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Wu SK, Tsai CL, Mir A, Hynynen K. MRI-guided focused ultrasound for treating Parkinson's disease with human mesenchymal stem cells. Sci Rep 2025; 15:2029. [PMID: 39815002 PMCID: PMC11735764 DOI: 10.1038/s41598-025-85811-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 01/06/2025] [Indexed: 01/18/2025] Open
Abstract
Parkinson's disease (PD) is a progressive disorder that affects the nervous system and causes regions of the brain to deteriorate. In this study, we investigated the effects of MR-guided focused ultrasound (MRgFUS) for the delivery of human mesenchymal stem cells (MSCs) on the 6-hydroxydopamine (6-HODA)-induced PD rat model. MRgFUS-induced blood-brain barrier (BBB) permeability modulation was conducted using an acoustic controller with the targets at the striatum (ST) and SN. Human MSCs were injected immediately before sonication. Here, we show that we can deliver human MSCs into Parkinsonian rats through MRgFUS-induced BBB modulation using an acoustic controller. Stem cells were identified in the sonicated brain regions using surface markers, indicating the feasibility of MSC delivery via MRgFUS. MSCs + FUS treatment significantly improved the behavioural outcomes compared with control, FUS alone, and MSCs alone groups (p < 0.05). In the quantification analysis of the TH stain, a significant reservation of dopamine neurons was seen in the MSCs + FUS group as compared with the MSCs group (ST: p = 0.03; SN: p = 0.0005). Mesenchymal stem cell therapy may be a viable treatment option for neurodegenerative diseases such as Parkinson's. Transcranial MRgFUS serves as an efficacious and safe method for targeted and minimally invasive stem cell homing.
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Affiliation(s)
- Sheng-Kai Wu
- Physical Sciences Platform, Sunnybrook Research Institute, Toronto, ON, Canada.
- Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
| | - Chia-Lin Tsai
- Physical Sciences Platform, Sunnybrook Research Institute, Toronto, ON, Canada
- Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Aisha Mir
- Physical Sciences Platform, Sunnybrook Research Institute, Toronto, ON, Canada
| | - Kullervo Hynynen
- Physical Sciences Platform, Sunnybrook Research Institute, Toronto, ON, Canada.
- Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada.
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Qu Q, Liu L, Wang L, Cui Y, Liu C, Jing X, Xu X. Exosomes derived from hypoxic mesenchymal stem cells restore ovarian function by enhancing angiogenesis. Stem Cell Res Ther 2024; 15:496. [PMID: 39709481 DOI: 10.1186/s13287-024-04111-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 12/10/2024] [Indexed: 12/23/2024] Open
Abstract
BACKGROUND hucMSC-exosomes can be engineered to strengthen their therapeutic potential, and the present study aimed to explore whether hypoxic preconditioning can enhance the angiogenic potential of hucMSC-exosomes in an experimental model of POF. METHODS Primary hucMSCs and ROMECs were isolated from fresh tissue samples and assessed through a series of experiments. Exosomes were isolated from hucMSCs under normoxic or hypoxic conditions (norm-Exos and hypo-Exos, respectively) and then characterized using classic experimental methods. Based on a series of angiogenesis-related assays, we found that hypo-Exos significantly promoted ROMEC proliferation, migration, and tube formation and increased angiogenesis-promoting molecules in vitro. Histology, immunohistochemistry, and immunofluorescence experiments in a rat model of POF demonstrated that hypoxia pretreatment strengthens the therapeutic angiogenic effect of hucMSC-exosomes in vivo. Subsequently, high-throughput miRNA sequencing, qRT‑PCR analysis, and western blotting were employed to identify the potential molecular mechanism. RESULTS We found that hypo-Exos enhance endothelial function and angiogenesis via the transfer of miR-205-5p in vitro and in vivo. Finally, based on the results of bioinformatics analysis, dual luciferase reporter assays, and gain- and loss-of-function studies, we found evidence indicating that exosomal miR-205-5p enhances angiogenesis by targeting the PTEN/PI3K/AKT/mTOR signalling pathway. These results indicated for the first time that exosomes derived from hypoxia-conditioned hucMSCs strongly enhance angiogenesis via the transfer of miR-205-5p by targeting the PTEN/PI3K/AKT/mTOR signalling pathway. CONCLUSIONS Our findings provide a theoretical basis and demonstrate the potential application of a novel cell-free approach with stem cell-derived products in the treatment of POF.
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Affiliation(s)
- Qingxi Qu
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, 250012, P.R. China
| | - Linghong Liu
- Research Center of Stem Cell and Regenerative Medicine, Shandong University, Jinan, 250012, P.R. China.
- Laboratory of Cryomedicine, Qilu Hospital of Shandong University, Jinan, 250012, P.R. China.
| | - Limei Wang
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, 250012, P.R. China
| | - Yuqian Cui
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, 250012, P.R. China
| | - Chunxiao Liu
- Department of Cardiovascular Surgery, Qilu Hospital of Shandong University, Jinan, 250012, P.R. China
| | - Xuanxuan Jing
- Department of Ultrasound, Qilu Hospital of Shandong University, Jinan, 250012, P.R. China
| | - Xiaoxuan Xu
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, 250012, P.R. China
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Akabane M, Imaoka Y, Kawashima J, Endo Y, Schenk A, Sasaki K, Pawlik TM. Innovative Strategies for Liver Transplantation: The Role of Mesenchymal Stem Cells and Their Cell-Free Derivatives. Cells 2024; 13:1604. [PMID: 39404368 PMCID: PMC11475694 DOI: 10.3390/cells13191604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 09/11/2024] [Accepted: 09/23/2024] [Indexed: 10/19/2024] Open
Abstract
Despite being the standard treatment for end-stage liver disease, liver transplantation has limitations like donor scarcity, high surgical costs, and immune rejection risks. Mesenchymal stem cells (MSCs) and their derivatives offer potential for liver regeneration and transplantation. MSCs, known for their multipotency, low immunogenicity, and ease of obtainability, can differentiate into hepatocyte-like cells and secrete bioactive factors that promote liver repair and reduce immune rejection. However, the clinical application of MSCs is limited by risks such as aberrant differentiation and low engraftment rates. As a safer alternative, MSC-derived secretomes and extracellular vesicles (EVs) offer promising therapeutic benefits, including enhanced graft survival, immunomodulation, and reduced ischemia-reperfusion injury. Current research highlights the efficacy of MSC-derived therapies in improving liver transplant outcomes, but further studies are necessary to standardize clinical applications. This review highlights the potential of MSCs and EVs to address key challenges in liver transplantation, paving the way for innovative therapeutic strategies.
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Affiliation(s)
- Miho Akabane
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH 43210, USA; (M.A.); (J.K.); (A.S.)
| | - Yuki Imaoka
- Division of Abdominal Transplant, Department of Surgery, Stanford University, Stanford, CA 94305, USA; (Y.I.); (K.S.)
| | - Jun Kawashima
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH 43210, USA; (M.A.); (J.K.); (A.S.)
| | - Yutaka Endo
- Department of Transplant Surgery, University of Rochester Medical Center, Rochester, NY 14642, USA;
| | - Austin Schenk
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH 43210, USA; (M.A.); (J.K.); (A.S.)
| | - Kazunari Sasaki
- Division of Abdominal Transplant, Department of Surgery, Stanford University, Stanford, CA 94305, USA; (Y.I.); (K.S.)
| | - Timothy M. Pawlik
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH 43210, USA; (M.A.); (J.K.); (A.S.)
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Wu S, Zhou Z, Li Y, Jiang J. Advancements in diabetic foot ulcer research: Focus on mesenchymal stem cells and their exosomes. Heliyon 2024; 10:e37031. [PMID: 39286219 PMCID: PMC11403009 DOI: 10.1016/j.heliyon.2024.e37031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 08/11/2024] [Accepted: 08/26/2024] [Indexed: 09/19/2024] Open
Abstract
Diabetes represents a widely acknowledged global public health concern. Diabetic foot ulcer (DFU) stands as one of the most severe complications of diabetes, its occurrence imposing a substantial economic burden on patients, profoundly impacting their quality of life. Despite the deepening comprehension regarding the pathophysiology and cellular as well as molecular responses of DFU, the current therapeutic arsenal falls short of efficacy, failing to offer a comprehensive remedy for deep-seated chronic wounds and microvascular occlusions. Conventional treatments merely afford symptomatic alleviation or retard the disease's advancement, devoid of the capacity to effectuate further restitution of compromised vasculature and nerves. An escalating body of research underscores the prominence of mesenchymal stem cells (MSCs) owing to their paracrine attributes and anti-inflammatory prowess, rendering them a focal point in the realm of chronic wound healing. Presently, MSCs have been validated as a highly promising cellular therapeutic approach for DFU, capable of effectuating cellular repair, epithelialization, granulation tissue formation, and neovascularization by means of targeted differentiation, angiogenesis promotion, immunomodulation, and paracrine activities, thereby fostering wound healing. The secretome of MSCs comprises cytokines, growth factors, chemokines, alongside exosomes harboring mRNA, proteins, and microRNAs, possessing immunomodulatory and regenerative properties. The present study provides a systematic exposition on the etiology of DFU and elucidates the intricate molecular mechanisms and diverse functionalities of MSCs in the context of DFU treatment, thereby furnishing pioneering perspectives aimed at harnessing the therapeutic potential of MSCs for DFU management and advancing wound healing processes.
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Affiliation(s)
- ShuHui Wu
- Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - ZhongSheng Zhou
- Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Yang Li
- Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Jinlan Jiang
- Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, China
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Trivedi A, Lin M, Miyazawa B, Nair A, Vivona L, Fang X, Bieback K, Schäfer R, Spohn G, McKenna D, Zhuo H, Matthay MA, Pati S. Inter- and Intra-donor variability in bone marrow-derived mesenchymal stromal cells: implications for clinical applications. Cytotherapy 2024; 26:1062-1075. [PMID: 38852094 DOI: 10.1016/j.jcyt.2024.03.486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 03/15/2024] [Accepted: 03/15/2024] [Indexed: 06/10/2024]
Abstract
BACKGROUND AIMS Mesenchymal stromal cells (MSCs) are attractive as a therapeutic modality in multiple disease conditions characterized by inflammation and vascular compromise. Logistically they are advantageous because they can be isolated from adult tissue sources, such as bone marrow (BM). The phase 2a START clinical trial determined BM-MSCs to be safe in patients with moderate-to-severe acute respiratory distress syndrome (ARDS). Herein, we examine a subset of the clinical doses of MSCs generated for the phase 2a START trial from three unique donors (1-3), where one of the donors' donated BM on two separate occasions (donor 3 and 3W). METHODS The main objective of this study was to correlate properties of the cells from the four lots with plasma biomarkers from treated patients and relevant to ARDS outcomes. To do this we evaluated MSC donor lots for (i) post-thaw viability, (ii) growth kinetics, (iii) metabolism, (iv) surface marker expression, (v) protein expression, (vi) immunomodulatory ability and (vii) their functional effects on regulating endothelial cell permeability. RESULTS MSC-specific marker expression and protection of thrombin-challenged endothelial barrier permeability was similar among all four donor lots. Inter and intra-donor variability was observed in all the other in vitro assays. Furthermore, patient plasma ANG-2 and protein C levels at 6 hours post-transfusion were correlated to cell viability in an inter- and intra-donor dependent manner. CONCLUSIONS These findings highlight the potential of donor dependent (inter-) and collection dependent (intra-) effects in patient biomarker expression.
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Affiliation(s)
- Alpa Trivedi
- Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA
| | - Maximillian Lin
- Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA
| | - Byron Miyazawa
- Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA
| | - Alison Nair
- Department of Pediatrics, University of California, San Francisco, San Francisco, California, USA
| | - Lindsay Vivona
- Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA
| | - Xiaohui Fang
- Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA
| | - Karen Bieback
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Richard Schäfer
- Goethe University Medical Center, Institute of Transfusion Medicine and Immunohematology, and German Red Cross Blood Center Frankfurt, Frankfurt, Germany; Institute for Transfusion Medicine and Gene Therapy, Center for Chronic Immunodeficiency (CCI), Medical Center - University of Freiburg, Germany
| | - Gabriele Spohn
- Goethe University Medical Center, Institute of Transfusion Medicine and Immunohematology, and German Red Cross Blood Center Frankfurt, Frankfurt, Germany
| | - David McKenna
- University of Minnesota, Molecular and Cellular Therapeutics, Saint Paul, Minnesota, USA
| | - Hanjing Zhuo
- Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA
| | - Michael A Matthay
- Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA; Department of Medicine and Anesthesia, University of California, San Francisco, San Francisco, California, USA
| | - Shibani Pati
- Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA; Department of Surgery, University of California, San Francisco, San Francisco, California, USA.
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Zhang K, Zhang C, Zhou H, Yang Y, Wen Y, Jiao X, Yao M, Wen Y. Elastic Nanofibrous Dressings with Mesenchymal Stem Cell-Recruiting and Protecting Characteristics for Promoting Diabetic Wound Healing. ACS APPLIED MATERIALS & INTERFACES 2024; 16:41869-41880. [PMID: 39101935 DOI: 10.1021/acsami.4c07369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/06/2024]
Abstract
Diabetic wounds that do not heal for a long time challenge global healthcare. Mesenchymal stem cell (MSC) therapy has positive significance in promoting diabetic wound healing. However, traditional MSC therapy involves exogenous MSCs, which brings many limitations and unsatisfactory treatment. Moreover, the maintenance of MSC viability and function is difficult because of the high level of reactive oxygen species (ROS) in diabetic wounds. Therefore, we developed a nanofibrous dressing to recruit and protect endogenous MSCs while avoiding the inherent disadvantages of exogenous MSCs. Ceria nanoparticles capable of ROS scavenging are integrated into the nanofibrous dressings, together with Apt19S, a DNA aptamer with affinity and selectivity for MSCs. In addition, the homogenization and freeze-drying technology give the nanofibrous dressings good elasticity, which protects the wound from external pressure. Further experiments in diabetic mice show that the dressing has excellent endogenous MSC recruitment and anti-inflammatory properties, thereby synergistically promoting diabetic wound healing. This study is expected to explore an efficient method of stem cell therapy, providing a new way to construct high-performance wound dressings.
