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Niu K, Zhang C, Liu C, Wu W, Yan Y, Zheng A, Liu S, Shi Z, Yang M, Wang W, Xiao Q. An unexpected role of IL10 in mesoderm induction and differentiation from pluripotent stem cells: Implications in zebrafish angiogenic sprouting, vascular organoid development, and therapeutic angiogenesis. Eur J Cell Biol 2024; 103:151465. [PMID: 39471724 DOI: 10.1016/j.ejcb.2024.151465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 09/21/2024] [Accepted: 10/21/2024] [Indexed: 11/01/2024] Open
Abstract
Mesoderm induction is a crucial step for vascular cell specification, vascular development and vasculogenesis. However, the cellular and molecular mechanisms underlying mesoderm induction remain elusive. In the present study, a chemically-defined differentiation protocol was used to induce mesoderm formation and generate functional vascular cells including smooth muscle cells (SMCs) and endothelial cells (ECs) from human induced pluripotent stem cells (hiPSCs). Zebrafish larvae were used to detect an in vivo function of interleukin 10 (IL10) in mesoderm formation and vascular development. A three dimensional approach was used to create hiPSC-derived blood vessel organoid (BVO) and explore a potential impact of IL10 on BVO formation. A murine model hind limb ischemia was applied to investigate a therapeutic potential of hiPSC-derived cells treated with or without IL10 during differentiation. We found that IL10 was significantly and specifically up-regulated during mesoderm stage of vascular differentiation. IL10 addition in mesoderm induction media dramatically increased mesoderm induction and vascular cell generation from hiPSCs, whereas an opposite effect was observed with IL10 inhibition. Mechanistic studies revealed that IL10 promotes mesoderm formation and vascular cell differentiation by activating signal transducer and activator of transcription 3 signal pathway. Functional studies with an in vivo model system confirmed that knockdown of IL10 using morpholino antisense oligonucleotides in zebrafish larvae caused defective mesoderm formation, angiogenic sprouting and vascular development. Additionally, our data also show IL10 promotes blood vessel organoid development and enhances vasculogenesis and angiogenesis. Importantly, we demonstrate that IL10 treatment during mesoderm induction stage enhances blood flow perfusion recovery and increases vasculogenesis and therapeutic angiogenesis after hind limb ischemia. Our data, therefore, demonstrate a regulatory role for IL10 in mesoderm formation from hiPSCs and during zebrafish vascular development, providing novel insights into mesoderm induction and vascular cell specifications.
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Affiliation(s)
- Kaiyuan Niu
- William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK; Institute of Bioengineering, School of Engineering and Materials Science, Queen Mary University of London, London EC1M 6BQ, UK; Department of Otolaryngology, Head & Neck Surgery, First Affiliated Hospital of Anhui Medical University, No. 218, Jixi Road, Shushan District, Hefei, Anhui 230022, PR China
| | - Chengxin Zhang
- Cardiovascular Surgery, First Affiliated Hospital of Anhui Medical University, No. 218, Jixi Road, Shushan District, Hefei, Anhui 230022, PR China
| | - Chenxin Liu
- William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
| | - Wei Wu
- William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK; Department of Pathophysiology, Key Lab for Shock and Microcirculation Research of Guangdong Province, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, PR China
| | - Yi Yan
- Department of Cardiology, Translational Research Center for Regenerative Medicine and 3D Printing Technologies, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, PR China
| | - Ancheng Zheng
- William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
| | - Silin Liu
- William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
| | - Zhenning Shi
- William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
| | - Mei Yang
- William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
| | - Wen Wang
- Institute of Bioengineering, School of Engineering and Materials Science, Queen Mary University of London, London EC1M 6BQ, UK.
| | - Qingzhong Xiao
- William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
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Kangari P, Salahlou R, Vandghanooni S. Harnessing the Therapeutic Potential of Mesenchymal Stem Cells in Cancer Treatment. Adv Pharm Bull 2024; 14:574-590. [PMID: 39494266 PMCID: PMC11530882 DOI: 10.34172/apb.2024.052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 06/12/2024] [Accepted: 06/19/2024] [Indexed: 11/05/2024] Open
Abstract
Cancer, as a complicated disease, is considered to be one of the major leading causes of death globally. Although various cancer therapeutic strategies have been established, however, some issues confine the efficacies of the treatments. In recent decades researchers for finding efficient therapeutic solutions have extensively focused on the abilities of stem cells in cancer inhibition. Mesenchymal stem cells (MSCs) are multipotent stromal cells that can the most widely extracted from various sources such as the bone marrow (BM), placenta, umbilical cord (UC), menses blood, Wharton's jelly (WJ), adipose tissue and dental pulp (DP). These cells are capable of differentiating into the osteoblasts, chondrocytes, and adipocytes. Due to the unique characteristics of MSCs such as paracrine effects, immunomodulation, tumor-tropism, and migration, they are considered promising candidates for cancer therapeutics. Currently, MSCs are an excellent living carrier for delivery of therapeutic genes and chemical agents to target tumor sites. Also, exosomes, the most important extracellular vesicle released from MSCs, act as a strong cell-free tool for cancer therapeutics. MSCs can prevent cancer progression by inhibiting several signaling pathways, such as wnt/β-catenin and PI3K/AKT/mTOR. However, there are several challenges associated with the use of MSCs and their exosomes in the field of therapy that need to be considered. This review explores the significance of MSCs in cell-based therapy, focusing on their homing properties and immunomodulatory characteristics. It also examines the potential of using MSCs as carriers for delivery of anticancer agents and their role in modulating the signal transduction pathways of cancer cells.
