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Culture-expanded mesenchymal stromal cell therapy: does it work in knee osteoarthritis? A pathway to clinical success

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cellular & Molecular Immunology 2023年第6期20卷 626-650页

作者： Grffn Copp Kevin P.Robb Sowmya Viswanathan Osteoarthritis Research Program Division of Orthopedic SurgerySchroeder Arthritis InstituteUniversity Health NetworkTorontoONCanada Krembil Research Institute University Health NetworkTorontoONCanada institute of Biomedical Engineering University of TorontoTorontoONCanada Department of Medicine Division of HematologyUniversity of TorontoTorontoONCanada

Osteoarthritis(OA)is a degenerative multifactorial disease with concomitant structural,inflammatory,and metabolic changes that fluctuate in a temporal and patient-specific *** complexity has contributed to refractory responses to various *** have shown promise as multimodal therapeutics in mitigating OA symptoms and disease ***,we evaluated 15 randomized controlled clinical trials(RCTs)and 11 nonrandomized RCTs using culture-expanded MSCs in the treatment of knee OA,and we found net positive effects of MSCs on mitigating pain and symptoms(improving function in 12/15 RCTs relative to baseline and in 11/15 RCTs relative to control groups at study endpoints)and on cartilage protection and/or repair(18/21 clinical studies).We examined MsC dose,tissue of origin,and autologous *** origins as well as patient clinical phenotype,endotype,age,sex and level of OA severity as key parameters in parsing MSC clinical *** relatively small sample size of 610 patients limited the drawing of definitive ***,we noted trends toward moderate to higher doses of MsCs in select OA patient clinical phenotypes mitigating pain and leading to structural improvements or cartilage *** from preclinical studies is supportive of MsC anti-inflammatory and immunomodulatory effects,but additional investigations on immunomodulatory,chondroprotective and other clinical mechanisms of action are *** hypothesize that MsC basal immunomodulatory"fitness"correlates with OA treatment efficacy,but this hypothesis needs to be validated in future *** conclude with a roadmap articulating the need to match an OA patient subset defined by molecular endotype and clinical phenotype with basally immunomodulatory"ft"or engineered-to-be-fit-for-OA MsCs in well-designed,data-intensive clinical trials to advance the field.

关键词： MSC Osteoarthritis cell therapy mesenchymal stromal cell RCT

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Anti-fibrotic and anti-inflammatory effect of mesenchymal stromal cell-derived extracellular vesicles in chronic kidney disease

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BIOcell 2023年第7期47卷 1499-1508页

作者： GIULIA CHIABOTTO STEFANIA BRUNO Department of Medical Sciences University of TorinoTorino10126Italy Molecular Biotechnology Center University of TorinoTorino10126Italy

Renal fibrosis and inflammation are common pathological features of chronic kidney disease(CKD).Since currently available treatments can only delay the progression of CKD,the outcome of patients with CKD is still *** therapeutic option for the prevention of CKD-related complications could be the use of mesenchymal stromal cells(MSCs),which have shown beneficial effects in tissue fibrosis and regeneration after ***,safety issues,such as cellular rejection and carcinogenicity,limit their clinical *** the bioactive factors secreted by MSCs,extracellular vesicles(EVs)have shown the same beneficial effect of MSCs,without any notable side *** heterogeneous population of membranous nano-sized particles can deliver genetic material and functional proteins to injured cells,prompting tissue *** we describe the anti-fibrotic and antiinflammatory properties of MSC-derived EVs in CKD preclinical models and summarize the potential molecular mechanisms involved in the regulation of renal fibrosis and inflammation.