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Affiliation(s)
- Kexin Zhang
- College of Chemical Engineering and Technology, Taiyuan University of Science and Technology, Taiyuan 030024, China
| | - Chenyu Zhang
- College of Chemical Engineering and Technology, Taiyuan University of Science and Technology, Taiyuan 030024, China
| | - Huanxin Zhou
- College of Chemical Engineering and Technology, Taiyuan University of Science and Technology, Taiyuan 030024, China
| | - Yan Yang
- College of Chemical Engineering and Technology, Taiyuan University of Science and Technology, Taiyuan 030024, China
| | - Yanzhen Wen
- College of Chemical Engineering and Technology, Taiyuan University of Science and Technology, Taiyuan 030024, China
| | - Xiangyu Jiao
- Beijing Key Laboratory for Bioengineering and Sensing Technology, Daxing Research Institute, School of Chemistry & Biological Engineering, University of Science & Technology Beijing, Beijing 100083, China
| | - Mingze Yao
- Institutes of Biomedical Sciences, Shanxi Provincial Key Laboratory for Medical Molecular Cell Biology, Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan 030006, China
| | - Yongqiang Wen
- Beijing Key Laboratory for Bioengineering and Sensing Technology, Daxing Research Institute, School of Chemistry & Biological Engineering, University of Science & Technology Beijing, Beijing 100083, China
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Sagar RL, Åström E, Chitty LS, Crowe B, David AL, DeVile C, Forsmark A, Franzen V, Hermeren G, Hill M, Johansson M, Lindemans C, Lindgren P, Nijhuis W, Oepkes D, Rehberg M, Sahlin NE, Sakkers R, Semler O, Sundin M, Walther-Jallow L, Verweij EJTJ, Westgren M, Götherström C. An exploratory open-label multicentre phase I/II trial evaluating the safety and efficacy of postnatal or prenatal and postnatal administration of allogeneic expanded fetal mesenchymal stem cells for the treatment of severe osteogenesis imperfecta in infants and fetuses: the BOOSTB4 trial protocol. BMJ Open 2024; 14:e079767. [PMID: 38834319 PMCID: PMC11163617 DOI: 10.1136/bmjopen-2023-079767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 05/22/2024] [Indexed: 06/06/2024] Open
Abstract
INTRODUCTION Severe osteogenesis imperfecta (OI) is a debilitating disease with no cure or sufficiently effective treatment. Mesenchymal stem cells (MSCs) have good safety profile, show promising effects and can form bone. The Boost Brittle Bones Before Birth (BOOSTB4) trial evaluates administration of allogeneic expanded human first trimester fetal liver MSCs (BOOST cells) for OI type 3 or severe type 4. METHODS AND ANALYSIS BOOSTB4 is an exploratory, open-label, multiple dose, phase I/II clinical trial evaluating safety and efficacy of postnatal (n=15) or prenatal and postnatal (n=3, originally n=15) administration of BOOST cells for the treatment of severe OI compared with a combination of historical (1-5/subject) and untreated prospective controls (≤30). Infants<18 months of age (originally<12 months) and singleton pregnant women whose fetus has severe OI with confirmed glycine substitution in COL1A1 or COL1A2 can be included in the trial.Each subject receives four intravenous doses of 3×106/kg BOOST cells at 4 month intervals, with 48 (doses 1-2) or 24 (doses 3-4) hours in-patient follow-up, primary follow-up at 6 and 12 months after the last dose and long-term follow-up yearly until 10 years after the first dose. Prenatal subjects receive the first dose via ultrasound-guided injection into the umbilical vein within the fetal liver (16+0 to 35+6 weeks), and three doses postnatally.The primary outcome measures are safety and tolerability of repeated BOOST cell administration. The secondary outcome measures are number of fractures from baseline to primary and long-term follow-up, growth, change in bone mineral density, clinical OI status and biochemical bone turnover. ETHICS AND DISSEMINATION The trial is approved by Competent Authorities in Sweden, the UK and the Netherlands (postnatal only). Results from the trial will be disseminated via CTIS, ClinicalTrials.gov and in scientific open-access scientific journals. TRIAL REGISTRATION NUMBERS EudraCT 2015-003699-60, EUCT: 2023-504593-38-00, NCT03706482.
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Affiliation(s)
- Rachel L Sagar
- Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, UK
- NIHR University College London Hospitals Biomedical Research Centre, London, UK
| | - Eva Åström
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
- Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden
| | - Lyn S Chitty
- North Thames Genomic Laboratory Hub, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
- Genetics and Genomics, UCL Great Ormond Street Institute of Child Health, London, UK
| | - Belinda Crowe
- Department of Neurosciences, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Anna L David
- Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, UK
- NIHR University College London Hospitals Biomedical Research Centre, London, UK
| | - Catherine DeVile
- Department of Neurosciences, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | | | | | - Göran Hermeren
- Department of Clinical Sciences, Lund University Faculty of Medicine, Lund, Sweden
| | - Melissa Hill
- North Thames Genomic Laboratory Hub, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
- Genetics and Genomics, UCL Great Ormond Street Institute of Child Health, London, UK
| | - Mats Johansson
- Department of Clinical Sciences, Lund University Faculty of Medicine, Lund, Sweden
| | - Caroline Lindemans
- Department of Pediatrics, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - Peter Lindgren
- Center for Fetal Medicine, Karolinska University Hospital, Stockholm, Sweden
- Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Wouter Nijhuis
- Department of Orthopedic Surgery, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - Dick Oepkes
- Department of Obstetrics, Leiden University Medical Center, Leiden, The Netherlands
| | - Mirko Rehberg
- Department of Pediatrics, University Hospital Cologne, Koln, Nordrhein-Westfalen, Germany
| | - Nils-Eric Sahlin
- Department of Clinical Sciences, Lund University Faculty of Medicine, Lund, Sweden
| | - Ralph Sakkers
- Department of Orthopedic Surgery, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - O Semler
- Department of Pediatrics, University Hospital Cologne, Koln, Nordrhein-Westfalen, Germany
| | - Mikael Sundin
- Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
- Section of Pediatic Hematology, Immunology and HCT, Karolinska University Hospital, Stockholm, Sweden
| | - Lilian Walther-Jallow
- Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - E J T Joanne Verweij
- Department of Obstetrics, Leiden University Medical Center, Leiden, The Netherlands
| | - Magnus Westgren
- Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Cecilia Götherström
- Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
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Malisetyan T, Harrison JL, Shahriari SR, Clarke TN, Rogol EV, Borah GL. Autologous Fat Transfer in Craniofacial Surgery. FACE 2024; 5:279-291. [DOI: 10.1177/27325016241238441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Abstract
Over the past two decades, autologous fat transfer has garnered significant recognition and widespread adoption within esthetic and reconstructive surgical domains. In craniofacial surgery, fat transplantation is frequently employed to address soft tissue volumetric deficiencies and asymmetries that influence facial contours. While adipose tissue (AT) is widely regarded as an optimal choice for augmentation due to its abundant availability and biocompatibility, the unpredictability and heightened resorption rates observed with traditional lipofilling techniques present a challenge for clinicians. Adipose-derived stem cells (ASCs) housed within the grafted tissue play a pivotal role in graft survival and offer avenues for tissue repair due to their angiogenic, anti-inflammatory, and immunosuppressive properties. Micro Fragmentation of Adipose Tissue (MFAT), utilized in several FDA-approved processing devices, has demonstrated promising outcomes in treating osteoarthritic joints, with success primarily attributed to enhanced paracrine function of ASCs via preservation of the perivascular niche. Currently, its application for treating bone or articular defects in the craniofacial region, including abnormalities of the temporomandibular joint, remains limited. This scarcity underscores the need for further investigation prior to its widespread integration into clinical practice.
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Affiliation(s)
- Tatevik Malisetyan
- Nova Southeastern University, Dr. Kiran C. Patel College of Allopathic Medicine, Fort Lauderdale, FL, USA
| | | | | | - Tegan N. Clarke
- University of New Mexico School of Medicine, Albuquerque, NM, USA
| | | | - Gregory L. Borah
- University of New Mexico School of Medicine, Albuquerque, NM, USA
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Mamachan M, Sharun K, Banu SA, Muthu S, Pawde AM, Abualigah L, Maiti SK. Mesenchymal stem cells for cartilage regeneration: Insights into molecular mechanism and therapeutic strategies. Tissue Cell 2024; 88:102380. [PMID: 38615643 DOI: 10.1016/j.tice.2024.102380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 03/15/2024] [Accepted: 04/09/2024] [Indexed: 04/16/2024]
Abstract
The use of mesenchymal stem cells (MSCs) in cartilage regeneration has gained significant attention in regenerative medicine. This paper reviews the molecular mechanisms underlying MSC-based cartilage regeneration and explores various therapeutic strategies to enhance the efficacy of MSCs in this context. MSCs exhibit multipotent capabilities and can differentiate into various cell lineages under specific microenvironmental cues. Chondrogenic differentiation, a complex process involving signaling pathways, transcription factors, and growth factors, plays a pivotal role in the successful regeneration of cartilage tissue. The chondrogenic differentiation of MSCs is tightly regulated by growth factors and signaling pathways such as TGF-β, BMP, Wnt/β-catenin, RhoA/ROCK, NOTCH, and IHH (Indian hedgehog). Understanding the intricate balance between these pathways is crucial for directing lineage-specific differentiation and preventing undesirable chondrocyte hypertrophy. Additionally, paracrine effects of MSCs, mediated by the secretion of bioactive factors, contribute significantly to immunomodulation, recruitment of endogenous stem cells, and maintenance of chondrocyte phenotype. Pre-treatment strategies utilized to potentiate MSCs, such as hypoxic conditions, low-intensity ultrasound, kartogenin treatment, and gene editing, are also discussed for their potential to enhance MSC survival, differentiation, and paracrine effects. In conclusion, this paper provides a comprehensive overview of the molecular mechanisms involved in MSC-based cartilage regeneration and outlines promising therapeutic strategies. The insights presented contribute to the ongoing efforts in optimizing MSC-based therapies for effective cartilage repair.
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Affiliation(s)
- Merlin Mamachan
- Division of Surgery, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India
| | - Khan Sharun
- Division of Surgery, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India; Graduate Institute of Medicine, Yuan Ze University, Taoyuan, Taiwan.
| | - S Amitha Banu
- Division of Surgery, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India
| | - Sathish Muthu
- Department of Biotechnology, Faculty of Engineering, Karpagam Academy of Higher Education, Coimbatore, Tamil Nadu, India; Orthopaedic Research Group, Coimbatore, Tamil Nadu, India; Department of Orthopaedics, Government Medical College, Kaur, Tamil Nadu, India
| | - Abhijit M Pawde
- Division of Surgery, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India
| | - Laith Abualigah
- Artificial Intelligence and Sensing Technologies (AIST) Research Center, University of Tabuk, Tabuk 71491, Saudi Arabia; Hourani Center for Applied Scientific Research, Al-Ahliyya Amman University, Amman 19328, Jordan; Computer Science Department, Al al-Bayt University, Mafraq 25113, Jordan; MEU Research Unit, Middle East University, Amman 11831, Jordan; Department of Electrical and Computer Engineering, Lebanese American University, Byblos 13-5053, Lebanon; Applied Science Research Center, Applied Science Private University, Amman 11931, Jordan; School of Engineering and Technology, Sunway University Malaysia, Petaling Jaya 27500, Malaysia
| | - Swapan Kumar Maiti
- Division of Surgery, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India
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Wang G, Li Z, Wang G, Sun Q, Lin P, Wang Q, Zhang H, Wang Y, Zhang T, Cui F, Zhong Z. Advances in Engineered Nanoparticles for the Treatment of Ischemic Stroke by Enhancing Angiogenesis. Int J Nanomedicine 2024; 19:4377-4409. [PMID: 38774029 PMCID: PMC11108071 DOI: 10.2147/ijn.s463333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 05/02/2024] [Indexed: 05/24/2024] Open
Abstract
Angiogenesis, or the formation of new blood vessels, is a natural defensive mechanism that aids in the restoration of oxygen and nutrition delivery to injured brain tissue after an ischemic stroke. Angiogenesis, by increasing vessel development, may maintain brain perfusion, enabling neuronal survival, brain plasticity, and neurologic recovery. Induction of angiogenesis and the formation of new vessels aid in neurorepair processes such as neurogenesis and synaptogenesis. Advanced nano drug delivery systems hold promise for treatment stroke by facilitating efficient transportation across the the blood-brain barrier and maintaining optimal drug concentrations. Nanoparticle has recently been shown to greatly boost angiogenesis and decrease vascular permeability, as well as improve neuroplasticity and neurological recovery after ischemic stroke. We describe current breakthroughs in the development of nanoparticle-based treatments for better angiogenesis therapy for ischemic stroke employing polymeric nanoparticles, liposomes, inorganic nanoparticles, and biomimetic nanoparticles in this study. We outline new nanoparticles in detail, review the hurdles and strategies for conveying nanoparticle to lesions, and demonstrate the most recent advances in nanoparticle in angiogenesis for stroke treatment.
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Affiliation(s)
- Guangtian Wang
- Teaching Center of Pathogenic Biology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, 150081, People’s Republic of China
- Department of Microbiology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, 150081, People’s Republic of China
| | - Zhihui Li
- Department of Neurology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150086, People’s Republic of China
| | - Gongchen Wang
- Department of Vascular Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150086, People’s Republic of China
| | - Qixu Sun
- Department of Gastroenterology, Penglai People’s Hospital, Yantai, Shandong, 265600, People’s Republic of China
| | - Peng Lin
- Teaching Center of Pathogenic Biology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, 150081, People’s Republic of China
| | - Qian Wang
- Department of Microbiology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, 150081, People’s Republic of China
| | - Huishu Zhang
- Teaching Center of Biotechnology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, 150081, People’s Republic of China
| | - Yanyan Wang
- Teaching Center of Morphology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, 150081, People’s Republic of China
| | - Tongshuai Zhang
- Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, 150081, People’s Republic of China
| | - Feiyun Cui
- Department of Physiology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, 150081, People’s Republic of China
| | - Zhaohua Zhong
- Teaching Center of Pathogenic Biology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, 150081, People’s Republic of China
- Department of Microbiology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, 150081, People’s Republic of China
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Ni J, Ye D, Zeng W, Ma S, Wang Z, Kuang Y, Yang L. Promotion of hair growth by a conditioned medium from human umbilical cord mesenchymal stem cells cultivated in a 3D scaffold of gelatin sponge. Eur J Med Res 2024; 29:270. [PMID: 38704575 PMCID: PMC11069168 DOI: 10.1186/s40001-024-01830-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 04/05/2024] [Indexed: 05/06/2024] Open
Abstract
BACKGROUND This study aims to investigate the effects of a conditioned medium (CM) from human umbilical cord mesenchymal stem cells (HuMSCs) cultivated in gelatin sponge (GS-HuMSCs-CM) on hair growth in a mouse model. METHODS CM was collected from the HuMSCs cultivated in a monolayer or in a gelatin sponge. Vascular endothelial growth factor (VEGF), insulin-like growth factor-1 (IGF-1), keratinocyte growth factor (KGF), and hepatocyte growth factor (HGF) levels in CMs were measured by enzyme-linked immunosorbent assays (ELISAs). A hair loss model by a C57 BL/6J mouse was prepared. The effects of GS-HuMSCs-CM and HuMSCs on hair regrowth in mice were investigated by intradermal injection in the depilated back skin with normal saline (NS) as the control. The time for hair regrowth and full covering in depilated areas was observed, and the hair growth was evaluated histologically and by grossly measuring hair length and diameter. RESULTS Compared with monolayer cultured cells, the three-dimensional (3D) culture of HuMSCs in gelatin sponge drastically increased VEGF, IGF-1, KGF, and HGF production. GS-HuMSCs-CM and HuMSCs injection both promoted hair regeneration in mice, while GS-HuMSCs-CM presented more enhanced effects in hair length, hair diameter, and growth rate. GS-HuMSCs-CM significantly promoted angiogenesis in injected skin areas, which might also contribute to faster hair regrowth. CONCLUSION GS-HuMSCs-CM exerted significant effects on inducing hair growth and promoted skin angiogenesis in C57BL/6J mice.