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Affiliation(s)
- Parisa Kangari
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Salahlou
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Somayeh Vandghanooni
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Dehnavi S, Sadeghi M, Tavakol Afshari J, Mohammadi M. Interactions of mesenchymal stromal/stem cells and immune cells following MSC-based therapeutic approaches in rheumatoid arthritis. Cell Immunol 2023; 393-394:104771. [PMID: 37783061 DOI: 10.1016/j.cellimm.2023.104771] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 09/21/2023] [Accepted: 09/21/2023] [Indexed: 10/04/2023]
Abstract
Rheumatoid arthritis (RA) is considered to be a degenerative and progressive autoimmune disorder. Although several medicinal regimens are used to treat RA, potential adverse events such as metabolic disorders and increased risk of infection, as well as drug resistance in some patients, make it essential to find an effective and safe therapeutic approach. Mesenchymal stromal/stem cells (MSCs) are a group of non-hematopoietic stromal cells with immunomodulatory and inhibitory potential. These cells exert their regulatory properties through direct cell-to-cell interactions and paracrine effects on various immune and non-immune cells. As conventional therapeutic approaches for RA are limited due to their side effects, and some patients became refractory to the treatment, MSCs are considered as a promising alternative treatment for RA. In this review, we introduced various experimental and clinical studies conducted to evaluate the therapeutic effects of MSCs on animal models of arthritis and RA patients. Then, possible modulatory and suppressive effects of MSCs on different innate and adaptive immune cells, including dendritic cells, neutrophils, macrophages, natural killer cells, B lymphocytes, and various subtypes of T cells, were categorized and summarized. Finally, limitations and future considerations for the efficient application of MSCs as a therapeutic approach in RA patients were presented.
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Affiliation(s)
- Sajad Dehnavi
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahvash Sadeghi
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | | | - Mojgan Mohammadi
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Yang H, Chen J, Li J. Isolation, culture, and delivery considerations for the use of mesenchymal stem cells in potential therapies for acute liver failure. Front Immunol 2023; 14:1243220. [PMID: 37744328 PMCID: PMC10513107 DOI: 10.3389/fimmu.2023.1243220] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 08/18/2023] [Indexed: 09/26/2023] Open
Abstract
Acute liver failure (ALF) is a high-mortality syndrome for which liver transplantation is considered the only effective treatment option. A shortage of donor organs, high costs and surgical complications associated with immune rejection constrain the therapeutic effects of liver transplantation. Recently, mesenchymal stem cell (MSC) therapy was recognized as an alternative strategy for liver transplantation. Bone marrow mesenchymal stem cells (BMSCs) have been used in clinical trials of several liver diseases due to their ease of acquisition, strong proliferation ability, multipotent differentiation, homing to the lesion site, low immunogenicity and anti-inflammatory and antifibrotic effects. In this review, we comprehensively summarized the harvest and culture expansion strategies for BMSCs, the development of animal models of ALF of different aetiologies, the critical mechanisms of BMSC therapy for ALF and the challenge of clinical application.
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Affiliation(s)
| | | | - Jun Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Qi W, Dong N, Wu L, Zhang X, Li H, Wu H, Ward N, Yu J, Liu H, Wang J, Deng X, Zhao RC. Promoting oral mucosal wound healing using a DCS-RuB2A2 hydrogel based on a photoreactive antibacterial and sustained release of BMSCs. Bioact Mater 2023; 23:53-68. [DOI: 10.1016/j.bioactmat.2022.10.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 10/18/2022] [Accepted: 10/25/2022] [Indexed: 11/11/2022] Open
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Ghasemi Darestani N, Gilmanova AI, Al-Gazally ME, Zekiy AO, Ansari MJ, Zabibah RS, Jawad MA, Al-Shalah SAJ, Rizaev JA, Alnassar YS, Mohammed NM, Mustafa YF, Darvishi M, Akhavan-Sigari R. Mesenchymal stem cell-released oncolytic virus: an innovative strategy for cancer treatment. Cell Commun Signal 2023; 21:43. [PMID: 36829187 PMCID: PMC9960453 DOI: 10.1186/s12964-022-01012-0] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 12/10/2022] [Indexed: 02/26/2023] Open
Abstract
Oncolytic viruses (OVs) infect, multiply, and finally remove tumor cells selectively, causing no damage to normal cells in the process. Because of their specific features, such as, the ability to induce immunogenic cell death and to contain curative transgenes in their genomes, OVs have attracted attention as candidates to be utilized in cooperation with immunotherapies for cancer treatment. This treatment takes advantage of most tumor cells' inherent tendency to be infected by certain OVs and both innate and adaptive immune responses are elicited by OV infection and oncolysis. OVs can also modulate tumor microenvironment and boost anti-tumor immune responses. Mesenchymal stem cells (MSC) are gathering interest as promising anti-cancer treatments with the ability to address a wide range of cancers. MSCs exhibit tumor-trophic migration characteristics, allowing them to be used as delivery vehicles for successful, targeted treatment of isolated tumors and metastatic malignancies. Preclinical and clinical research were reviewed in this study to discuss using MSC-released OVs as a novel method for the treatment of cancer. Video Abstract.
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Affiliation(s)
| | - Anna I Gilmanova
- Department of Prosthetic Dentistry of the I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation
| | | | - Angelina O Zekiy
- Department of Prosthetic Dentistry of the I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation
| | - Mohammad Javed Ansari
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Rahman S Zabibah
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | | | - Saif A J Al-Shalah
- Medical Laboratories Techniques Department, Al-Mustaqbal University College, Babylon, Iraq
| | - Jasur Alimdjanovich Rizaev
- Department of Public Health and Healthcare Management, Rector, Samarkand State Medical University, Samarkand, Uzbekistan
| | | | | | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq
| | - Mohammad Darvishi
- Department of Aerospace and Subaquatic Medicine, Infectious Diseases and Tropical Medicine Research Center (IDTMRC), AJA University of Medical Sciences, Tehran, Iran.