关键词： Chronic kidney disease Renal fibrosis Epithelial-to-mesenchymal transition mesenchymal stromal cell Extracellular vesicles

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mesenchymal stromal cell-dependent immunoregulation in chemically-induced acute liver failure

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World Journal of Stem cells 2021年第3期13卷 208-220页

作者： Jia-Hang Zhou Xuan Lu Cui-Lin Yan Xin-Yu Sheng Hong-Cui Cao State Key Laboratory for Diagnosis and Treatment of Infectious Diseases National Clinical Research Center for Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003Zhejiang ProvinceChina Zhejiang Provincial Key Laboratory for Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases The First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003Zhejiang ProvinceChina

Drug-induced liver injury(DILI),which refers to liver damage caused by a drug or its metabolites,has emerged as an important cause of acute liver failure(ALF)in recent ***-induced ALF in animal models mimics the pathology of DILI in humans;thus,these models are used to study the mechanism of potentially effective treatment *** stromal cells(MSCs)possess immunomodulatory properties,and they alleviate acute liver injury and decrease the mortality of animals with chemically-induced ***,we summarize some of the existing research on the interaction between MSCs and immune cells,and discuss the possible mechanisms underlying the immunomodulatory activity of MSCs in chemically-induced *** conclude that MSCs can impact the phenotype and function of macrophages,as well as the differentiation and maturation of dendritic cells,and inhibit the proliferation and activation of T lymphocytes or B *** also have immunomodulatory effects on the production of cytokines,such as prostaglandin E2 and tumor necrosis factor-alpha-stimulated gene 6,in animal ***,MSCs have significant benefits in the treatment of chemically-induced ALF by interacting with immune cells and they may be applied to DILI in humans in the near future.

关键词： mesenchymal stromal cell Immune response Drug-induced liver injury Acute liver failure Dendritic cell

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mesenchymal stromal cell secretome in liver failure:Perspectives on COVID-19 infection treatment

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World Journal of Gastroenterology 2021年第17期27卷 1905-1919页

作者： Cinzia Maria Chinnici Giovanna Russelli Matteo Bulati Vitale Miceli Alessia Gallo Rosalia Busà Rosaria Tinnirello Pier Giulio Conaldi Gioacchin Iannolo Department of Research Mediterranean Institute for Transplantation and Advanced Specialized Therapies(IRCCS-ISMETT)Palermo 90127Italy Department of Regenerative Medicine Fondazione Ri.MEDPalermo 90127Italy Neuroscience Unit CNR Institute of Biomedicine and Molecular ImmunologyPalermo 90146Italy

Due to their immunomodulatory potential and release of trophic factors that promote healing,mesenchymal stromal cells(MSCs)are considered important players in tissue homeostasis and *** have been widely used in clinical trials to treat multiple conditions associated with inflammation and tissue *** evidence suggests that most of the MSC therapeutic effects are derived from their secretome,including the extracellular vesicles,representing a promising approach in regenerative medicine application to treat organ failure as a result of inflammation/*** recent outbreak of respiratory syndrome coronavirus,caused by the newly identified agent severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has forced scientists worldwide to use all available instruments to fight the infection,including the inflammatory cascade caused by this pandemic *** use of MSCs is a valid approach to combat organ inflammation in different *** addition to the lungs,which are considered the main inflammatory target for this virus,other organs are compromised by the *** particular,the liver is involved in the inflammatory response to SARS-CoV-2 infection,which causes organ failure,leading to death in coronavirus disease 2019(COVID-19)*** herein summarize the current implications derived from the use of MSCs and their soluble derivatives in COVID-19 treatment,and emphasize the potential of MSCbased therapy in this clinical setting.

关键词： mesenchymal stromal cell COVID-19 SARS-CoV-2 Organ failure Inflammation Transplantation

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mesenchymal stromal cells-exosomes:a promising cell-free therapeutic tool for wound healing and cutaneous regeneration

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Burns & Trauma 2019年第1期7卷 346-355页

作者： Peng Hu Qinxin Yang Qi Wang Chenshuo Shi Dali Wang Ubaldo Armato Ilaria Dal Prà Anna Chiarini Department of Burns&Plastic Surgery The Affiliated Hospital of ZunYi Medical UniversityDalian Road 149ZunYi City 563000Gui Zhou ProvinceChina Human Histology and Embryology Unit University of Verona Medical SchoolStrada Le Grazie 837134 VeronaItaly