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Affiliation(s)
- Jintao Ni
- Department of Plastic Surgery and Burns Center, Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Danyan Ye
- Research Center for Translational Medicine, Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Weiping Zeng
- Department of Plastic Surgery and Burns Center, Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Siyi Ma
- Department of Plastic Surgery and Burns Center, Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Zhixia Wang
- Department of Plastic Surgery and Burns Center, Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Yuping Kuang
- Department of Plastic Surgery and Burns Center, Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Lujun Yang
- Department of Plastic Surgery and Burns Center, Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
- Research Center for Translational Medicine, Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
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Gualerzi A, Picciolini S, Bedoni M, Guerini FR, Clerici M, Agliardi C. Extracellular Vesicles as Biomarkers for Parkinson's Disease: How Far from Clinical Translation? Int J Mol Sci 2024; 25:1136. [PMID: 38256215 PMCID: PMC10816807 DOI: 10.3390/ijms25021136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 01/08/2024] [Accepted: 01/15/2024] [Indexed: 01/24/2024] Open
Abstract
Parkinson's disease (PD) is a neurodegenerative disorder affecting about 10 million people worldwide with a prevalence of about 2% in the over-80 population. The disease brings in also a huge annual economic burden, recently estimated by the Michael J Fox Foundation for Parkinson's Research to be USD 52 billion in the United States alone. Currently, no effective cure exists, but available PD medical treatments are based on symptomatic prescriptions that include drugs, surgical approaches and rehabilitation treatment. Due to the complex biology of a PD brain, the design of clinical trials and the personalization of treatment strategies require the identification of accessible and measurable biomarkers to monitor the events induced by treatment and disease progression and to predict patients' responsiveness. In the present review, we strive to briefly summarize current knowledge about PD biomarkers, focusing on the role of extracellular vesicles as active or involuntary carriers of disease-associated proteins, with particular attention to those research works that envision possible clinical applications.
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Affiliation(s)
- Alice Gualerzi
- IRCCS Fondazione Don Gnocchi Onlus, 20148 Milan, Italy; (A.G.); (S.P.); (M.C.); (C.A.)
| | - Silvia Picciolini
- IRCCS Fondazione Don Gnocchi Onlus, 20148 Milan, Italy; (A.G.); (S.P.); (M.C.); (C.A.)
| | - Marzia Bedoni
- IRCCS Fondazione Don Gnocchi Onlus, 20148 Milan, Italy; (A.G.); (S.P.); (M.C.); (C.A.)
| | - Franca Rosa Guerini
- IRCCS Fondazione Don Gnocchi Onlus, 20148 Milan, Italy; (A.G.); (S.P.); (M.C.); (C.A.)
| | - Mario Clerici
- IRCCS Fondazione Don Gnocchi Onlus, 20148 Milan, Italy; (A.G.); (S.P.); (M.C.); (C.A.)
- Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy
| | - Cristina Agliardi
- IRCCS Fondazione Don Gnocchi Onlus, 20148 Milan, Italy; (A.G.); (S.P.); (M.C.); (C.A.)
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Jakobsen KK, Carlander ALF, Grønhøj C, Todsen T, Melchiors J, Paaske N, Madsen AKØ, Kastrup J, Ekblond A, Haack-Sørensen M, Farhadi M, Maare C, Friborg J, Lynggard CD, von Buchwald C. Effectiveness and safety of mesenchymal stem/stromal cell for radiation-induced hyposalivation and xerostomia in previous head and neck cancer patients (MESRIX-III): a study protocol for a single-centre, double-blinded, randomised, placebo-controlled, phase II study. Trials 2023; 24:567. [PMID: 37658468 PMCID: PMC10474624 DOI: 10.1186/s13063-023-07594-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 08/17/2023] [Indexed: 09/03/2023] Open
Abstract
BACKGROUND A predominant side effect of radiotherapy for head and neck cancer is salivary gland hypofunction and xerostomia leading to debilitating oral disorders and impaired quality of life (QoL). Intraglandular mesenchymal stem cell therapy has shown promising results as a treatment for xerostomia. METHODS This is a randomised, double-blinded, placebo-controlled, parallel-group, prospective, single-centre trial investigating the safety, tolerability, and effectiveness of allogeneic stem cells as a treatment for radiation-induced hyposalivation and xerostomia for previous head and neck cancer patients. We will include a total of 120 patients who previously have been treated with radiotherapy for a head and neck cancer in Denmark. Participants will be randomly assigned using block randomisation to one of two parallel groups in a 1:1 ratio to receive ultrasound-guided injection of allogeneic adipose-derived mesenchymal stem cell (ASC) (n = 60) or placebo (n = 60) into the submandibular glands. Placebo will consist of CryoStor10 (BiolifeSolutions), the freeze media for ASCs containing 10% dimethyl sulfoxide (DMSO). The primary endpoint is change in unstimulated whole saliva flow rate. The secondary endpoints are change in stimulated whole saliva flow rate, QoL, and composition of saliva. Further secondary endpoints are safety and immune response (human leukocyte antigen (HLA) response) to the stem cells will be assessed. Patients are evaluated at baseline (before treatment), after 4 months, and after 12 months. All study personnel, except study personnel thawing and preparing the treatment for injection, and participants will be blinded to group assignment. Unblinded study personnel will not participate in the outcome assessment. DISCUSSION The trials will investigate the efficacy and safety of ASC injection to the submandibular gland as a potential new treatment for post-radiation xerostomia. We hope the results will pave the way for a clinically relevant treatment to ameliorate patients with xerostomia, a severely hampering condition. TRIAL REGISTRATION The study is approved by the Danish Data Protection Agency (protocol number P-2020-1164), the National Ethics Committee protocol number: (Protocol number: 1802872), and the Danish Medical Agency (2018-000348-24). The protocol was registered at the ClinicalTrials.gov database (NCT04776538).
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Affiliation(s)
- Kathrine Kronberg Jakobsen
- Department of Otorhinolaryngology, Head and Neck Surgery & Audiology, Rigshospitalet - Copenhagen University Hospital, Copenhagen, Denmark.
| | - Amanda-Louise Fenger Carlander
- Department of Otorhinolaryngology, Head and Neck Surgery & Audiology, Rigshospitalet - Copenhagen University Hospital, Copenhagen, Denmark
| | - Christian Grønhøj
- Department of Otorhinolaryngology, Head and Neck Surgery & Audiology, Rigshospitalet - Copenhagen University Hospital, Copenhagen, Denmark
| | - Tobias Todsen
- Department of Otorhinolaryngology, Head and Neck Surgery & Audiology, Rigshospitalet - Copenhagen University Hospital, Copenhagen, Denmark
| | - Jacob Melchiors
- Department of Otorhinolaryngology, Head and Neck Surgery & Audiology, Rigshospitalet - Copenhagen University Hospital, Copenhagen, Denmark
| | - Natasja Paaske
- Department of Otorhinolaryngology, Head and Neck Surgery & Audiology, Rigshospitalet - Copenhagen University Hospital, Copenhagen, Denmark
| | - Anne Kathrine Østergaard Madsen
- Department of Otorhinolaryngology, Head and Neck Surgery & Audiology, Rigshospitalet - Copenhagen University Hospital, Copenhagen, Denmark
| | - Jens Kastrup
- Cardiology Stem Cell Centre, The Heart Centre, Rigshospitalet, Copenhagen, Denmark
| | - Annette Ekblond
- Cardiology Stem Cell Centre, The Heart Centre, Rigshospitalet, Copenhagen, Denmark
| | | | - Mohammad Farhadi
- Department of Oncology, University Hospital Zealand, Roskilde, Denmark
| | | | - Jeppe Friborg
- Department of Oncology, Rigshospitalet, Copenhagen, Denmark
| | - Charlotte Duch Lynggard
- Department of Otorhinolaryngology, Head and Neck Surgery & Audiology, Rigshospitalet - Copenhagen University Hospital, Copenhagen, Denmark
| | - Christian von Buchwald
- Department of Otorhinolaryngology, Head and Neck Surgery & Audiology, Rigshospitalet - Copenhagen University Hospital, Copenhagen, Denmark
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Chen J, Ma S, Luo B, Hao H, Li Y, Yang H, Zhu F, Zhang P, Niu R, Pan P. Human umbilical cord mesenchymal stromal cell small extracellular vesicle transfer of microRNA-223-3p to lung epithelial cells attenuates inflammation in acute lung injury in mice. J Nanobiotechnology 2023; 21:295. [PMID: 37626408 PMCID: PMC10464265 DOI: 10.1186/s12951-023-02038-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 07/31/2023] [Indexed: 08/27/2023] Open
Abstract
BACKGROUND Acute lung injury (ALI), manifested as strong pulmonary inflammation and alveolar epithelial damage, is a life-threatening disease with high morbidity and mortality. Small extracellular vesicles (sEVs), secreted by multiple types of cells, are critical cellular communication mediators and can inhibit inflammation by transferring bioactive molecules, such as microRNAs (miRNAs). Thus, we hypothesized that sEVs derived from mesenchymal stromal cells (MSC sEVs) could transfer miRNAs to attenuate inflammation of lung epithelial cells during ALI. METHODS C57BL/6 male mice were intratracheally administered LPS (10 mg/kg). Six hours later, the mice were randomly administered with MSC sEVs (40 µg per mouse in 150 µl of saline), which were collected by ultracentrifugation. Control group received saline administration. After 48 h, the mice were sacrificed to evaluate pulmonary microvascular permeability and inflammatory responses. In vitro, A549 cells and primary human small airway epithelial cells (SAECs) were stimulated with LPS with or without MSC sEVs treatment. RESULTS In vitro, MSC sEVs could also inhibit the inflammation induced by LPS in A549 cells and SAECs (reducing TNF-α, IL-1β, IL-6 and MCP-1). Moreover, MSC sEV treatment improved the survival rate, alleviated pulmonary microvascular permeability, and inhibited proinflammatory responses (reducing TNF-α, IL-1β, IL-6 and JE-1) in ALI mice. Notably, miR-223-3p was found to be served as a critical mediator in MSC sEV-induced regulatory effects through inhibition of poly (adenosine diphosphate-ribose) polymerase-1 (PARP-1) in lung epithelial cells. CONCLUSIONS Overall, these findings suggest that MSC sEVs may offer a novel promising strategy for ALI.
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Affiliation(s)
- Jie Chen
- Department of Respiratory Medicine, Clinical Research Center for Respiratory Disease, Xiangya Hospital, National Key Clinical Specialty, Branch of National, Central South University, No.28 Xiangya Road, Kai-Fu District, Changsha, 410008, Hunan, China
- Center of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Clinical Research Center for Respiratory Diseases in Hunan Province, Changsha, 410008, Hunan, China
- Hunan Engineering Research Center for Intelligent Diagnosis and Treatment of Respiratory Disease, Chang-sha, 410008, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, 410008, Hunan, P.R. China
| | - Shiyang Ma
- Department of Respiratory Medicine, Clinical Research Center for Respiratory Disease, Xiangya Hospital, National Key Clinical Specialty, Branch of National, Central South University, No.28 Xiangya Road, Kai-Fu District, Changsha, 410008, Hunan, China
- Center of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Clinical Research Center for Respiratory Diseases in Hunan Province, Changsha, 410008, Hunan, China
- Hunan Engineering Research Center for Intelligent Diagnosis and Treatment of Respiratory Disease, Chang-sha, 410008, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, 410008, Hunan, P.R. China
| | - Baihua Luo
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Haojie Hao
- Institute of Basic Medicine Science, Chinese People's Liberation Army General Hospital, Chinese People's Liberation Army Medical College, Beijing, China
| | - Yanqin Li
- Center of Pulmonary & Critical Care Medicine, Chinese People's Liberation Army (PLA) General Hospital, Chinese PLA Medical College, Beijing, China
| | - Hang Yang
- Department of Respiratory Medicine, Clinical Research Center for Respiratory Disease, Xiangya Hospital, National Key Clinical Specialty, Branch of National, Central South University, No.28 Xiangya Road, Kai-Fu District, Changsha, 410008, Hunan, China
- Center of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Clinical Research Center for Respiratory Diseases in Hunan Province, Changsha, 410008, Hunan, China
- Hunan Engineering Research Center for Intelligent Diagnosis and Treatment of Respiratory Disease, Chang-sha, 410008, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, 410008, Hunan, P.R. China
| | - Fei Zhu
- Department of Respiratory Medicine, Clinical Research Center for Respiratory Disease, Xiangya Hospital, National Key Clinical Specialty, Branch of National, Central South University, No.28 Xiangya Road, Kai-Fu District, Changsha, 410008, Hunan, China
- Center of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Clinical Research Center for Respiratory Diseases in Hunan Province, Changsha, 410008, Hunan, China
- Hunan Engineering Research Center for Intelligent Diagnosis and Treatment of Respiratory Disease, Chang-sha, 410008, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, 410008, Hunan, P.R. China
| | - Peipei Zhang
- Department of Respiratory Medicine, Clinical Research Center for Respiratory Disease, Xiangya Hospital, National Key Clinical Specialty, Branch of National, Central South University, No.28 Xiangya Road, Kai-Fu District, Changsha, 410008, Hunan, China
- Center of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Clinical Research Center for Respiratory Diseases in Hunan Province, Changsha, 410008, Hunan, China
- Hunan Engineering Research Center for Intelligent Diagnosis and Treatment of Respiratory Disease, Chang-sha, 410008, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, 410008, Hunan, P.R. China
| | - Ruichao Niu
- Department of Respiratory Medicine, Clinical Research Center for Respiratory Disease, Xiangya Hospital, National Key Clinical Specialty, Branch of National, Central South University, No.28 Xiangya Road, Kai-Fu District, Changsha, 410008, Hunan, China.
- Center of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
- Clinical Research Center for Respiratory Diseases in Hunan Province, Changsha, 410008, Hunan, China.
- Hunan Engineering Research Center for Intelligent Diagnosis and Treatment of Respiratory Disease, Chang-sha, 410008, Hunan, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, 410008, Hunan, P.R. China.
- Department of Respiratory Medicine, The Second Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region, Urumqi, China.
| | - Pinhua Pan
- Department of Respiratory Medicine, Clinical Research Center for Respiratory Disease, Xiangya Hospital, National Key Clinical Specialty, Branch of National, Central South University, No.28 Xiangya Road, Kai-Fu District, Changsha, 410008, Hunan, China.
- Center of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
- Clinical Research Center for Respiratory Diseases in Hunan Province, Changsha, 410008, Hunan, China.
- Hunan Engineering Research Center for Intelligent Diagnosis and Treatment of Respiratory Disease, Chang-sha, 410008, Hunan, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, 410008, Hunan, P.R. China.
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Zhao J, Deng H, Xun C, Chen C, Hu Z, Ge L, Jiang Z. Therapeutic potential of stem cell extracellular vesicles for ischemic stroke in preclinical rodent models: a meta-analysis. Stem Cell Res Ther 2023; 14:62. [PMID: 37013588 PMCID: PMC10071642 DOI: 10.1186/s13287-023-03270-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Accepted: 03/08/2023] [Indexed: 04/05/2023] Open
Abstract
BACKGROUND Extracellular vesicles derived from stem cells (SC-EVs) have been proposed as a novel therapy for ischemic stroke. However, their effects remain incompletely understood. Therefore, we conducted this meta-analysis to systematically review the efficacy of SC-EVs on ischemic stroke in preclinical rodent models. METHODS Using PubMed, EMBASE, and the Web of Science, we searched through studies published up to August 2021 that investigated the treatment effects of SC-EVs in a rodent ischemic stroke model. Infarct volume was the primary outcome. Neurological severity scores (mNSS) were the secondary outcome. The standard mean difference (SMD) and the confidence interval (CI) were calculated using a random-effects model. R and Stata 15.1 were used to conduct the meta-analysis. RESULTS Twenty-one studies published from 2015 to 2021 met the inclusion criteria. We also found that SCs-EVs reduced infarct volume by an SMD of - 2.05 (95% CI - 2.70, - 1.40; P < 0.001). Meanwhile, our results revealed an overall positive effect of SCs-derived EVs on the mNSS with an SMD of - 1.42 (95% CI - 1.75, - 1.08; P < 0.001). Significant heterogeneity among studies was observed. Further stratified and sensitivity analyses did not identify the source of heterogeneity. CONCLUSION The present meta-analysis confirmed that SC-EV therapy could improve neuron function and reduce infarct volume in a preclinical rodent ischemic stroke model, providing helpful clues for human clinical trials on SC-EVs.
