydroxyapatite(PDA-hydroxyapatite,PHA)and PDA-modified barium titanate(PDABaTiO3,PBT)nanoparticles into a chitosan/gelatin(Cs/Gel)matrix.The physical and chemical properties of the Cs/Gel/PHA scafold with 0–10 wt%PBT were analyzed.Cell and animal experiments were performed to characterize the immunomodulatory,angiogenic,and osteogenic capabilities of the piezoelectric hydrogel scafold in vitro and in vivo.Results:The incorporation of BaTiO3into the scafold improved its mechanical properties and increased self-generated electricity.Due to their endogenous piezoelectric stimulation and bioactive constituents,the prepared Cs/Gel/PHA/PBT hydrogels exhibited cytocompatibility as well as immunomodulatory,angiogenic,and osteogenic capabilities;they not only effectively induced macrophage polarization to M2 phenotype but also promoted the migration,tube formation,and angiogenic differentiation of human umbilical vein endothelial cells(HUVECs)and facilitated the migration,osteodifferentiation,and extracellular matrix(ECM)mineralization of MC3T3-E1 cells.The in vivo evaluations showed that these piezoelectric hydrogels with versatile capabilities significantly facilitated new bone formation in a rat large-sized cranial injury model.The underlying molecular mechanism can be partly attributed to the immunomodulation of the Cs/Gel/PHA/PBT hydrogels as shown via transcriptome sequencing analysis,and the PI3K/Akt signaling axis plays an important role in regulating macrophage M2 polarization.Conclusion:The piezoelectric Cs/Gel/PHA/PBT hydrogels developed here with favorable immunomodulation,

关键词： Piezoelectric hydrogel Tissue engineering scafold immunomodulation Angiogenesis Osteogenic differentiation

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Remodeling the immune microenvironment for gastric cancer therapy through antagonism of prostaglandin E2 receptor 4

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Genes & Diseases 2024年第4期11卷 411-425页

作者： Mengmeng Guo Pan Hu Jiayi Xie Kefu Tang Shixiu Hu Jialiang Sun Yundong He Jing Li Weiqiang Lu Huirong Liu Mingyao Liu Zhengfang Yi Shihong Peng Shanghai Key Laboratory of Regulatory Biology School of Life SciencesEast China Normal UniversityShanghai 200241China Prenatal Diagnosis Center Department of Clinical LaboratoryChangning Maternity and Infant Health HospitalEast China Normal UniversityShanghai 200051China Key Laboratory of Acupuncture and Immunological Effects Shanghai University of Traditional Chinese MedicineShanghai 201203China Fengxian Hospital Affiliated to Southern Medical University Shanghai 201400China Shanghai Yuyao Biotech Co. Ltd.Shanghai 200241China

Gastric cancer is highly prevalent among digestive tract tumors.Due to the intri-cate nature of the gastric cancer immune microenvironment,there is currently no effective treatment available for advanced gastric cancer.However,there is promising potential for immunotherapy targeting the prostaglandin E2 receptor subtype 4(EP4)in gastric cancer.In our previous study,we identified a novel small molecule EP4 receptor antagonist called YY001.Treatment with YY001 alone demonstrated a significant reduction in gastric cancer growth and inhibited tumor metastasis to the lungs in a mouse model.Furthermore,adminis-tration of YYo01 stimulated a robust immune response within the tumor microenvironment,characterized by increased infiltration of antigen-presenting cells,T cells,and M1 macro-phages.Additionally,our research revealed that YYo01 exhibited remarkable synergistic ef-fects when combined with the PD-1 antibody and the clinically targeted drug apatinib,rather than fluorouracil.These findings suggest that YYo01 holds great promise as a potential therapeutic strategy for gastric cancer,whether used as a standalone treatment or in combination with other drugs.