Cutaneous regeneration at the wound site involves several intricate and dynamic processes which require a series of coordinated interactions implicating various cell types,growth factors,extracellular matrix(ECM),nerves,and blood *** stromal cells(MSCs)take part in all the skin wound healing stages playing active and beneficial roles in animal models and ***,which are among the key products MSCs release,mimic the effects of parental *** can shuttle various effector proteins,messenger RNA(mRNA)and microRNAs(miRNAs)to modulate the activity of recipient cells,playing important roles in wound ***,using exosomes avoids many risks associated with cell ***,as a novel type of cell-free therapy,MSC-exosome-mediated administration may be safer and more efficient than whole *** this review,we provide a comprehensive understanding of the latest studies and observations on the role of MSC-exosome therapy in wound healing and cutaneous *** addition,we address the hypothesis of MSCs microenvironment extracellular vesicles(MSCs-MEVs)or MSCs microenvironment exosomes(MSCs-MExos)that need to take stock of and solved urgently in the related research about MSC-exosomes therapeutic *** review can inspire investigators to explore new research directions of MSC-exosome therapy in cutaneous repair and regeneration.

关键词： Cutaneous regeneration mesenchymal stromal cell Exosomes Wound healing Microenvironment

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Stem cell technology for antitumor drug loading and delivery in oncology

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Oncology Research 2024年第3期32卷 433-437页

作者： FRANCESCO PETRELLA ENRICO MARIO CASSINA LIDIA LIBRETTI EMANUELE PIRONDINI FEDERICO RAVEGLIA ANTONIO TUORO Department of Thoracic Surgery Fondazione IRCCSS an Gerardo dei TintoriMonza20900Italy

The main aim of antineoplastic treatment is to maximize patient benefit by augmenting the drug accumulation within affected organs and tissues,thus incrementing drug effects and,at the same time,reducing the damage of non-involved tissues to cytotoxic *** stromal cells(MSC)represent a group of undifferentiated multipotent cells presenting wide self-renewal features and the capacity to differentiate into an assortment of mesenchymal family *** the last year,they have been proposed as natural carriers for the selective release of antitumor drugs to malignant cll,s thus optimizing cytotoxic action on cancer cll,while significantly reducing adverse side efect on healthy *** chemotherapeutic drug loading and delivery is an encouraging new area of cell therapy for several tumors,especially for those with unsatisfactory prognosis and limited treatment options *** some experim ental models have been sucesfuly developed,phase I dinical studies are needed to confirm this potential application of cell therapy,in particular in the case of primary and secondary lung cancers.

关键词： mesenchymal stromal cell Drug loading Drug delivery Mesothelioma Melanoma Glioblastoma Pancreatic ductal adenocarcinoma Multiple myeloma

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mesenchymal stem cell-derived extracellular vesicles therapy in traumatic central nervous system diseases:a systematic review and meta-analysis

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Neural Regeneration Research 2023年第11期18卷 2406-2412页

作者： Zhelun Yang Zeyan Liang Jian Rao Fabin Lin Yike Lin Xiongjie Xu Chunhua Wang Chunmei Chen Department of Neurosurgery Fujian Medical University Union HospitalFuzhouFujian ProvinceChina

Although there are challenges in treating traumatic central nervous system diseases,mesenchymal stem cell-de rived extracellular vesicles(MSC-EVs) have recently proven to be a promising non-cellular the *** comprehensively evaluated the efficacy of mesenchymal stem cell-de rived extracellular vesicles in traumatic central nervous system diseases in this meta-analysis based on preclinical *** meta-analysis was registered at PROSPERO(CRD42022327904,May 24,2022).To fully retrieve the most relevant articles,the following databases were thoro ughly searched:PubMed,Web of Science,The Cochrane Library,and Ovid-Embase(up to April 1,2022).The included studies were preclinical studies of mesenchymal stem cell-derived extracellular vesicles for traumatic central nervous system *** Systematic Review Centre for Laboratory Animal Experimentation(SYRCLE)’s risk of bias tool was used to examine the risk of publication bias in animal *** screening 2347studies,60 studies were included in this study.A meta-analysis was conducted for spinal co rd injury(n=52) and traumatic brain injury(n=8).The results indicated that mesenchymal stem cell-derived extracellular vesicles treatment prominently promoted motor function recovery in spinal co rd injury animals,including rat Basso,Beattie and Bresnahan locomotor rating scale scores(standardized mean difference [SMD]:2.36,95% confidence interval [CI]:1.96-2.76,P mesenchymal stem cell-de rived extracellular vesicles treatment significantly promoted neurological recovery in traumatic brain injury animals,including the modified N eurological Severity Score(SMD=-4.48,95% CI:-6.12 to-2.84,P mesenchymal stem cel