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Affiliation(s)
- Jing Zhao
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, 410011, People's Republic of China
| | - Huiyin Deng
- Department of Anesthesiology, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan Province, People's Republic of China
| | - Chengfeng Xun
- Hunan Provincial Key Laboratory of Neurorestoratology, The Second Affiliated Hospital, Hunan Normal University, Changsha, 410003, People's Republic of China
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410006, People's Republic of China
| | - Chunli Chen
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, 410011, People's Republic of China
| | - Zhiping Hu
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, 410011, People's Republic of China
| | - Lite Ge
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, 410011, People's Republic of China.
- Hunan Provincial Key Laboratory of Neurorestoratology, The Second Affiliated Hospital, Hunan Normal University, Changsha, 410003, People's Republic of China.
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410006, People's Republic of China.
| | - Zheng Jiang
- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, 410011, People's Republic of China.
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Adipose-Derived Mesenchymal Stromal Cells in Basic Research and Clinical Applications. Int J Mol Sci 2023; 24:ijms24043888. [PMID: 36835295 PMCID: PMC9962639 DOI: 10.3390/ijms24043888] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 01/09/2023] [Accepted: 02/14/2023] [Indexed: 02/17/2023] Open
Abstract
Adipose-derived mesenchymal stromal cells (AD-MSCs) have been extensively studied in recent years. Their attractiveness is due to the ease of obtaining clinical material (fat tissue, lipoaspirate) and the relatively large number of AD-MSCs present in adipose tissue. In addition, AD-MSCs possess a high regenerative potential and immunomodulatory activities. Therefore, AD-MSCs have great potential in stem cell-based therapies in wound healing as well as in orthopedic, cardiovascular, or autoimmune diseases. There are many ongoing clinical trials on AD-MSC and in many cases their effectiveness has been proven. In this article, we present current knowledge about AD-MSCs based on our experience and other authors. We also demonstrate the application of AD-MSCs in selected pre-clinical models and clinical studies. Adipose-derived stromal cells can also be the pillar of the next generation of stem cells that will be chemically or genetically modified. Despite much research on these cells, there are still important and interesting areas to explore.
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17
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Khaing ZZ, Chen JY, Safarians G, Ezubeik S, Pedroncelli N, Duquette RD, Prasse T, Seidlits SK. Clinical Trials Targeting Secondary Damage after Traumatic Spinal Cord Injury. Int J Mol Sci 2023; 24:3824. [PMID: 36835233 PMCID: PMC9960771 DOI: 10.3390/ijms24043824] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 02/06/2023] [Accepted: 02/09/2023] [Indexed: 02/17/2023] Open
Abstract
Spinal cord injury (SCI) often causes loss of sensory and motor function resulting in a significant reduction in quality of life for patients. Currently, no therapies are available that can repair spinal cord tissue. After the primary SCI, an acute inflammatory response induces further tissue damage in a process known as secondary injury. Targeting secondary injury to prevent additional tissue damage during the acute and subacute phases of SCI represents a promising strategy to improve patient outcomes. Here, we review clinical trials of neuroprotective therapeutics expected to mitigate secondary injury, focusing primarily on those in the last decade. The strategies discussed are broadly categorized as acute-phase procedural/surgical interventions, systemically delivered pharmacological agents, and cell-based therapies. In addition, we summarize the potential for combinatorial therapies and considerations.
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Affiliation(s)
- Zin Z. Khaing
- Department of Neurological Surgery, University of Washington, Seattle, WA 98195, USA
| | - Jessica Y. Chen
- Department of Bioengineering, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Gevick Safarians
- Department of Bioengineering, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Sohib Ezubeik
- Department of Bioengineering, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Nicolas Pedroncelli
- Department of Bioengineering, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Rebecca D. Duquette
- Department of Bioengineering, University of California Los Angeles, Los Angeles, CA 90095, USA
- Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712, USA
| | - Tobias Prasse
- Department of Neurological Surgery, University of Washington, Seattle, WA 98195, USA
- Department of Orthopedics and Trauma Surgery, University of Cologne, 50931 Cologne, Germany
| | - Stephanie K. Seidlits
- Department of Bioengineering, University of California Los Angeles, Los Angeles, CA 90095, USA
- Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712, USA
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Oncologic Safety and Efficacy of Cell-Assisted Lipotransfer for Breast Reconstruction in a Murine Model of Residual Breast Cancer. Aesthetic Plast Surg 2023; 47:412-422. [PMID: 35918436 DOI: 10.1007/s00266-022-03021-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 07/08/2022] [Indexed: 11/27/2022]
Abstract
BACKGROUND Cell-assisted lipotransfer (CAL) is a novel technique for fat grafting that combines the grafting of autologous fat and adipose-derived stromal cells (ASCs) to enhance fat graft retention; however, its oncologic safety is controversial. METHODS Herein, we investigated the oncologic safety of CAL for breast reconstruction using a murine model of residual breast cancer. Various concentrations of 4T1 cells (murine breast cancer cells) were injected into female mastectomized BALB/c mice to determine the appropriate concentration for injection. One week after injection, mice were divided into control (100 μL fat), low CAL (2.5 × 105 ASCs/100 μL fat), and high CAL (1.0 × 106 ASCs/100 μL fat) groups, and fat grafting was performed. The injection of 5.0 × 103 4T1 cells was appropriate to produce a murine model of residual breast cancer. RESULTS The weight of the fat tumor mass was significantly higher in the high CAL group than in the other groups (p < 0.05). However, the estimated tumor weight was not significantly different between the groups. Additionally, the fat graft survival rate was significantly higher in the high CAL group than in the control and low CAL groups (p < 0.05). No significant difference was noted in the percentage of Ki-67-positive cells, suggesting that tumor proliferation was not significantly different between the groups. CONCLUSION In summary, CAL significantly improved fat graft survival without affecting tumor size and proliferation in a murine model of residual breast cancer. These results highlight the oncologic safety of CAL for breast reconstruction. NO LEVEL ASSIGNED This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
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Caiati C, Jirillo E. Transplantation of Mesenchymal Stem Cells as a New Approach for Cardiovascular Diseases: From Bench to Bedside: A Perspective. Endocr Metab Immune Disord Drug Targets 2023; 23:1359-1364. [PMID: 37055907 DOI: 10.2174/1871530323666230411142308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 03/01/2023] [Indexed: 04/15/2023]
Affiliation(s)
- Carlo Caiati
- Interdisciplinary Department of Medicine, University of Bari "Aldo Moro", Bari, Italy
| | - Emilio Jirillo
- Interdisciplinary Department of Medicine, University of Bari "Aldo Moro", Bari, Italy
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20
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Extracellular Vesicles and Cellular Ageing. Subcell Biochem 2023; 102:271-311. [PMID: 36600137 DOI: 10.1007/978-3-031-21410-3_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Ageing is a complex process characterized by deteriorated performance at multiple levels, starting from cellular dysfunction to organ degeneration. Stem cell-based therapies aim to administrate stem cells that eventually migrate to the injured site to replenish the damaged tissue and recover tissue functionality. Stem cells can be easily obtained and cultured in vitro, and display several qualities such as self-renewal, differentiation, and immunomodulation that make them suitable candidates for stem cell-based therapies. Current animal studies and clinical trials are being performed to assess the safety and beneficial effects of stem cell engraftments for regenerative medicine in ageing and age-related diseases.Since alterations in cell-cell communication have been associated with the development of pathophysiological processes, new research is focusing on the modulation of the microenvironment. Recent research has highlighted the important role of some microenvironment components that modulate cell-cell communication, thus spreading signals from damaged ageing cells to neighbor healthy cells, thereby promoting systemic ageing. Extracellular vesicles (EVs) are small-rounded vesicles released by almost every cell type. EVs cargo includes several bioactive molecules, such as lipids, proteins, and genetic material. Once internalized by target cells, their specific cargo can induce epigenetic modifications and alter the fate of the recipient cells. Also, EV's content is dependent on the releasing cells, thus, EVs can be used as biomarkers for several diseases. Moreover, EVs have been proposed to be used as cell-free therapies that focus on their administration to slow or even reverse some hallmarks of physiological ageing. It is not surprising that EVs are also under study as next-generation therapies for age-related diseases.
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21
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Liang C, Wu S, Xia G, Huang J, Wen Z, Zhang W, Cao X. Engineered M2a macrophages for the treatment of osteoarthritis. Front Immunol 2022; 13:1054938. [PMID: 36582221 PMCID: PMC9792488 DOI: 10.3389/fimmu.2022.1054938] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 11/30/2022] [Indexed: 12/14/2022] Open
Abstract
Background Macrophage is a central regulator of innate immunity. Its M2 subsets, such as interstitial synovial macrophages, have been found to play critical roles in suppressing chronic inflammation and maintaining homeostasis within the joint. These macrophages have great potential as a disease-modifying cell therapy for osteoarthritis (OA). However, this has not yet been studied. Methods Macrophages were isolated from the bone marrow of rats. We constructed a stable macrophage that "locked" in anti-inflammatory and pro-regenerative M2a polarity (L-M2a) by simultaneously knocking out tumor necrosis factor receptor 1 (TNFR1) and overexpressing IL-4 using Cas9-ribonuclear proteins (Cas9-RNP) and electroporation. In vitro, these L-M2a macrophages were treated with OA synovial fluid or co-cultured with OA chondrocytes or fibroblast-like synoviocytes (FLS). In vivo, L-M2a macrophages were injected intra-articularly to evaluate their homing and engrafting abilities and therapeutic effects on OA progression using a rat model. Results L-M2a macrophages displayed a typical anti-inflammatory phenotype similar to that of M2 macrophages in vitro. In OA microenvironment, L-M2a macrophages maintained a stable anti-inflammatory phenotype, whereas unmodified M2 macrophages lost their phenotype and switched to M1 polarity. L-M2a macrophages demonstrated a potent anti-inflammatory effect in crosstalk with OA-FLSs and an anti-degenerative effect in crosstalk with senescent OA chondrocytes. In vivo, compared with M2 macrophages and exosomes, L-M2a macrophages exhibited significantly superior therapeutic effects in OA by successfully resolving inflammation, restoring tissue homeostasis, and promoting cartilage regeneration. Conclusion The engineered L-M2a macrophages maintained a superior anti-inflammatory and pro-regenerative capacity in the inflammatory OA microenvironment and represents an ideal new strategy for the disease-modifying therapy of OA.
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Affiliation(s)
- Chi Liang
- Department of Orthopaedics of the 3rd Xiangya Hospital, Central South University, Changsha, China
| | - Song Wu
- Department of Orthopaedics of the 3rd Xiangya Hospital, Central South University, Changsha, China
| | - Guang Xia
- Department of Orthopaedics of the 3rd Xiangya Hospital, Central South University, Changsha, China
| | - Junjie Huang
- Department of Orthopaedics of the 3rd Xiangya Hospital, Central South University, Changsha, China,Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Changsha, China
| | - Zi Wen
- Department of Orthopaedics of the 3rd Xiangya Hospital, Central South University, Changsha, China
| | - Wenxiu Zhang
- Department of Orthopaedics of the 3rd Xiangya Hospital, Central South University, Changsha, China
| | - Xu Cao
- Department of Orthopaedics of the 3rd Xiangya Hospital, Central South University, Changsha, China,Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Changsha, China,*Correspondence: Xu Cao,
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22
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Luijmes SH, Verstegen MMA, Hoogduijn MJ, Seghers L, Minnee RC, Mahtab EAF, Taverne YJHJ, Reinders MEJ, van der Laan LJW, de Jonge J. The current status of stem cell-based therapies during ex vivo graft perfusion: An integrated review of four organs. Am J Transplant 2022; 22:2723-2739. [PMID: 35896477 PMCID: PMC10087443 DOI: 10.1111/ajt.17161] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 06/26/2022] [Accepted: 07/15/2022] [Indexed: 01/25/2023]
Abstract
The use of extended criteria donor grafts is a promising strategy to increase the number of organ transplantations and reduce waitlist mortality. However, these organs are often compromised and/or damaged, are more susceptible to preservation injury, and are at risk for developing post-transplant complications. Ex vivo organ perfusion is a novel technology to preserve donor organs while providing oxygen and nutrients at distinct perfusion temperatures. This preservation method allows to resuscitate grafts and optimize function with therapeutic interventions prior to solid organ transplantation. Stem cell-based therapies are increasingly explored for their ability to promote regeneration and reduce the inflammatory response associated with in vivo reperfusion. The aim of this review is to describe the current state of stem cell-based therapies during ex vivo organ perfusion for the kidney, liver, lung, and heart. We discuss different strategies, including type of cells, route of administration, mechanisms of action, efficacy, and safety. The progress made within lung transplantation justifies the initiation of clinical trials, whereas more research is likely required for the kidney, liver, and heart to progress into clinical application. We emphasize the need for standardization of methodology to increase comparability between future (clinical) studies.
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Affiliation(s)
- Stefan H Luijmes
- Department of Surgery, Division of Hepatopancreatobiliary and Transplant Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Monique M A Verstegen
- Department of Surgery, Division of Hepatopancreatobiliary and Transplant Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Martin J Hoogduijn
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Leonard Seghers
- Department of Pulmonology, Thorax Center, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Robert C Minnee
- Department of Surgery, Division of Hepatopancreatobiliary and Transplant Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Edris A F Mahtab
- Department of Cardiothoracic Surgery, Thorax Center, Erasmus MC Transplant Institute, University Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Yannick J H J Taverne
- Department of Cardiothoracic Surgery, Thorax Center, Erasmus MC Transplant Institute, University Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Marlies E J Reinders
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Luc J W van der Laan
- Department of Surgery, Division of Hepatopancreatobiliary and Transplant Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Jeroen de Jonge
- Department of Surgery, Division of Hepatopancreatobiliary and Transplant Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
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23
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Heris RM, Shirvaliloo M, Abbaspour-Aghdam S, Hazrati A, Shariati A, Youshanlouei HR, Niaragh FJ, Valizadeh H, Ahmadi M. The potential use of mesenchymal stem cells and their exosomes in Parkinson's disease treatment. Stem Cell Res Ther 2022; 13:371. [PMID: 35902981 PMCID: PMC9331055 DOI: 10.1186/s13287-022-03050-4] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Accepted: 07/17/2022] [Indexed: 12/13/2022] Open
Abstract
Parkinson's disease (PD) is the second most predominant neurodegenerative disease worldwide. It is recognized clinically by severe complications in motor function caused by progressive degeneration of dopaminergic neurons (DAn) and dopamine depletion. As the current standard of treatment is focused on alleviating symptoms through Levodopa, developing neuroprotective techniques is critical for adopting a more pathology-oriented therapeutic approach. Regenerative cell therapy has provided us with an unrivalled platform for evaluating potentially effective novel methods for treating neurodegenerative illnesses over the last two decades. Mesenchymal stem cells (MSCs) are most promising, as they can differentiate into dopaminergic neurons and produce neurotrophic substances. The precise process by which stem cells repair neuronal injury is unknown, and MSC-derived exosomes are suggested to be responsible for a significant portion of such effects. The present review discusses the application of mesenchymal stem cells and MSC-derived exosomes in PD treatment.