| | - Reza Akhavan-Sigari
- Department of Neurosurgery, University Medical Center, Tuebingen, Germany.,Department of Health Care Management and Clinical Research, Collegium Humanum Warsaw Management University, Warsaw, Poland
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7
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Hattab D, Amer MFA, Mohd Gazzali A, Chuah LH, Bakhtiar A. Current status in cellular-based therapies for prevention and treatment of COVID-19. Crit Rev Clin Lab Sci 2023:1-25. [PMID: 36825325 DOI: 10.1080/10408363.2023.2177605] [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: 02/25/2023]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen responsible for the coronavirus disease 2019 (COVID-19) outbreaks that resulted in a catastrophic threat to global health, with more than 500 million cases detected and 5.5 million deaths worldwide. Patients with a COVID-19 infection presented with clinical manifestations ranging from asymptomatic to severe symptoms, resulting in acute lung injury, acute respiratory distress syndrome, and even death. Immune dysregulation through delayed innate immune response or impairment of the adaptive immune response is the key contributor to the pathophysiology of COVID-19 and SARS-CoV-2-induced cytokine storm. Symptomatic and supportive therapy is the fundamental strategy in treating COVID-19 infection, including antivirals, steroid-based therapies, and cell-based immunotherapies. Various studies reported substantial effects of immune-based therapies for patients with COVID-19 to modulate the over-activated immune system while simultaneously refining the body's ability to destroy the virus. However, challenges may arise from the complexity of the disease through the genetic variance of the virus itself and patient heterogeneity, causing increased transmissibility and heightened immune system evasion that rapidly change the intervention and prevention measures for SARS-CoV-2. Cell-based therapy, utilizing stem cells, dendritic cells, natural killer cells, and T cells, among others, are being extensively explored as other potential immunological approaches for preventing and treating SARS-CoV-2-affected patients the similar process was effectively proven in SARS-CoV-1 and MERS-CoV infections. This review provides detailed insights into the innate and adaptive immune response-mediated cell-based immunotherapies in COVID-19 patients. The immune response linking towards engineered autologous or allogenic immune cells for either treatment or preventive therapies is subsequently highlighted in an individual study or in combination with several existing treatments. Up-to-date data on completed and ongoing clinical trials of cell-based agents for preventing or treating COVID-19 are also outlined to provide a guide that can help in treatment decisions and future trials.
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Affiliation(s)
- Dima Hattab
- Faculty of Pharmacy, Al-Ahliyya Amman University, Amman, Jordan
| | - Mumen F A Amer
- Faculty of Pharmacy, Applied Science Private University, Amman, Jordan
| | - Amirah Mohd Gazzali
- School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang, Malaysia
| | - Lay Hong Chuah
- School of Pharmacy, Monash University Malaysia, Selangor, Malaysia
| | - Athirah Bakhtiar
- School of Pharmacy, Monash University Malaysia, Selangor, Malaysia
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8
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Huang Y, Wu Q, Tam PKH. Immunomodulatory Mechanisms of Mesenchymal Stem Cells and Their Potential Clinical Applications. Int J Mol Sci 2022; 23:ijms231710023. [PMID: 36077421 PMCID: PMC9456387 DOI: 10.3390/ijms231710023] [Citation(s) in RCA: 90] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 08/19/2022] [Accepted: 08/25/2022] [Indexed: 11/17/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent stem cells with the capacity of self-renewal, homing, and low immunogenicity. These distinct biological characteristics have already shown immense potential in regenerative medicine. MSCs also possess immunomodulatory properties that can maintain immune homeostasis when the immune response is over-activated or under-activated. The secretome of MSCs consists of cytokines, chemokines, signaling molecules, and growth factors, which effectively contribute to the regulation of immune and inflammatory responses. The immunomodulatory effects of MSCs can also be achieved through direct cell contact with microenvironmental factors and immune cells. Furthermore, preconditioned and engineered MSCs can specifically improve the immunomodulation effects in diverse clinical applications. These multifunctional properties of MSCs enable them to be used as a prospective therapeutic strategy to treat immune disorders, including autoimmune diseases and incurable inflammatory diseases. Here we review the recent exploration of immunomodulatory mechanisms of MSCs and briefly discuss the promotion of the genetically engineered MSCs. Additionally, we review the potential clinical applications of MSC-mediated immunomodulation in four types of immune diseases, including systemic lupus erythematosus, Crohn’s disease, graft-versus-host disease, and COVID-19.
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Affiliation(s)
- Yutong Huang
- The State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
| | - Qiang Wu
- The State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
- Correspondence: (Q.W.); (P.K.H.T.)
| | - Paul Kwong Hang Tam
- Faculty of Medicine, Macau University of Science and Technology, Macau 999078, China
- Correspondence: (Q.W.); (P.K.H.T.)
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Cross Talk between Mesenchymal Stem/Stromal Cells and Innate Immunocytes Concerning Lupus Disease. Stem Cell Rev Rep 2022; 18:2781-2796. [DOI: 10.1007/s12015-022-10397-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/15/2022] [Indexed: 10/16/2022]
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Molnar V, Pavelić E, Vrdoljak K, Čemerin M, Klarić E, Matišić V, Bjelica R, Brlek P, Kovačić I, Tremolada C, Primorac D. Mesenchymal Stem Cell Mechanisms of Action and Clinical Effects in Osteoarthritis: A Narrative Review. Genes (Basel) 2022; 13:genes13060949. [PMID: 35741711 PMCID: PMC9222975 DOI: 10.3390/genes13060949] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 05/21/2022] [Accepted: 05/24/2022] [Indexed: 02/04/2023] Open
Abstract
With the insufficient satisfaction rates and high cost of operative treatment for osteoarthritis (OA), alternatives have been sought. Furthermore, the inability of current medications to arrest disease progression has led to rapidly growing clinical research relating to mesenchymal stem cells (MSCs). The availability and function of MSCs vary according to tissue source. The three primary sources include the placenta, bone marrow, and adipose tissue, all of which offer excellent safety profiles. The primary mechanisms of action are trophic and immunomodulatory effects, which prevent the further degradation of joints. However, the function and degree to which benefits are observed vary significantly based on the exosomes secreted by MSCs. Paracrine and autocrine mechanisms prevent cell apoptosis and tissue fibrosis, initiate angiogenesis, and stimulate mitosis via growth factors. MSCs have even been shown to exhibit antimicrobial effects. Clinical results incorporating clinical scores and objective radiological imaging have been promising, but a lack of standardization in isolating MSCs prevents their incorporation in current guidelines.