关键词： EP4 immunomodulation Synergy Tumor microenvironment YY001

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The emerging tumor microbe microenvironment: From delineation to multidisciplinary approach-based interventions

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Acta Pharmaceutica Sinica B 2024年第4期14卷 1560-1591页

作者： Yu Fu Jia Li Wenyun Cai Yulan Huang Xinlong Liu Zhongyi Ma Zhongjie Tang Xufei Bian Ji Zheng Jiayun Jiang Chong Li Medical Research Institute College of Pharmaceutical SciencesSouthwest UniversityChongqing 400715China Institute of Hepatobiliary Surgery Southwest HospitalThird Military Medical University(Army Medical University)Chongqing 400038China Department of Urology Urologic Surgery CenterXinqiao HospitalThird Military Medical University(Army Medical University)Chongqing 400037China

Intratumoral microbiota has become research hotspots,and emerges as a non-negligent new component of tumor microenvironments(TME),due to its powerful infuence on tumor initiation,metas-tasis,immunosurveillance and prognosis despite in low-biomass.The accumulations of microbes,and their related components and metabolites within tumor tissues,endow TME with additional pluralistic features which are distinct from the conventional one.Therefore,it's definitely necessary to comprehen-sively delineate the sophisticated landscapes of tumor microbe microenvironment,as well as their func-tions and related underlying mechanisms.Herein,in this review,we focused on the fields of tumor microbe microenvironment,including the heterogeneity of intratumor microbiota in different types of tu-mors,the controversial roles of intratumoral microbiota,the basic features of tumor microbe microenvi-ronment(i.e.,pathogen-associated molecular patterns(PAMPs),typical microbial metabolites,autophagy,infammation,multi-faceted immunomodulation and chemoresistance),as well as the multi-disciplinary approach-based intervention of tumor microbiome for cancer therapy by applying wild-type or engineered live microbes,microbiota metabolites,antibiotics,synthetic biology and rationally de-signed biomaterials.We hope our work will provide valuable insight to deeply understand the interplay of cancer-immune-microbial,and facilitate the development of microbes-based tumor-specific treatments.

关键词： Tumor microbe microenvironment Microbiota metabolites immunomodulation Chemoresistance Multidisciplinary approach Genetically engineered microbiota Autophagy Outer membrane vesicles

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Advances in mesenchymal stem cells therapy for tendinopathies

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Chinese Journal of Traumatology 2024年第1期27卷 11-17页

作者： Xu-Feng Mao Xi-Qian Zhang Zhe-Yu Yao Hai-Jiao Mao Department of Orthopaedic Surgery The First Affiliated Hospital of Ningbo UniversityNingbo315010Zhejiang provinceChina

Tendinopathies are chronic diseases of an unknown etiology and associated with inflammation.Mesenchymal stem cells(MSCs)have emerged as a viable therapeutic option to combat the pathological progression of tendinopathies,not only because of their potential for multidirectional differentiation and self-renewal,but also their excellent immunomodulatory properties.The immunomodulatory effects of MSCs are increasingly being recognized as playing a crucial role in the treatment of tendinopathies,with MSCs being pivotal in regulating the inflammatory microenvironment by modulating the immune response,ultimately contributing to improved tissue repair.This review will discuss the current knowledge regarding the application of MSCs in tendinopathy treatments through the modulation of the immune response.

关键词： Mesenchymal stem cells Tendinopathy immunomodulation Treatment Review

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The expression mechanism of programmed cell death 1 ligand 1 and its role in immunomodulatory ability of mesenchymal stem cells

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Chinese Journal of Traumatology 2024年第1期27卷 1-10页

作者： Zhuo Chen Meng-Wei Yao Xiang Ao Qing-Jia Gong Yi Yang Jin-Xia Liu Qi-Zhou Lian Xiang Xu Ling-Jing Zuo Department of Stem Cell&Regenerative Medicine State Key Laboratory of TraumaBurn and Combined InjuryDaping HospitalArmy Medical UniversityChongqing400042China College of Basic Medical Sciences Army Medical UniversityChongqing400038China Department of Orthopedics 953 Hospital of PLAShigatse Branch of Xinqiao HospitalArmy Medical UniversityShigatse857000Tibet Autonomous RegionChina Department of Rheumatology and Immunology Daping HospitalArmy Medical UniversityChongqing400042China Department of Obstetrics and Gynecology Chongqing People's HospitalChongqing401121China Department of Medicine Li Ka Shing Faculty of MedicineThe University of Hong KongHong KongChina Department of Nuclear Medicine The First People's Hospital of Yunnan provinceAffiliated Hospital of Kunming University of Science and TechnologyKunming650034China

Programmed cell death 1 ligand 1(PD-L1)is an important immunosuppressive molecule,which inhibits the function of T cells and other immune cells by binding to the receptor programmed cell death-1.The PD-L1 expression disorder plays an important role in the occurrence,development,and treatment of sepsis or other inflammatory diseases,and has become an important target for the treatment of these diseases.Mesenchymal stem cells(MSCs)are a kind of pluripotent stem cells with multiple differentiation potential.In recent years,MSCs have been found to have a strong immunosuppressive ability and are used to treat various inflammatory insults caused by hyperimmune diseases.Moreover,PD-L1 is deeply involved in the immunosuppressive events of MSCs and plays an important role in the treatment of various diseases.In this review,we will summarize the main regulatory mechanism of PD-L1 expression,and discuss various biological functions of PD-L1 in the immune regulation of MSCs.