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Affiliation(s)
| | - Milad Shirvaliloo
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Ali Hazrati
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ali Shariati
- Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Farhad Jadidi Niaragh
- Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hamed Valizadeh
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Majid Ahmadi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. .,Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
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24
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Srinivasan A, Sathiyanathan P, Yin L, Liu TM, Lam A, Ravikumar M, Smith RAA, Loh HP, Zhang Y, Ling L, Ng SK, Yang YS, Lezhava A, Hui J, Oh S, Cool SM. Strategies to enhance immunomodulatory properties and reduce heterogeneity in mesenchymal stromal cells during ex vivo expansion. Cytotherapy 2022; 24:456-472. [PMID: 35227601 DOI: 10.1016/j.jcyt.2021.11.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 10/24/2021] [Accepted: 11/08/2021] [Indexed: 02/06/2023]
Abstract
Therapies using mesenchymal stromal cells (MSCs) to treat immune and inflammatory conditions are now at an exciting stage of development, with many MSC-based products progressing to phase II and III clinical trials. However, a major bottleneck in the clinical translation of allogeneic MSC therapies is the variable immunomodulatory properties of MSC products due to differences in their tissue source, donor heterogeneity and processes involved in manufacturing and banking. This variable functionality of MSC products likely contributes to the substantial inconsistency observed in the clinical outcomes of phase III trials of MSC therapies; several trials have failed to reach the primary efficacy endpoint. In this review, we discuss various strategies to consistently maintain or enhance the immunomodulatory potency of MSCs during ex vivo expansion, which will enable the manufacture of allogeneic MSC banks that have high potency and low variability. Biophysical and biochemical priming strategies, the use of culture additives such as heparan sulfates, and genetic modification can substantially enhance the immunomodulatory properties of MSCs during in vitro expansion. Furthermore, robust donor screening, the use of biomarkers to select for potent MSC subpopulations, and rigorous quality testing to improve the release criteria for MSC banks have the potential to reduce batch-to-batch heterogeneity and enhance the clinical efficacy of the final MSC product. Machine learning approaches to develop predictive models of individual patient response can enable personalized therapies and potentially establish correlations between in vitro potency measurements and clinical outcomes in human trials.
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Affiliation(s)
- Akshaya Srinivasan
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | | | - Lu Yin
- Bioprocessing Technology Institute, A*STAR, Singapore
| | - Tong Ming Liu
- Institute of Molecular and Cell Biology, A*STAR, Singapore
| | - Alan Lam
- Bioprocessing Technology Institute, A*STAR, Singapore
| | - Maanasa Ravikumar
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Institute of Molecular and Cell Biology, A*STAR, Singapore
| | | | - Han Ping Loh
- Bioprocessing Technology Institute, A*STAR, Singapore
| | - Ying Zhang
- Institute of Molecular and Cell Biology, A*STAR, Singapore
| | - Ling Ling
- Institute of Molecular and Cell Biology, A*STAR, Singapore
| | - Say Kong Ng
- Bioprocessing Technology Institute, A*STAR, Singapore
| | | | - Alexander Lezhava
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore
| | - James Hui
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Steve Oh
- Bioprocessing Technology Institute, A*STAR, Singapore.
| | - Simon M Cool
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Institute of Molecular and Cell Biology, A*STAR, Singapore.
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25
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Pan Y, Tan WF, Yang MQ, Li JY, Geller DA. The therapeutic potential of exosomes derived from different cell sources in liver diseases. Am J Physiol Gastrointest Liver Physiol 2022; 322:G397-G404. [PMID: 35107032 PMCID: PMC8917924 DOI: 10.1152/ajpgi.00054.2021] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Exosomes are small nanovesicles with a size of approximately 40-120 nm that are secreted from cells. They are involved in the regulation of cell homeostasis and mediate intercellular communication. In addition, they carry proteins, nucleic acids, and lipids that regulate the biological activity of receptor cells. Recent studies have shown that exosomes perform important functions in liver diseases. This review will focus on liver diseases (drug-induced liver injury, hepatic ischemia-reperfusion injury, liver fibrosis, acute liver failure, and hepatocellular carcinoma) and summarize the therapeutic potential of exosomes from different cell sources in liver disease.
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Affiliation(s)
- Yun Pan
- 1Colorectal Cancer Center, Tenth People’s Hospital of Tongji University, Tongji University School of Medicine, Shanghai, People’s Republic of China
| | - Wei-Feng Tan
- 2Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
| | - Mu-Qing Yang
- 3Department of General Surgery, Tenth People’s Hospital of Tongji University, Tongji University, Shanghai, People’s Republic of China
| | - Ji-Yu Li
- 3Department of General Surgery, Tenth People’s Hospital of Tongji University, Tongji University, Shanghai, People’s Republic of China
| | - David A. Geller
- 4Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
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26
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Xu Z, Gao H, Zhang Y, Feng W, Miao Y, Xu Z, Li W, Chen F, Lv Z, Huo J, Liu W, Shen X, Zong Y, Zhao J, Lu A. CCL7 and TGF-β secreted by MSCs play opposite roles in regulating CRC metastasis in a KLF5/CXCL5 dependent manner. Mol Ther 2022; 30:2327-2341. [DOI: 10.1016/j.ymthe.2022.03.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 01/12/2022] [Accepted: 03/07/2022] [Indexed: 11/29/2022] Open
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27
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Song BW, Oh S, Chang W. Multiplexed targeting of microRNA in stem cell-derived extracellular vesicles for regenerative medicine. BMB Rep 2022; 55:65-71. [PMID: 35000674 PMCID: PMC8891620 DOI: 10.5483/bmbrep.2022.55.2.182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 01/10/2022] [Accepted: 01/10/2022] [Indexed: 11/20/2022] Open
Abstract
Regenerative medicine is a research field that develops methods to restore damaged cell or tissue function by regeneration, repair or replacement. Stem cells are the raw material of the body that is ultimately used from the point of view of regenerative medicine, and stem cell therapy uses cells themselves or their derivatives to promote responses to diseases and dysfunctions, the ultimate goal of regenerative medicine. Stem cell-derived extracellular vesicles (EVs) are recognized as an attractive source because they can enrich exogenous microRNAs (miRNAs) by targeting pathological recipient cells for disease therapy and can overcome the obstacles faced by current cell therapy agents. However, there are some limitations that need to be addressed before using miRNA-enriched EVs derived from stem cells for multiplexed therapeutic targeting in many diseases. Here, we review various roles on miRNA-based stem cell EVs that can induce effective and stable functional improvement of stem cell-derived EVs. In addition, we introduce and review the implications of several miRNA-enriched EV therapies improved by multiplexed targeting in diseases involving the circulatory system and nervous system. This systemic review may offer potential roles for stem cell-derived therapeutics with multiplexed targeting. [BMB Reports 2022;55(2): 65-71].
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Affiliation(s)
- Byeong-Wook Song
- Institute for Bio-Medical Convergence, Catholic Kwandong University International St. Mary’s Hospital, Incheon 22711, Korea
- Department of Medical Science, College of Medicine, Catholic Kwandong University, Incheon 22711, Korea
| | - Sekyung Oh
- Department of Medical Science, College of Medicine, Catholic Kwandong University, Incheon 22711, Korea
| | - Woochul Chang
- Department of Biology Education, College of Education, Pusan National University, Busan 46241, Korea
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28
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Wu X, Jin S, Ding C, Wang Y, He D, Liu Y. Mesenchymal Stem Cell-Derived Exosome Therapy of Microbial Diseases: From Bench to Bed. Front Microbiol 2022; 12:804813. [PMID: 35046923 PMCID: PMC8761948 DOI: 10.3389/fmicb.2021.804813] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 11/30/2021] [Indexed: 12/12/2022] Open
Abstract
Microbial diseases are a global health threat, leading to tremendous casualties and economic losses. The strategy to treat microbial diseases falls into two broad categories: pathogen-directed therapy (PDT) and host-directed therapy (HDT). As the typical PDT, antibiotics or antiviral drugs directly attack bacteria or viruses through discerning specific molecules. However, drug abuse could result in antimicrobial resistance and increase infectious disease morbidity. Recently, the exosome therapy, as a HDT, has attracted extensive attentions for its potential in limiting infectious complications and targeted drug delivery. Mesenchymal stem cell-derived exosomes (MSC-Exos) are the most broadly investigated. In this review, we mainly focus on the development and recent advances of the application of MSC-Exos on microbial diseases. The review starts with the difficulties and current strategies in antimicrobial treatments, followed by a comprehensive overview of exosomes in aspect of isolation, identification, contents, and applications. Then, the underlying mechanisms of the MSC-Exo therapy in microbial diseases are discussed in depth, mainly including immunomodulation, repression of excessive inflammation, and promotion of tissue regeneration. In addition, we highlight the latest progress in the clinical translation of the MSC-Exo therapy, by summarizing related clinical trials, routes of administration, and exosome modifications. This review will provide fundamental insights and future perspectives on MSC-Exo therapy in microbial diseases from bench to bedside.
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Affiliation(s)
| | | | | | | | | | - Yan Liu
- Laboratory of Biomimetic Nanomaterials, Department of Orthodontics, Peking University School and Hospital of Stomatology and National Center of Stomatology and National Clinical Research Center for Oral Diseases and National Engineering Laboratory for Digital and Material Technology of Stomatology and Beijing Key Laboratory of Digital Stomatology and Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health and NMPA Key Laboratory for Dental Materials, Beijing, China
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29
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Bridger JM, Pereira RT, Pina C, Tosi S, Lewis A. Alterations to Genome Organisation in Stem Cells, Their Differentiation and Associated Diseases. Results Probl Cell Differ 2022; 70:71-102. [PMID: 36348105 DOI: 10.1007/978-3-031-06573-6_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
The organisation of the genome in its home, the cell nucleus, is reliant on a number of different aspects to establish, maintain and alter its functional non-random positioning. The genome is dispersed throughout a cell nucleus in specific chromosome territories which are further divided into topologically associated domains (TADs), where regions of the genome from different and the same chromosomes come together. This organisation is both controlled by DNA and chromatin epigenetic modification and the association of the genome with nuclear structures such as the nuclear lamina, the nucleolus and nuclear bodies and speckles. Indeed, sequences that are associated with the first two structures mentioned are termed lamina-associated domains (LADs) and nucleolar-associated domains (NADs), respectively. The modifications and nuclear structures that regulate genome function are altered through a cell's life from stem cell to differentiated cell through to reversible quiescence and irreversible senescence, and hence impacting on genome organisation, altering it to silence specific genes and permit others to be expressed in a controlled way in different cell types and cell cycle statuses. The structures and enzymes and thus the organisation of the genome can also be deleteriously affected, leading to disease and/or premature ageing.
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Affiliation(s)
- Joanna M Bridger
- Division of Biosciences, Department of Life Sciences, Centre for Genome Engineering and Maintenance (cenGEM), College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge, UK.
| | - Rita Torres Pereira
- Division of Biosciences, Department of Life Sciences, Centre for Genome Engineering and Maintenance (cenGEM), College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge, UK
| | - Cristina Pina
- Division of Biosciences, Department of Life Sciences, Centre for Genome Engineering and Maintenance (cenGEM), College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge, UK
| | - Sabrina Tosi
- Division of Biosciences, Department of Life Sciences, Centre for Genome Engineering and Maintenance (cenGEM), College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge, UK
| | - Annabelle Lewis
- Division of Biosciences, Department of Life Sciences, Centre for Genome Engineering and Maintenance (cenGEM), College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge, UK
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30
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Kulus M, Sibiak R, Stefańska K, Zdun M, Wieczorkiewicz M, Piotrowska-Kempisty H, Jaśkowski JM, Bukowska D, Ratajczak K, Zabel M, Mozdziak P, Kempisty B. Mesenchymal Stem/Stromal Cells Derived from Human and Animal Perinatal Tissues-Origins, Characteristics, Signaling Pathways, and Clinical Trials. Cells 2021; 10:cells10123278. [PMID: 34943786 PMCID: PMC8699543 DOI: 10.3390/cells10123278] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 11/13/2021] [Accepted: 11/19/2021] [Indexed: 12/15/2022] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are currently one of the most extensively researched fields due to their promising opportunity for use in regenerative medicine. There are many sources of MSCs, of which cells of perinatal origin appear to be an invaluable pool. Compared to embryonic stem cells, they are devoid of ethical conflicts because they are derived from tissues surrounding the fetus and can be safely recovered from medical waste after delivery. Additionally, perinatal MSCs exhibit better self-renewal and differentiation properties than those derived from adult tissues. It is important to consider the anatomy of perinatal tissues and the general description of MSCs, including their isolation, differentiation, and characterization of different types of perinatal MSCs from both animals and humans (placenta, umbilical cord, amniotic fluid). Ultimately, signaling pathways are essential to consider regarding the clinical applications of MSCs. It is important to consider the origin of these cells, referring to the anatomical structure of the organs of origin, when describing the general and specific characteristics of the different types of MSCs as well as the pathways involved in differentiation.
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Affiliation(s)
- Magdalena Kulus
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland; (M.K.); (K.R.)
| | - Rafał Sibiak
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (R.S.); (K.S.)
- Division of Reproduction, Department of Obstetrics, Gynecology, and Gynecologic Oncology, Poznan University of Medical Sciences, 60-535 Poznan, Poland
| | - Katarzyna Stefańska
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (R.S.); (K.S.)
| | - Maciej Zdun
- Department of Basic and Preclinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland; (M.Z.); (M.W.); (H.P.-K.)
| | - Maria Wieczorkiewicz
- Department of Basic and Preclinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland; (M.Z.); (M.W.); (H.P.-K.)
| | - Hanna Piotrowska-Kempisty
- Department of Basic and Preclinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland; (M.Z.); (M.W.); (H.P.-K.)
- Department of Toxicology, Poznan University of Medical Sciences, 60-631 Poznan, Poland
| | - Jędrzej M. Jaśkowski
- Department of Diagnostics and Clinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland; (J.M.J.); (D.B.)
| | - Dorota Bukowska
- Department of Diagnostics and Clinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland; (J.M.J.); (D.B.)
| | - Kornel Ratajczak
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland; (M.K.); (K.R.)
| | - Maciej Zabel
- Division of Anatomy and Histology, University of Zielona Gora, 65-046 Zielona Gora, Poland;
| | - Paul Mozdziak
- Prestage Department of Poultry Science, North Carolina State University, Raleigh, NC 27695, USA;
| | - Bartosz Kempisty
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland; (M.K.); (K.R.)
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (R.S.); (K.S.)