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Affiliation(s)
- Vilim Molnar
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia; (V.M.); (E.P.); (E.K.); (V.M.); (P.B.)
- Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
| | - Eduard Pavelić
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia; (V.M.); (E.P.); (E.K.); (V.M.); (P.B.)
| | - Kristijan Vrdoljak
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (K.V.); (M.Č.)
| | - Martin Čemerin
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (K.V.); (M.Č.)
| | - Emil Klarić
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia; (V.M.); (E.P.); (E.K.); (V.M.); (P.B.)
| | - Vid Matišić
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia; (V.M.); (E.P.); (E.K.); (V.M.); (P.B.)
| | - Roko Bjelica
- Department of Oral Surgery, School of Dental Medicine, University of Zagreb, 10000 Zagreb, Croatia;
| | - Petar Brlek
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia; (V.M.); (E.P.); (E.K.); (V.M.); (P.B.)
| | | | | | - Dragan Primorac
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia; (V.M.); (E.P.); (E.K.); (V.M.); (P.B.)
- Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
- Medical School, University of Split, 21000 Split, Croatia
- Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
- Medical School, University of Rijeka, 51000 Rijeka, Croatia
- Medical School REGIOMED, 96450 Coburg, Germany
- Eberly College of Science, The Pennsylvania State University, University Park, PA 16802, USA
- The Henry C. Lee College of Criminal Justice and Forensic Sciences, University of New Haven, West Haven, CT 06516, USA
- Correspondence:
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11
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Das UN. Arachidonic Acid as Mechanotransducer of Renin Cell Baroreceptor. Nutrients 2022; 14:nu14040749. [PMID: 35215399 PMCID: PMC8874622 DOI: 10.3390/nu14040749] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Revised: 01/31/2022] [Accepted: 02/02/2022] [Indexed: 11/16/2022] Open
Abstract
For normal maintenance of blood pressure and blood volume a well-balanced renin-angiotensin-aldosterone system (RAS) is necessary. For this purpose, renin is secreted as the situation demands by the juxtaglomerular cells (also called as granular cells) that are in the walls of the afferent arterioles. Juxtaglomerular cells can sense minute changes in the blood pressure and blood volume and accordingly synthesize, store, and secrete appropriate amounts of renin. Thus, when the blood pressure and blood volume are decreased JGA cells synthesize and secrete higher amounts of renin and when the blood pressure and blood volume is increased the synthesis and secretion of renin is decreased such that homeostasis is restored. To decipher this important function, JGA cells (renin cells) need to sense and transmit the extracellular physical forces to their chromatin to control renin gene expression for appropriate renin synthesis. The changes in perfusion pressure are sensed by Integrin β1 that is transmitted to the renin cell’s nucleus via lamin A/C that produces changes in the architecture of the chromatin. This results in an alteration (either increase or decrease) in renin gene expression. Cell membrane is situated in an unique location since all stimuli need to be transmitted to the cell nucleus and messages from the DNA to the cell external environment can be conveyed only through it. This implies that cell membrane structure and integrity is essential for all cellular functions. Cell membrane is composed to proteins and lipids. The lipid components of the cell membrane regulate its (cell membrane) fluidity and the way the messages are transmitted between the cell and its environment. Of all the lipids present in the membrane, arachidonic acid (AA) forms an important constituent. In response to pressure and other stimuli, cellular and nuclear shape changes occur that render nucleus to act as an elastic mechanotransducer that produces not only changes in cell shape but also in its dynamic behavior. Cell shape changes in response to external pressure(s) result(s) in the activation of cPLA2 (cytosolic phospholipase 2)-AA pathway that stretches to recruit myosin II which produces actin-myosin cytoskeleton contractility. Released AA can undergo peroxidation and peroxidized AA binds to DNA to regulate the expression of several genes. Alterations in the perfusion pressure in the afferent arterioles produces parallel changes in the renin cell membrane leading to changes in renin release. AA and its metabolic products regulate not only the release of renin but also changes in the vanilloid type 1 (TRPV1) expression in renal sensory nerves. Thus, AA and its metabolites function as intermediate/mediator molecules in transducing changes in perfusion and mechanical pressures that involves nuclear mechanotransduction mechanism. This mechanotransducer function of AA has relevance to the synthesis and release of insulin, neurotransmitters, and other soluble mediators release by specialized and non-specialized cells. Thus, AA plays a critical role in diseases such as diabetes mellitus, hypertension, atherosclerosis, coronary heart disease, sepsis, lupus, rheumatoid arthritis, and cancer.