关键词： PD-L1 MSCs immunomodulation

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Mesenchymal stem cells and their derived exosomes for the treatment of COVID-19

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World Journal of Stem Cells 2024年第4期16卷 353-374页

作者： Xiang-Yi Hou La-Mu Danzeng Yi-Lin Wu Qian-Hui Ma Zheng Yu Mei-Ying Li Li-Sha Li The Key Laboratory of Pathobiology Ministry of EducationCollege of Basic Medical SciencesJilin UniversityChangchun 130021Jilin ProvinceChina Department of Pharmacy Jilin UniversityChangchun 130021Jilin ProvinceChina The First Hospital of Jilin University Jilin UniversityChangchun 130021Jilin ProvinceChina

Coronavirus disease 2019(COVID-19)is an acute respiratory infection caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).SARS-CoV-2 infection typically presents with fever and respiratory symptoms,which can progress to severe respiratory distress syndrome and multiple organ failure.In severe cases,these complications may even lead to death.One of the causes of COVID-19 deaths is the cytokine storm caused by an overactive immune response.Therefore,suppressing the overactive immune response may be an effective strategy for treating COVID-19.Mesenchymal stem cells(MSCs)and their derived exosomes(MSCs-Exo)have potent homing abilities,immunomodulatory functions,regenerative repair,and antifibrotic effects,promising an effective tool in treating COVID-19.In this paper,we review the main mechanisms and potential roles of MSCs and MSCs-Exo in treating COVID-19.We also summarize relevant recent clinical trials,including the source of cells,the dosage and the efficacy,and the clinical value and problems in this field,providing more theoretical references for the clinical use of MSCs and MSCs-Exo in the treatment of COVID-19.

关键词： COVID-19 Cytokine storm immunomodulation Mesenchymal stem cell Mesenchymal stem cell-derived exosomes

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Adiponectin restores the obesity-induced impaired immunomodulatory function of mesenchymal stromal cells via glycolytic reprogramming

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Acta Pharmaceutica Sinica B 2024年第1期14卷 273-291页

作者： Duc-Vinh Pham Thi-Kem Nguyen Bao-Loc Nguyen Jong-Oh Kim Jee-Heon Jeong Inho Choi Pil-Hoon Park Department of Pharmacology Hanoi University of PharmacyHanoi 100000Viet Nam College of Pharmacy Yeungnam UniversityGyeongsan 38541Republic of Korea Department of Medical Biotechnology Yeungnam UniversityGyeongsan 38541Republic of Korea Research Institute of Cell Culture Yeungnam UniversityGyeongsan 38541Republic of Korea Department of Precision Medicine School of MedicineSungkyunkwan UniversitySuwon 16419Republic of Korea

Obesity has been known to negatively modulate the life-span and immunosuppressive potential of mesenchymal stromal cells(MSC).However,it remains unclear what drives the compromised potency of obese MSC.In this study,we examined the involvement of adiponectin,an adipose tissuederived hormone,in obesity-induced impaired therapeutic function of MSC.Diet-induced obesity leads to a decrease in serum adiponectin,accompanied by impairment of survival and immunomodulatory effects of adipose-derived MSC(ADSC).Interestingly,priming with globular adiponectin(gAcrp)improved the immunomodulatory potential of obese ADSC.Similar effects were also observed in lean ADSC.In addition,gAcrp potentiated the therapeutic effectiveness of ADSC in a mouse model of DSS-induced colitis.Mechanistically,while obesity inhibited the glycolytic capacity of MSC,gAcrp treatment induced a metabolic shift toward glycolysis through activation of adiponectin receptor type 1/p38 MAPK/hypoxia inducible factor-1a axis.These findings suggest that activation of adiponectin signaling is a promising strategy for enhancing the therapeutic efficacy of MSC against immune-mediated disorders.

关键词： Adiponectin Adipose-derived stromal cells Colitis Glycolytic induction HIF1a immunomodulation Mesenchymal stromal cells Obesity

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