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Senescent mesenchymal stem/stromal cells in pre-metastatic bone marrow of untreated advanced breast cancer patients

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Oncology Research 2023年第3期31卷 361-374页

作者： FRANCISCO RAÚL BORZONE MARÍA BELÉN GIORELLO LEANDRO MARCELO MARTINEZ MARÍA CECILIA SANMARTIN LEONARDO FELDMAN FEDERICO DIMASE EMILIO BATAGELJ GUSTAVO YANNARELLI NORMA ALEJANDRA CHASSEING Laboratorio de Inmunohematología Instituto de Biología y Medicina Experimental(IBYME)Consejo Nacional de Investigaciones Científicas y Técnicas(CONICET)Buenos AiresArgentina Division of Hematology and Medical Oncology Department of MedicineWeill Cornell Medical CollegeNew YorkUSA Laboratorio de Regulación Génica y Células Madre Instituto de Medicina TraslacionalTrasplante y Bioingeniería(IMeTTyB)Universidad Favaloro-CONICETBuenos AiresArgentina Facultad de Ciencias de la Salud Universidad Nacional del Centro de la Provincia de Buenos Aires(UNCPB)TandilBuenos AiresArgentina Servicio de Hematología Hospital Militar CentralBuenos AiresArgentina Servicio de Oncología Hospital Militar CentralBuenos AiresArgentina

Breast cancer is the predominant form of carcinoma among women worldwide,with 70%of advanced patients developing bone metastases,with a high mortality rate.In this sense,the bone marrow(BM)mesenchymal stem/stromal cells(MSCs)are critical for BM/bone homeostasis,and failures in their functionality,transform the BM into a premetastatic niche(PMN).We previously found that BM-MSCs from advanced breast cancer patients(BCPs,infiltrative ductal carcinoma,stage III-B)have an abnormal profile.This work aims to study some of the metabolic and molecular mechanisms underlying MSCs shift from a normal to an abnormal profile in this group of patients.A comparative analysis was undertaken,which included self-renewal capacity,morphology,proliferation capacity,cell cycle,reactive oxygen species(ROS)levels,and senescence-associatedβ‑galactosidase(SA‑β‑gal)staining of BMderived MSCs isolated from 14 BCPs and 9 healthy volunteers(HVs).Additionally,the expression and activity of the telomerase subunit TERT,as well as telomere length,were measured.Expression levels of pluripotency,osteogenic,and osteoclastogenic genes(OCT-4,SOX-2,M-CAM,RUNX-2,BMP-2,CCL-2,M-CSF,and IL-6)were also determined.The results showed that MSCs from BCPs had reduced,self-renewal and proliferation capacity.These cells also exhibited inhibited cell cycle progression and phenotypic changes,such as an enlarged and flattened appearance.Additionally,there was an increase in ROS and senescence levels and a decrease in the functional capacity of TERT to preserve telomere length.We also found an increase in pro-inflammatory/pro-osteoclastogenic gene expression and a decrease in pluripotency gene expression.We conclude that these changes could be responsible for the abnormal functional profile that MSCs show in this group of patients.

关键词： mesenchymal stem/stromal cells Senescence Breast cancer Bone marrow Pre-metastatic niche Bone metastasis

Therapeutic prospects of mesenchymal stem/stromal cells in COVID-19 associated pulmonary diseases:From bench to bedside

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World Journal of stem cells 2021年第8期13卷 1058-1071页

作者： Lei-Sheng Zhang Yi Yu Hao Yu Zhong-Chao Han Qianfoshan Hospital&The First Affiliated Hospital Shandong First Medical UniversityJinan 250014Shandong ProvinceChina State Key Laboratory of Experimental Hematology&National Clinical Research Center for Blood Disease Institute of Hematology&Blood Diseases HospitalChinese Academy of Medical Sciences&Peking Union Medical CollegeTianjin 300020China School of Medicine Nankai UniversityTianjin 300071China Precision Medicine Division Health-Biotech(Tianjin)Stem Cell Research Institute Co.Ltd.Tianjin 301700China The First Affiliated Hospital Zhejiang UniversityHangzhou 310003Zhejiang ProvinceChina Cell Products of National Engineering Center&National stem Cell Engineering Research Center Tianjin IMCELL Stem Cell and Gene Technology Co.Ltd.Tianjin 300457China