关键词： animals central nervous system diseases extracellular vesicles mesenchymal stromal cell meta-analysis spinal cord injury traumatic brain injury

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New perspectives for mesenchymal stromal cells as an adjuvant therapy for infectious disease-associated encephalopathies

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Neural Regeneration Research 2022年第1期17卷 48-52页

作者： Maiara N.Lima Maria C.Barbosa-Silva Tatiana Maron-Gutierrez Laboratory of Immunopharmacology Oswaldo Cruz InstituteOswaldo Cruz FoundationFiocruzRio de JaneiroRJBrazil National Institute of Science and Technology on Neuroimmunomodulation Rio de JaneiroBrazil

Knowledge of the mechanisms that trigger infection-related encephalopathies is still very limited and cell therapies are one of the most promising alternatives for neurodegenerative diseases,and its application in infectious diseases can be of great *** stromal cells are cells with great immunomodulatory potential;therefore,their use in clinical and preclinical studies in a variety of diseases,including central nervous system diseases,increased in the last *** stromal cells can exert their beneficial effects through several mechanisms,such as direct cell contact,through surface receptors,and also through paracrine or endocrine *** paracrine mechanism is widely accepted by the scientific community and involves the release of soluble factors,which include cytokines,chemokines and trophic factors,and extracellular *** mini review discusses mesenchymal stromal cells mechanisms of action in neurological disorders,the neuroinflammatory process that takes place in the brain as a result of peripheral inflammation and changes in the brain’s cellular scenario as a common factor in central nervous system diseases,and mesenchymal stromal cells therapy in *** stromal cells have been shown to act in neuroinflammation processes,leading to improved survival and mitigating behavioral *** recently,these cells have been tested in preclinical models of infectious diseases-associated encephalopathies(e.g.,cerebral malaria and sepsis associated encephalopathy)and have shown satisfactory results.

关键词： behavior cell therapy cognition encephalopathy malaria mesenchymal stromal cell sepsis

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Comparative effectiveness of adipose-derived mesenchymal stromal cells in the management of knee osteoarthritis:A meta-analysis

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World Journal of Orthopedics 2023年第1期14卷 23-41页

作者： Sathish Muthu Sandesh C Patil Naveen Jeyaraman Madhan Jeyaraman Prakash Gangadaran Ramya Lakshmi Rajendran Eun Jung Oh Manish Khanna Ho Yun Chung Byeong-Cheol Ahn Department of Orthopaedics Government Medical College and HospitalDindigul 624001Tamil NaduIndia Department of Biotechnology School of Engineering and TechnologySharda UniversityGreater Noida 201310Uttar PradeshIndia Jeyaraman Research AssociateOrthopaedic Research GroupCoimbatore 641045Tamil NaduIndia Indian Stem cell Study Group Association Lucknow 226001Uttar PradeshIndia Department of Orthopaedic Rheumatology Dr.RML National Law UniversityLucknow 226012Uttar PradeshIndia ACS Medical College&Hospital Dr MGR Educational and Research InstituteChennai 600056Tamil NaduIndia BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents Department of Biomedical SciencesSchool of MedicineKyungpook National UniversityDaegu 41944South Korea Department of Nuclear Medicine School of MedicineKyungpook National UniversityDaegu 41944South Korea Department of Plastic and Reconstructive Surgery CMRIKyungpook National UniversityKyungpook National University HospitalDaegu 41944South Korea Department of Plastic and Reconstructive Surgery School of MedicineKyungpook National UniversityDaegu 41944South Korea Department of Nuclear Medicine Kyungpook National University HospitalDaegu 41944South Korea