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Affiliation(s)
- Undurti N Das
- UND Life Sciences, 2221 NW 5th St., Battle Ground, WA 98604, USA
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Zhu R, Yan T, Feng Y, Liu Y, Cao H, Peng G, Yang Y, Xu Z, Liu J, Hou W, Wang X, Li Z, Deng L, Wang S, Li J, Han Q, Li H, Shan G, Cao Y, An X, Yan J, Zhang Z, Li H, Qu X, Zhu J, Zhou S, Wang J, Zhang F, Gao J, Jin R, Xu D, Ma YQ, Huang T, Peng S, Zheng Z, Stambler I, Gilson E, Lim LW, Moskalev A, Cano A, Chakrabarti S, Ulfhake B, Su H, Xu H, Xu S, Wei F, Brown-Borg HM, Min KJ, Ellison-Hughes G, Caruso C, Jin K, Zhao RC. Mesenchymal stem cell treatment improves outcome of COVID-19 patients via multiple immunomodulatory mechanisms. Cell Res 2021; 31:1244-1262. [PMID: 34702946 PMCID: PMC8546390 DOI: 10.1038/s41422-021-00573-y] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Accepted: 09/09/2021] [Indexed: 12/24/2022] Open
Abstract
The infusion of coronavirus disease 2019 (COVID-19) patients with mesenchymal stem cells (MSCs) potentially improves clinical symptoms, but the underlying mechanism remains unclear. We conducted a randomized, single-blind, placebo-controlled (29 patients/group) phase II clinical trial to validate previous findings and explore the potential mechanisms. Patients treated with umbilical cord-derived MSCs exhibited a shorter hospital stay (P = 0.0198) and less time required for symptoms remission (P = 0.0194) than those who received placebo. Based on chest images, both severe and critical patients treated with MSCs showed improvement by day 7 (P = 0.0099) and day 21 (P = 0.0084). MSC-treated patients had fewer adverse events. MSC infusion reduced the levels of C-reactive protein, proinflammatory cytokines, and neutrophil extracellular traps (NETs) and promoted the maintenance of SARS-CoV-2-specific antibodies. To explore how MSCs modulate the immune system, we employed single-cell RNA sequencing analysis on peripheral blood. Our analysis identified a novel subpopulation of VNN2+ hematopoietic stem/progenitor-like (HSPC-like) cells expressing CSF3R and PTPRE that were mobilized following MSC infusion. Genes encoding chemotaxis factors - CX3CR1 and L-selectin - were upregulated in various immune cells. MSC treatment also regulated B cell subsets and increased the expression of costimulatory CD28 in T cells in vivo and in vitro. In addition, an in vivo mouse study confirmed that MSCs suppressed NET release and reduced venous thrombosis by upregulating kindlin-3 signaling. Together, our results underscore the role of MSCs in improving COVID-19 patient outcomes via maintenance of immune homeostasis.
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Affiliation(s)
- Rongjia Zhu
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Tingdong Yan
- School of Life Sciences, Shanghai University, Shanghai, China
| | - Yingmei Feng
- You'an Hospital, Capital Medical University, Beijing, China
| | - Yan Liu
- Puren Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei, China
| | - Hongcui Cao
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- National Clinical Research Center for Infectious Diseases, Hangzhou, Zhejiang, China
| | - Gongxin Peng
- Center for Bioinformatics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Yanlei Yang
- Department of Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhen Xu
- School of Life Sciences, Shanghai University, Shanghai, China
- Versiti Blood Research Institute, Milwaukee, WI, USA
| | - Jingqi Liu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Wei Hou
- You'an Hospital, Capital Medical University, Beijing, China
| | - Xiaoyue Wang
- Center for Bioinformatics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Zhe Li
- School of Life Sciences, Shanghai University, Shanghai, China
| | - Luchan Deng
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Shihua Wang
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Jing Li
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Qin Han
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Hongling Li
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Guangliang Shan
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Yinghao Cao
- Center for Bioinformatics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Xingyan An
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Jianshe Yan
- School of Life Sciences, Shanghai University, Shanghai, China
| | - Zhonghui Zhang
- School of Life Sciences, Shanghai University, Shanghai, China
| | - Huafei Li
- School of Life Sciences, Shanghai University, Shanghai, China
| | - Xuebin Qu
- School of Life Sciences, Shanghai University, Shanghai, China
| | - Jiaqi Zhu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- National Clinical Research Center for Infectious Diseases, Hangzhou, Zhejiang, China
| | - Shumin Zhou
- School of Life Sciences, Shanghai University, Shanghai, China
| | - Jiao Wang
- School of Life Sciences, Shanghai University, Shanghai, China
| | - Fengchun Zhang
- Department of Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jinming Gao
- Department of Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ronghua Jin
- You'an Hospital, Capital Medical University, Beijing, China.
| | - Dayong Xu
- Puren Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei, China
| | - Yan-Qing Ma
- Versiti Blood Research Institute, Milwaukee, WI, USA.
| | - Tao Huang
- Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Shuang Peng
- Qingdao Walson Standard Biopharmaceutical Co, Ltd, Qingdao, Shangdong, China
| | - Zhi Zheng
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Ilia Stambler
- International Society on Aging and Disease, Bryan, TX, USA
- Department of Science, Technology and Society, Bar Ilan University, Ramat Gan, Israel
| | - Eric Gilson
- International Society on Aging and Disease, Bryan, TX, USA
- Université Côte d'Azur, CNRS, Inserm, IRCAN, Faculty of Medicine, Nice, France
- Department of Medical Genetics, Centre Hospitalier Universitaire (CHU), Nice, France
| | - Lee Wei Lim
- International Society on Aging and Disease, Bryan, TX, USA
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China
| | - Alexey Moskalev
- International Society on Aging and Disease, Bryan, TX, USA
- Institute of Biology, Komi Science Center of Russian Academy of Sciences, Syktyvkar, Russia
- Russian Gerontological Research Clinical Center, Moscow, Russia
| | - Antonio Cano
- International Society on Aging and Disease, Bryan, TX, USA
- Department of Pediatrics, Obstetrics and Gynecology, University of Valencia, Valencia, Spain
| | - Sasanka Chakrabarti
- International Society on Aging and Disease, Bryan, TX, USA
- Maharishi Markandeshwar Deemed University, Mullana-Ambala, India
| | - Brun Ulfhake
- International Society on Aging and Disease, Bryan, TX, USA
- Karolinska University Hospital, Stockholm, Sweden
| | - Huanxing Su
- International Society on Aging and Disease, Bryan, TX, USA
- Institute of Chinese Medical Science, University of Macau, Taipa, Macau, China
| | - Haoying Xu
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Sihuan Xu
- Puren Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei, China
| | - Feng Wei
- State Key Laboratory of Advanced Materials for Smart Sensing, GRINM GROUP Co, Ltd, Beijing, China
| | - Holly M Brown-Borg
- International Society on Aging and Disease, Bryan, TX, USA
- Department of Biomedical Sciences, University of North Dakota, School of Medicine & Health Sciences, Grand Forks, ND, USA
| | - Kyung-Jin Min
- International Society on Aging and Disease, Bryan, TX, USA
- Department of Biological Sciences, Inha University, Incheon, Republic of Korea
| | - Georgina Ellison-Hughes
- International Society on Aging and Disease, Bryan, TX, USA
- School of Basic and Medical Biosciences, Faculty of Life Sciences & Medicine, King's College London, London, UK
| | - Calogero Caruso
- International Society on Aging and Disease, Bryan, TX, USA
- Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, Palermo, Italy
| | - Kunlin Jin
- International Society on Aging and Disease, Bryan, TX, USA
- University of North Texas Health Science Center, Bryan, TX, USA
| | - Robert Chunhua Zhao
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
- School of Life Sciences, Shanghai University, Shanghai, China.