- Prestage Department of Poultry Science, North Carolina State University, Raleigh, NC 27695, USA;
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznan, Poland
- Correspondence:
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Zhang L, Wei W, Ai X, Kilic E, Hermann DM, Venkataramani V, Bähr M, Doeppner TR. Extracellular vesicles from hypoxia-preconditioned microglia promote angiogenesis and repress apoptosis in stroke mice via the TGF-β/Smad2/3 pathway. Cell Death Dis 2021; 12:1068. [PMID: 34753919 PMCID: PMC8578653 DOI: 10.1038/s41419-021-04363-7] [Citation(s) in RCA: 93] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 09/15/2021] [Accepted: 10/20/2021] [Indexed: 12/17/2022]
Abstract
Systemic transplantation of oxygen-glucose deprivation (OGD)-preconditioned primary microglia enhances neurological recovery in rodent stroke models, albeit the underlying mechanisms have not been sufficiently addressed. Herein, we analyzed whether or not extracellular vesicles (EVs) derived from such microglia are the biological mediators of these observations and which signaling pathways are involved in the process. Exposing bEnd.3 endothelial cells (ECs) and primary cortical neurons to OGD, the impact of EVs from OGD-preconditioned microglia on angiogenesis and neuronal apoptosis by the tube formation assay and TUNEL staining was assessed. Under these conditions, EV treatment stimulated both angiogenesis and tube formation in ECs and repressed neuronal cell injury. Characterizing microglia EVs by means of Western blot analysis and other techniques revealed these EVs to be rich in TGF-β1. The latter turned out to be a key compound for the therapeutic potential of microglia EVs, affecting the Smad2/3 pathway in both ECs and neurons. EV infusion in stroke mice confirmed the aforementioned in vitro results, demonstrating an activation of the TGF-β/Smad2/3 signaling pathway within the ischemic brain. Furthermore, enriched TGF-β1 in EVs secreted from OGD-preconditioned microglia stimulated M2 polarization of residing microglia within the ischemic cerebral environment, which may contribute to a regulation of an early inflammatory response in postischemic hemispheres. These observations are not only interesting from the mechanistic point of view but have an immediate therapeutic implication as well, since stroke mice treated with such EVs displayed a better functional recovery in the behavioral test analyses. Hence, the present findings suggest a new way of action of EVs derived from OGD-preconditioned microglia by regulating the TGF-β/Smad2/3 pathway in order to promote tissue regeneration and neurological recovery in stroke mice.
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Affiliation(s)
- Lin Zhang
- Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
| | - Wei Wei
- Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
| | - Xiaoyu Ai
- Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
| | - Ertugrul Kilic
- Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Istanbul, Turkey
| | - Dirk M Hermann
- Department of Neurology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Vivek Venkataramani
- Department of Medicine II, University Hospital Frankfurt, Frankfurt, Germany
- Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany
| | - Mathias Bähr
- Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
| | - Thorsten R Doeppner
- Department of Neurology, University Medical Center Göttingen, Göttingen, Germany.
- Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Istanbul, Turkey.
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32
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Gupta PK, Dutta S, Kala S, Nekkanti M, Desai SC, Mahapatra SS, Dhar A, Raju R, M. R, Behera A, P. S, Raviraja N, Viswanathan P, Chandrashekar M, Thej C, K.V. P, Abraham J, Boggarapu H, Udaykumar K. Phase IV postmarketing surveillance study shows continued efficacy and safety of stempeucel® in patients with critical limb ischemia due to Buerger's disease. Stem Cells Transl Med 2021; 10:1602-1613. [PMID: 34519179 PMCID: PMC8641082 DOI: 10.1002/sctm.21-0197] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/15/2021] [Accepted: 07/28/2021] [Indexed: 01/02/2023] Open
Abstract
Buerger's disease or thromboangiitis obliterans is a type of obstructive vascular diseases categorized as vasculitis and usually present in 95% of young smoker men. The main pathogenetic mechanism is interplay between immune system and inflammation. Earlier our phase II study has shown that Stempeucel is safe when injected at 2 million cells/kg body weight by virtue of its anti‐inflammatory, immunomodulatory, and angiogenetic properties. The present study was conducted to further assess the safety and efficacy of Stempeucel in critical limb ischemia due to Buerger's disease after obtaining approval from Indian FDA based on the data generated in the phase II study. This is an open label, multicenteric phase IV PMS study conducted across India with experienced vascular surgeons. Fifty patients of critical limb ischemia due to Buerger's disease with Rutherford III‐5 or III‐6 were included in the study and each individual received a dose of 2 million cells/kg body weight of Stempeucel in the calf muscles and around the ulcer. These patients were evaluated over 12 months from drug administration. The present study showed the continued long term efficacy over a period of 12 months follow up in these patients corroborating the result obtained in the previous phase II studies. There was significant improvement in rest pain, ankle systolic pressure, and ankle brachial pressure index with accelerated ulcer healing. In conclusion, the present study shows that the intramuscular administration of Stempeucel continues to be safe, tolerable, and effective alternative treatment in patients with Buerger's disease.
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Affiliation(s)
| | | | | | | | | | | | - Anita Dhar
- All India Institute of Medical SciencesNew DelhiIndia
| | | | | | - Arunanshu Behera
- Post‐Graduate Institute of Medical Education & ResearchChandigarhIndia
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Kirkham AM, Bailey AJM, Tieu A, Maganti HB, Montroy J, Shorr R, Campbell TM, Fergusson DA, Lalu MM, Elmoazzen H, Allan DS. MSC-Derived Extracellular Vesicles in Preclinical Animal Models of Bone Injury: A Systematic Review and Meta-Analysis. Stem Cell Rev Rep 2021; 18:1054-1066. [PMID: 34313927 DOI: 10.1007/s12015-021-10208-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/17/2021] [Indexed: 12/23/2022]
Abstract
BACKGROUND AND OBJECTIVE Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) are a promising treatment for bone injuries, although studies remain preclinical. A systematic review and meta-analysis can assess the efficacy of MSC-EVs and identify treatment aspects associated with enhanced bone repair. METHODS English language, preclinical, controlled, in vivo studies identified in our systematic search (up to May 8, 2020) examining the use of MSC-EVs in bone healing were included. Risk of bias (ROB) was assessed using the SYRCLE tool. Aggregate Data Meta-Analysis was performed to determine the effect of MSC-EVs on Bone Volume/Total Volume (BV/TV) and New Bone Formation (NBF). RESULTS Thirteen studies were included. Twelve reported either BV/TV or NBF and were included in meta-analysis. ROB was unclear in all studies. Overall, MSC-EVs displayed benefit in terms of bone healing for both BV/TV (22.2% mean difference (MD); 95% CI: 15.8-28.5%, p < 0.001) and NBF (26.1% MD; 10.3-41.8%, p = 0.001) versus controls. Substantial heterogeneity, however, was observed between studies. MSC-EVs were reported to activate multiple signaling pathways including mTOR/AKT, AMPK and BMP2. Subgroup analysis indicated no significant difference in the improvement of BV/TV when using modified EVs isolated after gene transfection, preconditioning (p = 0.61), or using EVs in combination with a tissue scaffold and/or hydrogel versus other delivery methods (p = 0.20). CONCLUSION Use of MSC-EVs to promote healing of bone injury appears promising, however, heterogeneity between studies and the potential for reporting bias limits confidence in the extent of benefit. Reducing bias between studies and addressing aspects of potential reporting bias should augment confidence in future meta-analyses and propel the field towards clinical studies. Forest Plot analysis assessing the percentage change in bone volume (BV) / total volume (TV) in the presence (experimental) or absence (control) of MSC-EVs.
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Affiliation(s)
- Aidan M Kirkham
- Stem Cells, Canadian Blood Services, Ottawa, ON, Canada.,Clinical Epidemiology, Ottawa Hospital Research Institute, 501 Smyth Rd, Box 704, Ottawa, ON, K1H 8L6, Canada
| | - Adrian J M Bailey
- Stem Cells, Canadian Blood Services, Ottawa, ON, Canada.,Clinical Epidemiology, Ottawa Hospital Research Institute, 501 Smyth Rd, Box 704, Ottawa, ON, K1H 8L6, Canada
| | - Alvin Tieu
- Clinical Epidemiology, Ottawa Hospital Research Institute, 501 Smyth Rd, Box 704, Ottawa, ON, K1H 8L6, Canada.,Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, ON, Canada.,Medicine, The Ottawa Hospital, Ottawa, ON, Canada.,Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Harinad B Maganti
- Stem Cells, Canadian Blood Services, Ottawa, ON, Canada.,Clinical Epidemiology, Ottawa Hospital Research Institute, 501 Smyth Rd, Box 704, Ottawa, ON, K1H 8L6, Canada
| | - Joshua Montroy
- Clinical Epidemiology, Ottawa Hospital Research Institute, 501 Smyth Rd, Box 704, Ottawa, ON, K1H 8L6, Canada
| | - Risa Shorr
- Medical Information and Education Services, The Ottawa Hospital, Ottawa, ON, Canada
| | - T Mark Campbell
- Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, ON, Canada.,Medicine, The Ottawa Hospital, Ottawa, ON, Canada.,Department of Physical Medicine and Rehabilitation, Elisabeth Bruyère Hospital, Ottawa, ON, Canada
| | - Dean A Fergusson
- Clinical Epidemiology, Ottawa Hospital Research Institute, 501 Smyth Rd, Box 704, Ottawa, ON, K1H 8L6, Canada.,Medicine, The Ottawa Hospital, Ottawa, ON, Canada.,Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Manoj M Lalu
- Clinical Epidemiology, Ottawa Hospital Research Institute, 501 Smyth Rd, Box 704, Ottawa, ON, K1H 8L6, Canada.,Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, ON, Canada.,Departments of Anesthesiology and Pain Medicine, The Ottawa Hospital, Ottawa, ON, Canada.,School of Public Health and Epidemiology, University of Ottawa, Ottawa, ON, Canada
| | | | - David S Allan
- Stem Cells, Canadian Blood Services, Ottawa, ON, Canada. .,Clinical Epidemiology, Ottawa Hospital Research Institute, 501 Smyth Rd, Box 704, Ottawa, ON, K1H 8L6, Canada. .,Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, ON, Canada. .,Medicine, The Ottawa Hospital, Ottawa, ON, Canada. .,Biochemistry, Microbiology & Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
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Gratpain V, Mwema A, Labrak Y, Muccioli GG, van Pesch V, des Rieux A. Extracellular vesicles for the treatment of central nervous system diseases. Adv Drug Deliv Rev 2021; 174:535-552. [PMID: 33991589 DOI: 10.1016/j.addr.2021.05.006] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 04/14/2021] [Accepted: 05/11/2021] [Indexed: 02/07/2023]
Abstract
The interest in extracellular vesicles (EVs) increased during the last decade. It is now established that these vesicles play a role in the pathogenesis of central nervous system diseases (CNS), which explains why they are studied as biomarkers in these pathologies. On the other hand, EVs can also present therapeutic properties, often similar to their parent cells, as observed with mesenchymal stem cell-derived EVs. They can then be used as therapeutics, alone or combined with a bioactive molecule, for the treatment of CNS diseases, as they can cross the blood-brain barrier more easily than synthetic nanomedicines and are less immunogenic. A few clinical trials are currently on-going but there are still challenges to overcome for further clinical translation such as the scale-up of the production, the lack of standardization for isolation and characterization methods and the low encapsulation efficiency.
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Affiliation(s)
- Viridiane Gratpain
- Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, Université Catholique de Louvain, UCLouvain, 1200 Brussels, Belgium
| | - Ariane Mwema
- Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, Université Catholique de Louvain, UCLouvain, 1200 Brussels, Belgium; Louvain Drug Research Institute, Bioanalysis and Pharmacology of Bioactive Lipids, Université Catholique de Louvain, UCLouvain, 1200 Brussels, Belgium
| | - Yasmine Labrak
- Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, Université Catholique de Louvain, UCLouvain, 1200 Brussels, Belgium; Louvain Drug Research Institute, Bioanalysis and Pharmacology of Bioactive Lipids, Université Catholique de Louvain, UCLouvain, 1200 Brussels, Belgium
| | - Giulio G Muccioli
- Louvain Drug Research Institute, Bioanalysis and Pharmacology of Bioactive Lipids, Université Catholique de Louvain, UCLouvain, 1200 Brussels, Belgium
| | - Vincent van Pesch
- Institute of Neuroscience, Neurochemistry Unit, Université Catholique de Louvain, UCLouvain, 1200 Brussels, Belgium; Cliniques Universitaires Saint-Luc, 1200 Brussels, Belgium
| | - Anne des Rieux
- Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, Université Catholique de Louvain, UCLouvain, 1200 Brussels, Belgium.
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35
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Shi H, Jiang C, Yao H, Zhang Y, Zhang Q, Hou X, Lin R. CD44 fucosylation on bone marrow-derived mesenchymal stem cells enhances homing and promotes enteric nervous system remodeling in diabetic mice. Cell Biosci 2021; 11:118. [PMID: 34193268 PMCID: PMC8243650 DOI: 10.1186/s13578-021-00632-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 06/18/2021] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND Diabetes can cause extensive enteric nervous system (ENS) injuries and gastrointestinal motility disorder. In developing possible treatments, researchers have engaged in tissue regeneration engineering with the very promising bone marrow-derived mesenchymal stem cells (BMSCs). However, BMSCs have poor homing ability to the targeted tissues after intravenous injection. Thus, we aimed to investigate whether enhancing the expression of E-selectin ligand on BMSCs could improve their homing ability and subsequently influence their role in ENS remodeling in diabetic mice. METHODS First, we constructed the fucosylation modification of CD44 on BMSCs through a fucosyltransferase VII (FTVII) system to generate a Hematopoietic Cell E-/L-selectin Ligand (HCELL) property, a fucosylated sialyllactosaminyl glycovariant of CD44 that potently binds E-selectin. Next, FTVII-modified and unmodified BMSCs labeled with green fluorescent protein (GFP) were injected into diabetic mice through the tail vein to compare their homing ability to the gastrointestinal tract and their effect on ENS remodeling, respectively. A bioluminescent imaging system was used to evaluate the homing ability of GFP-labeled BMSCs with and without FTVII modification, to the gastrointestinal tract. Gastrointestinal motility was assessed by gastrointestinal transient time, defecation frequency, stool water content and colon strips contractility. Immunofluorescence staining and western blotting were used to assess the expression levels of protein gene product 9.5 (PGP9.5), glial fibrillary acidic protein (GFAP) and glial cell line-derived neurotrophic factor (GDNF). RESULTS The FTVII-mediated α(1,3)-fucosylation modification of CD44 on BMSCs generated a HCELL property. Bioluminescent imaging assays showed that FTVII-modified BMSCs had enhanced homing ability to gastrointestinal tract, mainly to the colon, 24 h after injection through the tail vein. Compared with diabetic mice, FTVII-modified BMSCs significantly promoted the gastrointestinal motility and the ENS remodeling, including intestinal peristalsis (P < 0.05), increased feces excretion (P < 0.05) and the water content of the feces (P < 0.05), restored the spontaneous contraction of the colon (P < 0.05), and upregulated the protein expression levels of PGP9.5 (P < 0.01), GFAP (P < 0.001), and GDNF (P < 0.05), while unmodified BMSCs did not (P > 0.05). CONCLUSIONS CD44 fucosylation modification on murine BMSCs promotes homing ability to the gastrointestinal tract and ENS remodeling in diabetic mice.