The ongoing outbreak of coronavirus disease 2019(COVID-19)caused by the novel severe acute respiratory syndrome coronavirus 2 has become a sudden public emergency of international concern and seriously threatens millions of people’s life health.Two current studies have indicated a favorable role for mesenchymal stem/stromal cells(MSCs)in clinical remission of COVID-19 associated pulmonary diseases,yet the systematical elaboration of the therapeutics and underlying mechanism is far from satisfaction.In the present review,we summarize the therapeutic potential of MSCs in COVID-19 associated pulmonary diseases such as pneumonia induced acute lung injury,acute respiratory distress syndrome,and pulmonary fibrosis.Furthermore,we review the underlying mechanism of MSCs including direct-and trans-differentiation,autocrine and paracrine anti-inflammatory effects,homing,and neovascularization,as well as constitutive microenvironment.Finally,we discuss the prospects and supervision of MSC-based cytotherapy for COVID-19 management before large-scale application in clinical practice.Collectively,this review supplies overwhelming new references for understanding the landscapes of MSCs in the remission of COVID-19 associated pulmonary diseases.

关键词： mesenchymal stem/stromal cells COVID-19 Acute lung injury Acute respiratory distress syndrome Pulmonary fibrosis Molecular mechanism

mesenchymal stem cell-derived extracellular vesicles as a cell-free therapy for traumatic brain injury via neuroprotection and neurorestoration

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Neural Regeneration Research 2024年第1期19卷 49-54页

作者： Ye Xiong Asim Mahmood Michael Chopp Department of Neurosurgery Henry Ford HospitalDetroitMIUSA Department of Neurology Henry Ford HospitalDetroitMIUSA Department of Physics Oakland UniversityRochesterMIUSA

Traumatic brain injury is a serious and complex neurological condition that affects millions of people worldwide.Despite significant advancements in the field of medicine,effective treatments for traumatic brain injury remain limited.Recently,extracellular vesicles released from mesenchymal stem/stromal cells have emerged as a promising novel therapy for traumatic brain injury.Extracellular vesicles are small membrane-bound vesicles that are naturally released by cells,including those in the brain,and can be engineered to contain therapeutic cargo,such as anti-inflammatory molecules,growth factors,and microRNAs.When administered intravenously,extra cellular vesicles can cross the blood-brain barrier and deliver their cargos to the site of injury,where they can be taken up by recipient cells and modulate the inflammatory response,promote neuroregeneration,and improve functional outcomes.In preclinical studies,extracellular vesicle-based therapies have shown promising results in promoting recove ry after traumatic brain injury,including reducing neuronal damage,improving cognitive function,and enhancing motor recovery.While further research is needed to establish the safety and efficacy of extra cellular vesicle-based therapies in humans,extra cellular vesicles represent a promising novel approach for the treatment of traumatic brain injury.In this review,we summarize mesenchymal ste m/stromal cell-de rived extracellular vesicles as a cell-free therapy for traumatic brain injury via neuroprotection and neurorestoration and brainderived extracellular vesicles as potential biofluid biomarkers in small and large animal models of traumatic brain injury.

关键词： biomarkers extracellular vesicles functional outcome mesenchymal stem/stromal cells neuroinflammation neuroplasticity neuroprotection traumatic brain injury

NAD^(+) salvage governs the immunosuppressive capacity of mesenchymal stem cells

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Cellular & Molecular Immunology 2023年第10期20卷 1171-1185页

作者： Jiankai Fang Pengbo Hou Shisong Liu Muqiu Zuo Zhanhong Liu Wangwang Chen Yuyi Han Yanan Li Tingting Wang Chao Feng Peishan Li Changshun Shao Yufang Shi The Third Affiliated Hospital of Soochow University Institutes for Translational MedicineState Key Laboratory of Radiation Medicine and ProtectionSuzhou Medical College of Soochow UniversitySuzhouChina Department of Experimental Medicine and Biochemical Sciences TORUniversity of Rome“Tor Vergata”RomeItaly Laboratory Animal Center Suzhou Medical College of Soochow UniversitySuzhouChina Shanghai Institute of Nutrition and Health Chinese Academy of SciencesShanghaiChina