- International Society on Aging and Disease, Bryan, TX, USA.
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Wang X, Zhao X, He Z. Mesenchymal stem cell carriers enhance anti-tumor efficacy of oncolytic virotherapy. Oncol Lett 2021; 21:238. [PMID: 33664802 PMCID: PMC7882891 DOI: 10.3892/ol.2021.12499] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Accepted: 12/09/2020] [Indexed: 12/21/2022] Open
Abstract
Oncolytic viruses (OVs) specifically infect, replicate and eventually destroy tumor cells, with no concomitant toxicity to adjacent normal cells. Furthermore, OVs can regulate tumor microenvironments and stimulate anti-tumor immune responses. Mesenchymal stem cells (MSCs) have inherent tumor tropisms and immunosuppressive functions. MSCs carrying OVs not only protect viruses from clearing by the immune system, but they also deliver the virus to tumor lesions. Equally, cytokines released by MSCs enhance anti-tumor immune responses, suggesting that MSCs carrying OVs may be considered as a promising strategy in enhancing the anti-tumor efficacies of virotherapy. In the present review, preclinical and clinical studies were evaluated and discussed, as well as the effectiveness of MSCs carrying OVs for tumor treatment.
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Affiliation(s)
- Xianyao Wang
- Center for Tissue Engineering and Stem Cell Research, Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
- Key Laboratory of Adult Stem Cell Translational Research, Chinese Academy of Medical Sciences, Guiyang, Guizhou 550004, P.R. China
- Department of Immunology, Guizhou Medical University, Guiyang, Guizhou 550025, P.R. China
| | - Xing Zhao
- Center for Tissue Engineering and Stem Cell Research, Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
- Key Laboratory of Adult Stem Cell Translational Research, Chinese Academy of Medical Sciences, Guiyang, Guizhou 550004, P.R. China
- Department of Immunology, Guizhou Medical University, Guiyang, Guizhou 550025, P.R. China
| | - Zhixu He
- Key Laboratory of Adult Stem Cell Translational Research, Chinese Academy of Medical Sciences, Guiyang, Guizhou 550004, P.R. China
- Department of Pediatrics, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
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14
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Zhou JH, Lu X, Yan CL, Sheng XY, Cao HC. Mesenchymal stromal cell-dependent immunoregulation in chemically-induced acute liver failure. World J Stem Cells 2021; 13:208-220. [PMID: 33815670 PMCID: PMC8006015 DOI: 10.4252/wjsc.v13.i3.208] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 01/08/2021] [Accepted: 02/15/2021] [Indexed: 02/06/2023] Open
Abstract
Drug-induced liver injury (DILI), which refers to liver damage caused by a drug or its metabolites, has emerged as an important cause of acute liver failure (ALF) in recent years. Chemically-induced ALF in animal models mimics the pathology of DILI in humans; thus, these models are used to study the mechanism of potentially effective treatment strategies. Mesenchymal stromal cells (MSCs) possess immunomodulatory properties, and they alleviate acute liver injury and decrease the mortality of animals with chemically-induced ALF. Here, we summarize some of the existing research on the interaction between MSCs and immune cells, and discuss the possible mechanisms underlying the immuno-modulatory activity of MSCs in chemically-induced ALF. We conclude that MSCs can impact the phenotype and function of macrophages, as well as the differentiation and maturation of dendritic cells, and inhibit the proliferation and activation of T lymphocytes or B lymphocytes. MSCs also have immuno-modulatory effects on the production of cytokines, such as prostaglandin E2 and tumor necrosis factor-alpha-stimulated gene 6, in animal models. Thus, MSCs have significant benefits in the treatment of chemically-induced ALF by interacting with immune cells and they may be applied to DILI in humans in the near future.
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Affiliation(s)
- Jia-Hang Zhou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Xuan Lu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Cui-Lin Yan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Xin-Yu Sheng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Hong-Cui Cao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
- Zhejiang Provincial Key Laboratory for Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China.