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Affiliation(s)
- Huiying Shi
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Chen Jiang
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Hailing Yao
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yurui Zhang
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Qin Zhang
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xiaohua Hou
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Rong Lin
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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Liu Y, Su YY, Yang Q, Zhou T. Stem cells in the treatment of renal fibrosis: a review of preclinical and clinical studies of renal fibrosis pathogenesis. Stem Cell Res Ther 2021; 12:333. [PMID: 34112221 PMCID: PMC8194041 DOI: 10.1186/s13287-021-02391-w] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 05/14/2021] [Indexed: 02/05/2023] Open
Abstract
Renal fibrosis commonly leads to glomerulosclerosis and renal interstitial fibrosis and the main pathological basis involves tubular atrophy and the abnormal increase and excessive deposition of extracellular matrix (ECM). Renal fibrosis can progress to chronic kidney disease. Stem cells have multilineage differentiation potential under appropriate conditions and are easy to obtain. At present, there have been some studies showing that stem cells can alleviate the accumulation of ECM and renal fibrosis. However, the sources of stem cells and the types of renal fibrosis or renal fibrosis models used in these studies have differed. In this review, we summarize the pathogenesis (including signaling pathways) of renal fibrosis, and the effect of stem cell therapy on renal fibrosis as described in preclinical and clinical studies. We found that stem cells from various sources have certain effects on improving renal function and alleviating renal fibrosis. However, additional clinical studies should be conducted to confirm this conclusion in the future.
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Affiliation(s)
- Yiping Liu
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, No. 69 Dongsha Road, Shantou, 515041, China
| | - Yan-Yan Su
- Department of Nephrology, Huadu District People's Hospital of Guangzhou, Southern Medical University, Guangzhou, China
| | - Qian Yang
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, No. 69 Dongsha Road, Shantou, 515041, China
| | - Tianbiao Zhou
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, No. 69 Dongsha Road, Shantou, 515041, China.
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Taurine Augments Telomerase Activity and Promotes Chondrogenesis in Dental Pulp Stem Cells. J Pers Med 2021; 11:jpm11060491. [PMID: 34072707 PMCID: PMC8228366 DOI: 10.3390/jpm11060491] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 05/24/2021] [Accepted: 05/28/2021] [Indexed: 12/30/2022] Open
Abstract
Background: Stem cell therapy has become an advanced and state-of-the-art procedure to regenerate lost tissues of the human body. Cartilage repair is a challenging task in which stem cells find potential application. One of the important biologic modifiers that can cause chondrogenic differentiation of stem cells is taurine. However, taurine has not been investigated for its effects on dental pulp derived stem cell (DPSC) chondrogenic differentiation. Objective: The objective of the study was to investigate if taurine administration to DPSCs heralds chondrogenic differentiation as ascertained by expression of SOX9, COL2A1, ACAN, ELN, and COMP. The study also investigated if the differentiated cells synthesized glycosaminoglycans, a marker of cartilage formation. The study also aimed to assess proliferative activity of the cells after taurine administration by measuring the hTERT gene and protein expression. Materials and methods: DPSCs were obtained from a molecular biology laboratory and characterization of stem cell markers was done by flow cytometry. The cells were subjected to a MTT assay using various concentrations of taurine. Following this, hTERT gene and protein estimation was done in the control, telomerase inhibitor treated DPSC (TI-III), 10 μM taurine treated DPSC, and TI-III + 10 μM taurine treated DPSCs. A polymerase chain reaction was done to assess gene expression of SOX9, COL2A1, ACAN, ELN, and COMP genes and glycosaminoglycans were estimated in control cells, Induced DPSCs, induced and TI-III treated DPSCs, and 10 μM taurine treated DPSCs. Results: DPSCs expressed CD73, CD90, and CD105 and did not express CD34, CD45, and HLA-DR, which demonstrated that they were mesenchymal stem cells. The MTT assay revealed that various concentrations of taurine did not affect the cell viability of DPSCs. A concentration of 10 μM of taurine was used for further assays. With regard to the hTERT gene and protein expression, the taurine treated cells expressed the highest levels that were statistically significant compared to the other groups. Taurine was also found to restore hTERT expression in telomerase inhibitor treated cells. With regard to chondrogenesis related genes, taurine administration significantly increased the expression of SOX9, COL2A1, ACAN, and ELN genes in DPSCs and caused a significant increase in glycosaminoglycan production by the cells. Conclusions: Taurine can be regarded a biologic modifier that can significantly augment chondrogenic differentiation of DPSCs and can find potential applications in regenerative medicine in the area of cartilage regeneration.
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38
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Su Y, Guo H, Liu Q. Effects of mesenchymal stromal cell-derived extracellular vesicles in acute respiratory distress syndrome (ARDS): Current understanding and future perspectives. J Leukoc Biol 2021; 110:27-38. [PMID: 33955590 PMCID: PMC8242476 DOI: 10.1002/jlb.3mr0321-545rr] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 03/22/2021] [Accepted: 04/11/2021] [Indexed: 12/11/2022] Open
Abstract
Acute respiratory distress syndrome (ARDS) is a devastating and life‐threatening syndrome that results in high morbidity and mortality. Current pharmacologic treatments and mechanical ventilation have limited value in targeting the underlying pathophysiology of ARDS. Mesenchymal stromal cells (MSCs) have shown potent therapeutic advantages in experimental and clinical trials through direct cell‐to‐cell interaction and paracrine signaling. However, safety concerns and the indeterminate effects of MSCs have resulted in the investigation of MSC‐derived extracellular vesicles (MSC‐EVs) due to their low immunogenicity and tumorigenicity. Over the past decades, soluble proteins, microRNAs, and organelles packaged in EVs have been identified as efficacious molecules to orchestrate nearby immune responses, which attenuate acute lung injury by facilitating pulmonary epithelium repair, reducing acute inflammation, and restoring pulmonary vascular leakage. Even though MSC‐EVs possess similar bio‐functional effects to their parental cells, there remains existing barriers to employing this alternative from bench to bedside. Here, we summarize the current established research in respect of molecular mechanisms of MSC‐EV effects in ARDS and highlight the future challenges of MSC‐EVs for clinical application.
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Affiliation(s)
- Yue Su
- Department of Respiratory Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, P.R. China
| | - Haiyan Guo
- Department of Paediatrics, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, P.R. China
| | - Qinghua Liu
- Department of Respiratory Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, P.R. China
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Prantl L, Eigenberger A, Brix E, Kempa S, Baringer M, Felthaus O. Adipose Tissue-Derived Stem Cell Yield Depends on Isolation Protocol and Cell Counting Method. Cells 2021; 10:cells10051113. [PMID: 34063138 PMCID: PMC8148142 DOI: 10.3390/cells10051113] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 04/27/2021] [Accepted: 04/30/2021] [Indexed: 12/15/2022] Open
Abstract
In plastic surgery, lipofilling is a frequent procedure. Unsatisfactory vascularization and impaired cell vitality can lead to unpredictable take rates in the fat graft. The proliferation and neovascularization inducing properties of adipose tissue-derived stem cells may contribute to solve this problem. Therefore, the enrichment of fat grafts with stem cells is studied intensively. However, it is difficult to compare these studies because many factors—often not precisely described—are influencing the results. Our study summarizes some factors which influence the cell yield like harvesting, isolation procedure and quantification. Stem cells were isolated after liposuction. Quantification was done using a cell chamber, colony counting, or flow cytometry with changes to one parameter, only, for each comparison. Quantification of cells isolated after liposuction at the same harvesting site from the same patient can vary greatly depending on the details of the isolation protocol and the method of quantification. Cell yield can be influenced strongly by many factors. Therefore, a comparison of different studies should be handled with care.
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40
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Tong Y, Zuo J, Yue D. Application Prospects of Mesenchymal Stem Cell Therapy for Bronchopulmonary Dysplasia and the Challenges Encountered. BIOMED RESEARCH INTERNATIONAL 2021; 2021:9983664. [PMID: 33997051 PMCID: PMC8110410 DOI: 10.1155/2021/9983664] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 04/27/2021] [Accepted: 04/29/2021] [Indexed: 01/01/2023]
Abstract
Bronchopulmonary dysplasia (BPD) is a common chronic lung disease in premature babies, especially affecting those with very low or extremely low birth weights. Survivors experience adverse lung and neurological defects including cognitive dysfunction. This impacts the prognosis of children with BPD and may result in developmental delays. The currently available options for the treatment of BPD are limited owing to low efficacy or several side effects; therefore, there is a lack of effective treatments for BPD. The treatment for BPD must help in the repair of damaged lung tissue and promote further growth of the lung tissue. In recent years, the emergence of stem cell therapy, especially mesenchymal stem cell (MSC) therapy, has improved the treatment of BPD to a great extent. This article briefly reviews the advantages, research progress, and challenges faced with the use of MSCs in the treatment of BPD. Stem cell therapy is beneficial as it repairs damaged tissues by reducing inflammation, fibrosis, and by acting against oxidative stress damage. Experimental trials have also proven that MSCs provide a promising avenue for BPD treatment. However, there are challenges such as the possibility of MSCs contributing to tumorous growths, the presence of heterogeneous cell populations resulting in variable efficacy, and the ethical considerations regarding the use of this treatment in humans. Therefore, more research must be conducted to determine whether MSC therapy can be approved as a treatment option for BPD.
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Affiliation(s)
- Yajie Tong
- Department of Pediatrics, Shengjing Hospital of China Medical University, No. 36, Sanhao Street, Heping District, Shenyang, 110004 Liaoning, China
| | - Jingye Zuo
- Department of Pediatrics, Shengjing Hospital of China Medical University, No. 36, Sanhao Street, Heping District, Shenyang, 110004 Liaoning, China
| | - Dongmei Yue
- Department of Pediatrics, Shengjing Hospital of China Medical University, No. 36, Sanhao Street, Heping District, Shenyang, 110004 Liaoning, China
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41
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An T, Chen Y, Tu Y, Lin P. Mesenchymal Stromal Cell-Derived Extracellular Vesicles in the Treatment of Diabetic Foot Ulcers: Application and Challenges. Stem Cell Rev Rep 2021; 17:369-378. [PMID: 32772239 DOI: 10.1007/s12015-020-10014-9] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Diabetic foot ischemia and ulcer (DFU) persists as a serious diabetes mellitus complication in spite of increased understanding of the pathophysiology and the cellular and molecular responses. Contributing to this pessimistic situation is the lack of effective treatments that are slow to heal the deep chronic wounds and microvascular obstruction. Mesenchymal stromal cells (MSCs) have been tested as a promising cell-based therapy for diabetes in vitro and in vivo, which is able to accelerate wound closure with increased epithelialization, granulation tissue formation and angiogenesis by differentiation into skin cells and paracrine pathways to repair injured cells. The secretomes of MSCs, including cytokines, growth factors, chemokines, and extracellular vesicles containing mRNA, proteins and microRNAs, have immunomodulatory and regenerative effects. This review will shed new light on the therapeutic potential of MSC-derived extracellular vesicles (MSC-EVs) for the treatment of diabetes-induced lower limb ischemia and ulcers. The identification of underlying mechanisms for MSC-EVs regulation on impaired diabetic wound healing might provide a new direction for MSC-centered treatment for diabetic lower limb ischemia and ulcers. Immunomodulatory and angiogenic effects of MSC-derived extracellular vesicles on diabetic foot ulcer.
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Affiliation(s)
- Tao An
- Department of hand and foot surgery, Jinhua Hospital of Zhejiang University, Jinhua, People's Republic of China
- Department of hand and foot surgery, Jinhua Central Hospital, 365 Renmin East Road, Jinhua, Zhejiang Province, People's Republic of China
| | - Yi Chen
- Department of hand and foot surgery, Jinhua Hospital of Zhejiang University, Jinhua, People's Republic of China
- Department of hand and foot surgery, Jinhua Central Hospital, 365 Renmin East Road, Jinhua, Zhejiang Province, People's Republic of China
| | - Yingchun Tu
- Department of hand and foot surgery, Jinhua Hospital of Zhejiang University, Jinhua, People's Republic of China
- Department of hand and foot surgery, Jinhua Central Hospital, 365 Renmin East Road, Jinhua, Zhejiang Province, People's Republic of China
| | - Ping Lin
- Department of hand and foot surgery, Jinhua Hospital of Zhejiang University, Jinhua, People's Republic of China.
- Department of hand and foot surgery, Jinhua Central Hospital, 365 Renmin East Road, Jinhua, Zhejiang Province, People's Republic of China.
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Song N, Wakimoto H, Rossignoli F, Bhere D, Ciccocioppo R, Chen KS, Khalsa JK, Mastrolia I, Samarelli AV, Dominici M, Shah K. Mesenchymal stem cell immunomodulation: In pursuit of controlling COVID-19 related cytokine storm. STEM CELLS (DAYTON, OHIO) 2021; 39:707-722. [PMID: 33586320 PMCID: PMC8014246 DOI: 10.1002/stem.3354] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Accepted: 01/26/2021] [Indexed: 11/09/2022]
Abstract
The coronavirus disease 2019 (COVID-19) pandemic has grown to be a global public health crisis with no safe and effective treatments available yet. Recent findings suggest that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the coronavirus pathogen that causes COVID-19, could elicit a cytokine storm that drives edema, dysfunction of the airway exchange, and acute respiratory distress syndrome in the lung, followed by acute cardiac injury and thromboembolic events leading to multiorgan failure and death. Mesenchymal stem cells (MSCs), owing to their powerful immunomodulatory abilities, have the potential to attenuate the cytokine storm and have therefore been proposed as a potential therapeutic approach for which several clinical trials are underway. Given that intravenous infusion of MSCs results in a significant trapping in the lung, MSC therapy could directly mitigate inflammation, protect alveolar epithelial cells, and reverse lung dysfunction by normalizing the pulmonary microenvironment and preventing pulmonary fibrosis. In this review, we present an overview and perspectives of the SARS-CoV-2 induced inflammatory dysfunction and the potential of MSC immunomodulation for the prevention and treatment of COVID-19 related pulmonary disease.
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Affiliation(s)
- Na Song
- Center for Stem Cell Therapeutics and Imaging (CSTI), Harvard Medical School, Boston, Massachusetts, USA.,Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Hiroaki Wakimoto
- Center for Stem Cell Therapeutics and Imaging (CSTI), Harvard Medical School, Boston, Massachusetts, USA.,Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.,Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Filippo Rossignoli
- Center for Stem Cell Therapeutics and Imaging (CSTI), Harvard Medical School, Boston, Massachusetts, USA.,Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Deepak Bhere
- Center for Stem Cell Therapeutics and Imaging (CSTI), Harvard Medical School, Boston, Massachusetts, USA.,Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Rachele Ciccocioppo
- Gastroenterology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Verona, Italy
| | - Kok-Siong Chen
- Center for Stem Cell Therapeutics and Imaging (CSTI), Harvard Medical School, Boston, Massachusetts, USA.,Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Jasneet Kaur Khalsa
- Center for Stem Cell Therapeutics and Imaging (CSTI), Harvard Medical School, Boston, Massachusetts, USA.,Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Ilenia Mastrolia
- Laboratory of Cellular Therapy, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Anna Valeria Samarelli
- Laboratory of Cellular Therapy, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Massimo Dominici
- Laboratory of Cellular Therapy, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Khalid Shah
- Center for Stem Cell Therapeutics and Imaging (CSTI), Harvard Medical School, Boston, Massachusetts, USA.,Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.,Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA
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Mebarki M, Abadie C, Larghero J, Cras A. Human umbilical cord-derived mesenchymal stem/stromal cells: a promising candidate for the development of advanced therapy medicinal products. Stem Cell Res Ther 2021; 12:152. [PMID: 33637125 PMCID: PMC7907784 DOI: 10.1186/s13287-021-02222-y] [Citation(s) in RCA: 90] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 02/11/2021] [Indexed: 02/06/2023] Open
Abstract
Umbilical cord-derived mesenchymal stem/stromal cells (UC-MSCs) emerge as a perspective for therapeutic use in immune and inflammatory diseases. Indeed, immunomodulatory and anti-inflammatory properties, associated to fewer ethical, availability, and safety issues, position UC-MSCs as a promising active substance to develop medicinal products. Since 2007, UC-MSC-based products are classified as advanced therapy medicinal products (ATMP) according to the European Regulation 1394/2007/EC. This new regulatory status required a total adaptation of stakeholders wishing to develop UC-MSC-based ATMPs. Cell production in tissue and cell banks has been replaced by the manufacturing of a medicine, in authorized establishments, according to the good manufacturing practices (GMP) specific to ATMPs. After a brief description of UC-MSCs, we described in this review their recent use in a large panel of immune and inflammatory pathologies, including early and late phase clinical trials. Despite the use of the same product, we noticed an important heterogeneity in terms of indication, posology and study design. Then, we discussed regulatory and manufacturing challenges for stakeholders, especially in terms of process harmonization and cells characterization. Our aim was to point that despite MSCs use for several decades, the development of an UC-MSC-based ATMP remains at this day a real challenge for both academic institutions and pharmaceutical companies.