mesenchymal stem/stromal cells(MSCs)possess robust immunoregulatory functions and are promising therapeutics for inflammatory disorders.This capacity is not innate but is activated or‘licensed’by inflammatory cytokines.The licensing mechanism remains unclear.Here,we examined whether inflammatory cytokines metabolically reprogrammed MSCs to confer this immunoregulatory capacity.In response to stimulation by inflammatory cytokines,MSCs exhibited a dramatic increase in the consumption of glucose,which was accompanied by an enhanced use of nicotinamide adenine dinucleotide(NAD^(+))and increased expression of nicotinamide phosphoribosyltransferase(NAMPT),a central enzyme in the salvage pathway for NAD^(+) production.When NAD^(+) synthesis was blocked by inhibiting or depleting NAMPT,the immunosuppressive function of MSCs induced by inflammatory cytokines was greatly attenuated.Consequently,when NAD^(+) metabolism in MSCs was perturbed,their therapeutic benefit was decreased in mice suffering from inflammatory bowel disease and acute liver injury.Further analysis revealed that NAMPT-driven production of NAD^(+) was critical for the inflammatory cytokine-induced increase in glycolysis in MSCs.Furthermore,the increase in glycolysis led to succinate accumulation in the tricarboxylic acid cycle,which led to hypoxia-inducible factor 1α(HIF-1α)stabilization and subsequently increased the transcription of key glycolytic genes,thereby persistently maintaining glycolytic flux.This study demonstrated that unlike its proinflammatory role in immune cells,NAD^(+) metabolism governs the anti-inflammatory function of MSCs during inflammation.

关键词： mesenchymal stem/stromal cells NAD^(+)metabolism Immunomodulation Glycolysis HIF-1a Succinate

Local administration of porcine immunomodulatory,chemotactic and angiogenic extracellular vesicles using engineered cardiac scaffolds for myocardial infarction

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Bioactive Materials 2021年第10期6卷 3314-3327页

作者： Marta Monguió-Tortajada Cristina Prat-Vidal Miriam Moron-Font Marta Clos-Sansalvador Alexandra Calle Paloma Gastelurrutia Adriana Cserkoova Anna Morancho Miguel Angel Ramírez Anna Rosell Antoni Bayes-Genis Carolina Gàlvez-Montón Francesc E.Borràs Santiago Roura ICREC Research Program Health Science Research Institute Germans Trias i Pujol(IGTP)Can Ruti CampusBadalonaSpain REMAR-IVECAT Group Health Science Research Institute Germans Trias i Pujol(IGTP)Can Ruti CampusBadalonaSpain Department of Cell Biology Physiology and ImmunologyUniversitat Autónoma de Barcelona(UAB)BellaterraSpain CIBERCV Instituto de Salud Carlos IIIMadridSpain Institut d’InvestigacióBiomèdica de Bellvitge-IDIBELL L’Hospitalet de LlobregatSpain Departamento de Reproducción Animal Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria(INIA)MadridSpain Neurovascular Research Laboratory Vall d’Hebron Research Institute(VHIR)UABBarcelonaSpain Cardiology Service Germans Trias i Pujol University HospitalBadalonaSpain Department of Medicine UABBarcelonaSpain Nephrology Service Germans Trias i Pujol University HospitalBadalonaSpain Faculty of Medicine University of Vic-Central University of Catalonia(UVic-UCC)VicBarcelona08500Spain

The administration of extracellular vesicles(EV)from mesenchymal stromal cells(MSC)is a promising cell-free nanotherapy for tissue repair after myocardial infarction(MI).However,the optimal EV delivery strategy remains undetermined.Here,we designed a novel MSC-EV delivery,using 3D scaffolds engineered from decellularised cardiac tissue as a cell-free product for cardiac repair.EV from porcine cardiac adipose tissue-derived MSC(cATMSC)were purified by size exclusion chromatography(SEC),functionally analysed and loaded to scaffolds.cATMSC-EV markedly reduced polyclonal proliferation and pro-inflammatory cytokines production(IFNγ,TNFα,IL12p40)of allogeneic PBMC.Moreover,cATMSC-EV recruited outgrowth endothelial cells(OEC)and allogeneic MSC,and promoted angiogenesis.Fluorescently labelled cATMSC-EV were mixed with peptide hydrogel,and were successfully retained in decellularised scaffolds.Then,cATMSC-EV-embedded pericardial scaffolds were administered in vivo over the ischemic myocardium in a pig model of MI.Six days from implantation,the engineered scaffold efficiently integrated into the post-infarcted myocardium.cATMSC-EV were detected within the construct and MI core,and promoted an increase in vascular density and reduction in macrophage and T cell infiltration within the damaged myocardium.The confined administration of multifunctional MSC-EV within an engineered pericardial scaffold ensures local EV dosage and release,and generates a vascularised bioactive niche for cell recruitment,engraftment and modulation of short-term post-ischemic inflammation.

关键词： Exosomes mesenchymal stem/stromal cells Migration Infiltration Cardiac tissue engineering