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15
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Das UN. "Cell Membrane Theory of Senescence" and the Role of Bioactive Lipids in Aging, and Aging Associated Diseases and Their Therapeutic Implications. Biomolecules 2021; 11:biom11020241. [PMID: 33567774 PMCID: PMC7914625 DOI: 10.3390/biom11020241] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 01/28/2021] [Accepted: 02/01/2021] [Indexed: 12/12/2022] Open
Abstract
Lipids are an essential constituent of the cell membrane of which polyunsaturated fatty acids (PUFAs) are the most important component. Activation of phospholipase A2 (PLA2) induces the release of PUFAs from the cell membrane that form precursors to both pro- and ant-inflammatory bioactive lipids that participate in several cellular processes. PUFAs GLA (gamma-linolenic acid), DGLA (dihomo-GLA), AA (arachidonic acid), EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) are derived from dietary linoleic acid (LA) and alpha-linolenic acid (ALA) by the action of desaturases whose activity declines with age. Consequently, aged cells are deficient in GLA, DGLA, AA, AA, EPA and DHA and their metabolites. LA, ALA, AA, EPA and DHA can also be obtained direct from diet and their deficiency (fatty acids) may indicate malnutrition and deficiency of several minerals, trace elements and vitamins some of which are also much needed co-factors for the normal activity of desaturases. In many instances (patients) the plasma and tissue levels of GLA, DGLA, AA, EPA and DHA are low (as seen in patients with hypertension, type 2 diabetes mellitus) but they do not have deficiency of other nutrients. Hence, it is reasonable to consider that the deficiency of GLA, DGLA, AA, EPA and DHA noted in these conditions are due to the decreased activity of desaturases and elongases. PUFAs stimulate SIRT1 through protein kinase A-dependent activation of SIRT1-PGC1α complex and thus, increase rates of fatty acid oxidation and prevent lipid dysregulation associated with aging. SIRT1 activation prevents aging. Of all the SIRTs, SIRT6 is critical for intermediary metabolism and genomic stability. SIRT6-deficient mice show shortened lifespan, defects in DNA repair and have a high incidence of cancer due to oncogene activation. SIRT6 overexpression lowers LDL and triglyceride level, improves glucose tolerance, and increases lifespan of mice in addition to its anti-inflammatory effects at the transcriptional level. PUFAs and their anti-inflammatory metabolites influence the activity of SIRT6 and other SIRTs and thus, bring about their actions on metabolism, inflammation, and genome maintenance. GLA, DGLA, AA, EPA and DHA and prostaglandin E2 (PGE2), lipoxin A4 (LXA4) (pro- and anti-inflammatory metabolites of AA respectively) activate/suppress various SIRTs (SIRt1 SIRT2, SIRT3, SIRT4, SIRT5, SIRT6), PPAR-γ, PARP, p53, SREBP1, intracellular cAMP content, PKA activity and peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1-α). This implies that changes in the metabolism of bioactive lipids as a result of altered activities of desaturases, COX-2 and 5-, 12-, 15-LOX (cyclo-oxygenase and lipoxygenases respectively) may have a critical role in determining cell age and development of several aging associated diseases and genomic stability and gene and oncogene activation. Thus, methods designed to maintain homeostasis of bioactive lipids (GLA, DGLA, AA, EPA, DHA, PGE2, LXA4) may arrest aging process and associated metabolic abnormalities.
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Affiliation(s)
- Undurti N. Das
- UND Life Sciences, 2221 NW 5th St, Battle Ground, WA 98604, USA; ; Tel.: +508-904-5376
- BioScience Research Centre and Department of Medicine, GVP Medical College and Hospital, Visakhapatnam 530048, India
- International Research Centre, Biotechnologies of the third Millennium, ITMO University, 191002 Saint-Petersburg, Russia
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16
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Dabrowska S, Andrzejewska A, Janowski M, Lukomska B. Immunomodulatory and Regenerative Effects of Mesenchymal Stem Cells and Extracellular Vesicles: Therapeutic Outlook for Inflammatory and Degenerative Diseases. Front Immunol 2021; 11:591065. [PMID: 33613514 PMCID: PMC7893976 DOI: 10.3389/fimmu.2020.591065] [Citation(s) in RCA: 131] [Impact Index Per Article: 32.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 12/21/2020] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are non-hematopoietic, multipotent stem cells derived from mesoderm, which can be easily isolated from many sources such as bone marrow, umbilical cord or adipose tissue. MSCs provide support for hematopoietic stem cells and have an ability to differentiate into multiple cell lines. Moreover, they have proangiogenic, protective and immunomodulatory properties. MSCs have the capacity to modulate both innate and adaptive immune responses, which accompany many diseases, by inhibiting pro-inflammatory reactions and stimulating anti-inflammatory activity. Recent findings revealed that the positive effect of MSCs is at least partly associated with the production of extracellular vesicles (EVs). EVs are small membrane structures, containing proteins, lipids and nuclei acids, which take part in intra-cellular communication. Many studies indicate that EVs contain protective and pro-regenerative properties and can modulate an immune response that is activated in various diseases such as CNS diseases, myocardial infarction, liver injury, lung diseases, ulcerative colitis or kidney injury. Thus, EVs have similar functions as their cells of origin and since they do not carry the risk of cell transplantation, such as tumor formation or small vessel blockage, they can be considered a potential therapeutic tool for cell-free therapy.
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Affiliation(s)
- Sylwia Dabrowska
- NeuroRepair Department, Mossakowski Medical Research Centre, PAS, Warsaw, Poland
| | - Anna Andrzejewska
- NeuroRepair Department, Mossakowski Medical Research Centre, PAS, Warsaw, Poland
| | - Miroslaw Janowski
- NeuroRepair Department, Mossakowski Medical Research Centre, PAS, Warsaw, Poland.,University of Maryland School of Medicine, Baltimore, MD, United States.,Center for Advanced Imaging Research, Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Barbara Lukomska
- NeuroRepair Department, Mossakowski Medical Research Centre, PAS, Warsaw, Poland
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Abstract
The COVID-19 pandemic has led to a major setback in both the health and economic sectors across the globe. The scale of the problem is enormous because we still do not have any specific anti-SARS-CoV-2 antiviral agent or vaccine. The human immune system has never been exposed to this novel virus, so the viral interactions with the human immune system are completely naive. New approaches are being studied at various levels, including animal in vitro models and human-based studies, to contain the COVID-19 pandemic as soon as possible. Many drugs are being tested for repurposing, but so far only remdesivir has shown some positive benefits based on preliminary reports, but these results also need further confirmation via ongoing trials. Otherwise, no other agents have shown an impactful response against COVID-19. Recently, research exploring the therapeutic application of mesenchymal stem cells (MSCs) in critically ill patients suffering from COVID-19 has gained momentum. The patients belonging to this subset are most likely beyond the point where they could benefit from an antiviral therapy because most of their illness at this stage of disease is driven by inflammatory (over)response of the immune system. In this review, we discuss the potential of MSCs as a therapeutic option for patients with COVID-19, based on the encouraging results from the preliminary data showing improved outcomes in the progression of COVID-19 disease.