BACKGROUND Osteoarthritis(OA)is the most common joint disorder,is associated with an increasing socioeconomic impact owing to the ageing *** To analyze and compare the efficacy and safety of bone-marrow-derived mesenchymal stromal cells(BM-MSCs)and adipose tissue-derived MSCs(AD-MSCs)in knee OA management from published randomized controlled trials(RCTs).METHODS Independent and duplicate electronic database searches were performed,including PubMed,EMBASE,Web of Science,and Cochrane Library,until August 2021 for RCTs that analyzed the efficacy and safety of AD-MSCs and BM-MSCs in the management of knee *** visual analog scale(VAS)score for pain,Western Ontario McMaster Universities Osteoarthritis Index(WOMAC),Lysholm score,Tegner score,magnetic resonance observation of cartilage repair tissue score,knee osteoarthritis outcome score(KOOS),and adverse events were *** was performed on the R-platform using OpenMeta(Analyst)***-one studies,involving 936 patients,were *** one study compared the two MSC sources without patient randomization;hence,the results of all included studies from both sources were pooled,and a comparative critical analysis was *** At six months,both AD-MSCs and BM-MSCs showed significant VAS improvement(P=0.015,P=0.012);this was inconsistent at 1 year for BM-MSCs(P<0.001,P=0.539),and AD-MSCs outperformed BM-MSCs compared to controls in measures such as WOMAC(P<0.001,P=0.541),Lysholm scores(P=0.006;P=0.933),and KOOS(P=0.002;P=0.012).BM-MSC-related procedures caused significant adverse events(P=0.003)compared to AD-MSCs(P=0.673).CONCLUSION Adipose tissue is superior to bone marrow because of its safety and consistent efficacy in improving pain and functional *** trials are urgently warranted to validate our findings and reach a consensus on the ideal source of MSCs for managing knee OA.

关键词： mesenchymal stromal cell Adipose tissue-derived mesenchymal stromal cell Bone-marrow derived mesenchymal stromal cell Cartilage regeneration Knee osteoarthritis Meta-analysis Efficacy Safety

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Supportive angiogenic and osteogenic differentiation of mesenchymal stromal cells and endothelial cells in monolayer and co-cultures

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International Journal of Oral Science 2016年第4期8卷 223-230页

作者： Florian Bohrnsen Henning Schliephake Clinic of Oral and Maxillofacial Surgery Georg August University Gottingen Germany

Sites of implantation with compromised biology may be unable to achieve the required level of angiogenic and osteogenic regeneration. The specific function and contribution of different cell types to the formation of prevascularized, osteogenic networks in co-culture remains unclear. To determine how bone marrow-derived mesenchymal stromal cells （BMSCs） and endothelial cells （ECs） contribute to cellular proangiogenic differentiation, we analysed the differentiation of BMSCs and ECs in standardized monolayer, Transwell and co-cultures. BMSCs were derived from the iliac bone marrow of five patients, characterized and differentiated in standardized monolayers, permeable Transwells and co-cultures with human umbilical vein ECs （HUVECs）. The expression levels of CD31, von Willebrand factor, osteonectin （ON） and Runx2 were assessed by quantitative reverse transcriptase polymerase chain reaction. The protein expression of alkaline phosphatase, ON and CD31 was demonstrated via histochemical and immunofluorescence analysis. The results showed that BMSCs and HUVECs were able to retain their lineage-specific osteogenic and angiogenic differentiation in direct and indirect co-cultures. In addition, BMSCs demonstrated a supportive expression of angiogenic function in co-culture, while HUVEC was able to improve the expression of osteogenic marker molecules in BMSCs.

关键词： angiogenic co-culture differentiation endothelial cell mesenchymal stromal cell osteogenic

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