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Affiliation(s)
- Miryam Mebarki
- Assistance Publique - Hôpitaux de Paris, Hôpital Saint-Louis, DMU PRISM, Unité de Thérapie Cellulaire, 1 avenue Claude Vellefaux, 75010 Paris, France
- INSERM CIC de Biothérapies CBT501, 1 avenue Claude Vellefaux, 75010 Paris, France
- Université de Paris, INSERM U976, 1 avenue Claude Vellefaux, 75010 Paris, France
- Faculté de Pharmacie, Université de Paris, 4 Avenue de l’Observatoire, 75006 Paris, France
| | - Camille Abadie
- INSERM CIC de Biothérapies CBT501, 1 avenue Claude Vellefaux, 75010 Paris, France
| | - Jérôme Larghero
- Assistance Publique - Hôpitaux de Paris, Hôpital Saint-Louis, DMU PRISM, Unité de Thérapie Cellulaire, 1 avenue Claude Vellefaux, 75010 Paris, France
- INSERM CIC de Biothérapies CBT501, 1 avenue Claude Vellefaux, 75010 Paris, France
- Université de Paris, INSERM U976, 1 avenue Claude Vellefaux, 75010 Paris, France
| | - Audrey Cras
- Assistance Publique - Hôpitaux de Paris, Hôpital Saint-Louis, DMU PRISM, Unité de Thérapie Cellulaire, 1 avenue Claude Vellefaux, 75010 Paris, France
- INSERM CIC de Biothérapies CBT501, 1 avenue Claude Vellefaux, 75010 Paris, France
- Faculté de Pharmacie, Université de Paris, 4 Avenue de l’Observatoire, 75006 Paris, France
- Université de Paris, INSERM UMR1140, 4 Avenue de l’Observatoire, 75006 Paris, France
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Ischemia-reperfusion Injury in the Transplanted Lung: A Literature Review. Transplant Direct 2021; 7:e652. [PMID: 33437867 PMCID: PMC7793349 DOI: 10.1097/txd.0000000000001104] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 11/04/2020] [Accepted: 11/06/2020] [Indexed: 02/07/2023] Open
Abstract
Lung ischemia-reperfusion injury (LIRI) and primary graft dysfunction are leading causes of morbidity and mortality among lung transplant recipients. Although extensive research endeavors have been undertaken, few preventative and therapeutic treatments have emerged for clinical use. Novel strategies are still needed to improve outcomes after lung transplantation. In this review, we discuss the underlying mechanisms of transplanted LIRI, potential modifiable targets, current practices, and areas of ongoing investigation to reduce LIRI and primary graft dysfunction in lung transplant recipients.
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45
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CXCR4 expression by mesenchymal stromal cells is lost after use of enzymatic dissociation agents, but preserved by use of non-enzymatic methods. Int J Hematol 2021; 113:5-9. [PMID: 33389659 DOI: 10.1007/s12185-020-03043-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 11/13/2020] [Accepted: 11/17/2020] [Indexed: 01/09/2023]
Abstract
In recent years, multipotent mesenchymal stromal cells (MSCs) have demonstrated tremendous potential for use in regenerative medicine. CXCR4, the receptor for CXCL12, is highly expressed by bone marrow (BM) MSCs and the CXCR4/CXCL12 axis has been shown to be important for migration and homing of BM-MSCs. Typically, MSCs used for clinical applications are collected after culture expansion using enzymatic methods, such as trypsin. Here, we compared different commercially available enzymatic and non-enzymatic methods for collection and dissociation of MSCs from culture plastics and their effects on CXCR4 expression by MSCs. We found that whereas non-enzymatic dissociation buffers and methods maintained CXCR4 expression, all tested enzymatic dissociation solutions dramatically decreased expression of CXCR4. We, therefore, strongly recommend the use of non-enzymatic dissociation methods, followed by filtration through a cell strainer to obtain single cell suspensions, in order to preserve maximal CXCR4 expression and optimal homing of cells.
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46
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Li FXZ, Lin X, Xu F, Shan SK, Guo B, Lei LM, Zheng MH, Wang Y, Xu QS, Yuan LQ. The Role of Mesenchymal Stromal Cells-Derived Small Extracellular Vesicles in Diabetes and Its Chronic Complications. Front Endocrinol (Lausanne) 2021; 12:780974. [PMID: 34987478 PMCID: PMC8721875 DOI: 10.3389/fendo.2021.780974] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 11/29/2021] [Indexed: 12/16/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) are applied in regenerative medicine of several tissues and organs nowadays by virtue of their self-renewal capabilities, multiple differentiation capacity, potent immunomodulatory properties, and their ability to be favourably cultured and manipulated. With the continuous development of "cell-free therapy" research, MSC-derived small extracellular vesicles (MSC-sEVs) have increasingly become a research hotspot in the treatment of various diseases. Small extracellular vesicles (SEVs) are membrane vesicles with diameters of 30 to 150 nm that mediate signal transduction between adjacent or distal cells or organs by delivering non-coding RNA, protein, and DNA. The contents and effects of sEVs vary depending on the properties of the originating cell. In recent years, MSC-sEVs have been found to play an important role in the occurrence and development of diabetes mellitus as a new way of communication between cells. Diabetes mellitus is a common metabolic disease in clinic. Its complications of the heart, brain, kidney, eyes, and peripheral nerves are a serious threat to human health and has been a hot issue for clinicians. MSC-sEVs could be applied to repair or prevent damage from the complications of diabetes mellitus through anti-inflammatory effects, reduction of endoplasmic reticulum-related protein stress, polarization of M2 macrophages, and increasing autophagy. Therefore, we highly recommend that MSC-sEVs-based therapies to treat diabetes mellitus and its chronic complication be further explored. The analysis of the role and molecular mechanisms of MSC-sEVs in diabetes and its related complications will provide new idea and insights for the prevention and treatment of diabetes.
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Affiliation(s)
- Fu-Xing-Zi Li
- National Clinical Research Center for Metabolic Disease, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Xiao Lin
- Department of Radiology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Feng Xu
- National Clinical Research Center for Metabolic Disease, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Su-Kang Shan
- National Clinical Research Center for Metabolic Disease, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Bei Guo
- National Clinical Research Center for Metabolic Disease, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Li-Min Lei
- National Clinical Research Center for Metabolic Disease, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Ming-Hui Zheng
- National Clinical Research Center for Metabolic Disease, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yi Wang
- National Clinical Research Center for Metabolic Disease, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Qiu-Shuang Xu
- National Clinical Research Center for Metabolic Disease, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Ling-Qing Yuan
- National Clinical Research Center for Metabolic Disease, Department of Endocrinology and Metabolism, The Second Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Ling-Qing Yuan,
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Woods N, MacLoughlin R. Defining a Regulatory Strategy for ATMP/Aerosol Delivery Device Combinations in the Treatment of Respiratory Disease. Pharmaceutics 2020; 12:E922. [PMID: 32993197 PMCID: PMC7601063 DOI: 10.3390/pharmaceutics12100922] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Revised: 09/13/2020] [Accepted: 09/21/2020] [Indexed: 12/12/2022] Open
Abstract
Advanced Therapeutic Medicinal Products (ATMP) are a heterogenous group of investigational medicinal products at the forefront of innovative therapies with direct applicability in respiratory diseases. ATMPs include, but are not limited to, stem cells, their secretome, or extracellular vesicles, and each have shown some potential when delivered topically within the lung. This review focuses on that subset of ATMPs. One key mode of delivery that has enabling potential in ATMP validation is aerosol-mediated delivery. The selection of the most appropriate aerosol generator technology is influenced by several key factors, including formulation, patient type, patient intervention, and healthcare economics. The aerosol-mediated delivery of ATMPs has shown promise for the treatment of both chronic and acute respiratory disease in pre-clinical and clinical trials; however, in order for these ATMP device combinations to translate from the bench through to commercialization, they must meet the requirements set out by the various global regulatory bodies. In this review, we detail the potential for ATMP utility in the lungs and propose the nebulization of ATMPs as a viable route of administration in certain circumstances. Further, we provide insight to the current regulatory guidance for nascent ATMP device combination product development within the EU and US.
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Affiliation(s)
- Niamh Woods
- College of Medicine, Nursing & Health Sciences, National University of Ireland, H91 TK33 Galway, Ireland;
| | - Ronan MacLoughlin
- School of Pharmacy & Biomolecular Sciences, Royal College of Surgeons in Ireland, D02 YN77 Dublin, Ireland
- School of Pharmacy and Pharmaceutical Sciences, Trinity College, D02 PN40 Dublin, Ireland
- Aerogen Ltd., Galway Business Park, H91 HE94 Galway, Ireland
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48
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Hu C, Zhao L, Zhang L, Bao Q, Li L. Mesenchymal stem cell-based cell-free strategies: safe and effective treatments for liver injury. Stem Cell Res Ther 2020; 11:377. [PMID: 32883343 PMCID: PMC7469278 DOI: 10.1186/s13287-020-01895-1] [Citation(s) in RCA: 89] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 08/17/2020] [Accepted: 08/21/2020] [Indexed: 02/07/2023] Open
Abstract
Various hepatoxic factors, such as viruses, drugs, lipid deposition, and autoimmune responses, induce acute or chronic liver injury, and 3.5% of all worldwide deaths result from liver cirrhosis, liver failure, or hepatocellular carcinoma. Liver transplantation is currently limited by few liver donors, expensive surgical costs, and severe immune rejection. Cell therapy, including hepatocyte transplantation and stem cell transplantation, has recently become an attractive option to reduce the overall need for liver transplantation and reduce the wait time for patients. Recent studies showed that mesenchymal stem cell (MSC) administration was a promising therapeutic approach for promoting liver regeneration and repairing liver injury by the migration of cells into liver sites, hepatogenic differentiation, immunoregulation, and paracrine mechanisms. MSCs secrete a large number of molecules into the extracellular space, and soluble proteins, free nucleic acids, lipids, and extracellular vesicles (EVs) effectively repair tissue injury in response to fluctuations in physiological states or pathological conditions. Cell-free-based therapies avoid the potential tumorigenicity, rejection of cells, emboli formation, undesired differentiation, and infection transmission of MSC transplantation. In this review, we focus on the potential mechanisms of MSC-based cell-free strategies for attenuating liver injury in various liver diseases. Secretome-mediated paracrine effects participate in the regulation of the hepatic immune microenvironment and promotion of hepatic epithelial repair. We look forward to completely reversing liver injury through an MSC-based cell-free strategy in regenerative medicine in the near future.
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Affiliation(s)
- Chenxia Hu
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases,
- The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.,National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Lingfei Zhao
- Kidney Disease Center, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, Zhejiang Province, People's Republic of China.,Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Lingjian Zhang
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases,
- The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.,National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Qiongling Bao
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases,
- The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.,National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Lanjuan Li
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases,
- The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China. .,National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
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49
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Articular cartilage regeneration by activated skeletal stem cells. Nat Med 2020; 26:1583-1592. [PMID: 32807933 DOI: 10.1038/s41591-020-1013-2] [Citation(s) in RCA: 215] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Accepted: 07/07/2020] [Indexed: 02/07/2023]
Abstract
Osteoarthritis (OA) is a degenerative disease resulting in irreversible, progressive destruction of articular cartilage1. The etiology of OA is complex and involves a variety of factors, including genetic predisposition, acute injury and chronic inflammation2-4. Here we investigate the ability of resident skeletal stem-cell (SSC) populations to regenerate cartilage in relation to age, a possible contributor to the development of osteoarthritis5-7. We demonstrate that aging is associated with progressive loss of SSCs and diminished chondrogenesis in the joints of both mice and humans. However, a local expansion of SSCs could still be triggered in the chondral surface of adult limb joints in mice by stimulating a regenerative response using microfracture (MF) surgery. Although MF-activated SSCs tended to form fibrous tissues, localized co-delivery of BMP2 and soluble VEGFR1 (sVEGFR1), a VEGF receptor antagonist, in a hydrogel skewed differentiation of MF-activated SSCs toward articular cartilage. These data indicate that following MF, a resident stem-cell population can be induced to generate cartilage for treatment of localized chondral disease in OA.
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50
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Shin JY, Lee PH. Mesenchymal stem cells modulate misfolded α-synuclein in parkinsonian disorders: A multitarget disease-modifying strategy. Stem Cell Res 2020; 47:101908. [PMID: 32683319 DOI: 10.1016/j.scr.2020.101908] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 05/22/2020] [Accepted: 07/05/2020] [Indexed: 02/07/2023] Open
Abstract
α-Synuclein (α-Syn) aggregates, the major toxic component of Lewy bodies, are proteinaceous fibrillar cytoplasmic inclusions observed in α-synucleinopathies, such as Parkinson's disease (PD), multiple system atrophy, and dementia with Lewy bodies. Overexpression of α-syn induce neuronal loss and α-syn aggregation in PD animals. Recent studies show that α-syn is released by exocytosis and can be transmitted between brain areas through cell-to-cell propagation. Moreover, aggregates of extracellular α-syn can induce neuroinflammation-mediated neurotoxic signaling through microglial activation and release of pro-inflammatory factors. Thus, modulation of α-syn might be a potential therapeutic strategy for modifying disease progression of α-synucleinopathies. Our previous studies have revealed that MSCs have potent neuroprotective effects in PD animal through modulation of neuroinflammation, inhibition of cell death, and promotion of neurogenesis. Here, we provide further evidence that MSCs have the potential to modulate α-syn-related microenvironments via enhancement of autophagy, proteolysis of α-syn aggregates, inhibition of cell-to-cell transmission of α-syn, stabilization of axonal transport, and phagocytic clearance of α-syn by microglial M2 polarization. With advantages in clinical applications, these data suggests that the use of MSCs as pharmacological modulators of α-syn propagation would be an effective therapeutic approach in PD.
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Affiliation(s)
- Jin Young Shin
- Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea; Severance Biomedical Science Institute, Yonsei University, Seoul, South Korea
| | - Phil Hyu Lee
- Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea; Severance Biomedical Science Institute, Yonsei University, Seoul, South Korea.
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