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Affiliation(s)
- Kamal Kant Sahu
- Department of Hematology and Oncology, Department of Internal Medicine, Saint Vincent Hospital, Worcester, Massachusetts
| | - Ahmad Daniyal Siddiqui
- Department of Hematology and Oncology, Department of Internal Medicine, Saint Vincent Hospital, Worcester, Massachusetts
| | - Jan Cerny
- Division of Hematology and Oncology, Department of Medicine, UMass Memorial Health Care, University of Massachusetts Medical School, Worcester, Massachusetts
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Choudhery MS, Harris DT. Stem cell therapy for COVID-19: Possibilities and challenges. Cell Biol Int 2020; 44:2182-2191. [PMID: 32767687 PMCID: PMC7436138 DOI: 10.1002/cbin.11440] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 08/04/2020] [Accepted: 08/05/2020] [Indexed: 02/05/2023]
Abstract
Since its eruption in China, novel coronavirus disease (COVID-19) has been reported in most of the countries and territories (>200) of the world with ∼18 million confirmed cases (as of August 3, 2020). In most of the countries, COVID-19 upsurge is uncontrolled with a significant mortality rate. Currently, no treatment effective for COVID-19 is available in the form of vaccines or antiviral drugs and patients are currently treated symptomatically. Although the majority of the patients develop mild symptoms and recover without mechanical ventilation for respiratory management, severe respiratory illness develops in a significant portion of affected patients and may result in death. While the scientific community is working to develop vaccines and drugs against the COVID-19 pandemic, novel alternative therapies may reduce the mortality rate. Recent use of stem cells for critically ill COVID-19 patients in a small group of patients in China and subsequent Emergency Use Authorization of stem cells by Food and Drug Administration to Global Institute of Stem Cell Therapy and Research and Athersys has created excitement among the medical community. As a result, several clinical trials have been registered using stem cells for COVID-19 treatment that aim to use different cell sources, dosage, and importantly diverse targeted patient groups. In this brief review, the possibilities of stem cell use in COVID-19 patients and relevant challenges in their use have been discussed.
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Affiliation(s)
- Mahmood S. Choudhery
- Tissue Engineering and Regenerative Medicine Laboratory, Department of Biomedical SciencesKing Edward Medical UniversityLahorePakistan
| | - David T. Harris
- Department of ImmunobiologyThe University of ArizonaTucsonArizona
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19
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Abstract
Over the past decade, the clinical application of mesenchymal stromal cells (MSCs) has generated growing enthusiasm as an innovative cell-based approach in solid organ transplantation (SOT). These expectations arise from a significant number of both transplant- and non-transplant-related experimental studies investigating the complex anti-inflammatory, immunomodulatory, and tissue-repair properties of MSCs. Promising preclinical results have prompted clinical trials using MSC-based therapy in SOT. In the present review, the general properties of MSCs are summarized, with a particular emphasis on MSC-mediated impact on the immune system and in the ischemic conditioning strategy. Next, we chronologically detail all clinical trials using MSCs in the field of SOT. Finally, we envision the challenges and perspectives of MSC-based cell therapy in SOT.
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Sarajlic M, Neuper T, Vetter J, Schaller S, Klicznik MM, Gratz IK, Wessler S, Posselt G, Horejs-Hoeck J. H. pylori modulates DC functions via T4SS/TNFα/p38-dependent SOCS3 expression. Cell Commun Signal 2020; 18:160. [PMID: 33023610 PMCID: PMC7541176 DOI: 10.1186/s12964-020-00655-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 09/06/2020] [Indexed: 12/11/2022] Open
Abstract
Background Helicobacter pylori (H. pylori) is a gram-negative bacterium that chronically infects approximately 50% of the world’s human population. While in most cases the infection remains asymptomatic, 10% of infected individuals develop gastric pathologies and 1–3% progress to gastric cancer. Although H. pylori induces severe inflammatory responses, the host’s immune system fails to clear the pathogen and H. pylori can persist in the human stomach for decades. As suppressor of cytokine signaling (SOCS) proteins are important feedback regulators limiting inflammatory responses, we hypothesized that H. pylori could modulate the host’s immune responses by inducing SOCS expression. Methods The phenotype of human monocyte-derived DCs (moDCs) infected with H. pylori was analyzed by flow cytometry and multiplex technology. SOCS expression levels were monitored by qPCR and signaling studies were conducted by means of Western blot. For functional studies, RNA interference-based silencing of SOCS1–3 and co-cultures with CD4+ T cells were performed. Results We show that H. pylori positive gastritis patients express significantly higher SOCS3, but not SOCS1 and SOCS2, levels compared to H. pylori negative patients. Moreover, infection of human moDCs with H. pylori rapidly induces SOCS3 expression, which requires the type IV secretion system (T4SS), release of TNFα, and signaling via the MAP kinase p38, but appears to be independent of TLR2, TLR4, MEK1/2 and STAT proteins. Silencing of SOCS3 expression in moDCs prior to H. pylori infection resulted in increased release of both pro- and anti-inflammatory cytokines, upregulation of PD-L1, and decreased T-cell proliferation. Conclusions This study shows that H. pylori induces SOCS3 via an autocrine loop involving the T4SS and TNFα and p38 signaling. Moreover, we demonstrate that high levels of SOCS3 in DCs dampen PD-L1 expression on DCs, which in turn drives T-cell proliferation.
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