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Dunbar H, Hawthorne IJ, Tunstead C, McNamee EN, Weiss DJ, Armstrong ME, Donnelly SC, English K. Mesenchymal stromal cells dampen trained immunity in house dust mite-primed macrophages expressing human macrophage migration inhibitory factor polymorphism. Cytotherapy 2024; 26:1245-1251. [PMID: 38819366 DOI: 10.1016/j.jcyt.2024.05.010] [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: 02/07/2024] [Revised: 05/08/2024] [Accepted: 05/08/2024] [Indexed: 06/01/2024]
Abstract
BACKGROUND Trained immunity results in long-term immunological memory, provoking a faster and greater immune response when innate immune cells encounter a secondary, often heterologous, stimulus. We have previously shown that house dust mite (HDM)-induced innate training is amplified in mice expressing the human macrophage migration inhibitory factor (MIF) CATT7 functional polymorphism. AIM This study investigated the ability of mesenchymal stromal cells (MSCs) to modulate MIF-driven trained immunity both in vitro and in vivo. METHODS Compared with wild-type mice, in vivo HDM-primed bone marrow-derived macrophages (BMDMs) from CATT7 mice expressed significantly higher levels of M1-associated genes following lipopolysaccharide stimulation ex vivo. Co-cultures of CATT7 BMDMs with MSCs suppressed this HDM-primed effect, with tumor necrosis factor alpha (TNF-α) being significantly decreased in a cyclooxygenase 2 (COX-2)-dependent manner. Interestingly, interleukin 6 (IL-6) was suppressed by MSCs independently of COX-2. In an in vitro training assay, MSCs significantly abrogated the enhanced production of pro-inflammatory cytokines by HDM-trained CATT7 BMDMs when co-cultured at the time of HDM stimulus on day 0, displaying their therapeutic efficacy in modulating an overzealous human MIF-dependent immune response. Utilizing an in vivo model of HDM-induced trained immunity, MSCs administered systemically on day 10 and day 11 suppressed this trained phenomenon by significantly reducing TNF-α and reducing IL-6 and C-C motif chemokine ligand 17 (CCL17) production. CONCLUSIONS This novel study elucidates how MSCs can attenuate an MIF-driven, HDM-trained response in CATT7 mice in a model of allergic airway inflammation.
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Affiliation(s)
- Hazel Dunbar
- Department of Biology, Maynooth University, Maynooth, Ireland; Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Ireland
| | - Ian J Hawthorne
- Department of Biology, Maynooth University, Maynooth, Ireland; Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Ireland
| | - Courteney Tunstead
- Department of Biology, Maynooth University, Maynooth, Ireland; Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Ireland
| | - Eóin N McNamee
- Department of Biology, Maynooth University, Maynooth, Ireland; Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Ireland
| | - Daniel J Weiss
- Department of Medicine, Larner College of Medicine, University of Vermont, Burlington, Vermont, USA
| | - Michelle E Armstrong
- Department of Medicine, Trinity College Dublin and Tallaght University Hospital, Dublin, Ireland
| | - Seamas C Donnelly
- Department of Medicine, Trinity College Dublin and Tallaght University Hospital, Dublin, Ireland
| | - Karen English
- Department of Biology, Maynooth University, Maynooth, Ireland; Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Ireland.
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Hassan ZR, El-Sayed S, Zekry KM, Ahmed SG, Hassan Abd Elhamid A, Salama DEA, Taha AK, Mahmoud NA, Mohammed SF, Amin MM, Mohamed RE, Eraque AMS, Mohamed SA, Abdelgalil RM, Atta SA, Fahmy NT, Badr MS. Evaluation of muscular apoptotic changes and myogenin gene expression in experimental trichinosis after stem cells and atorvastatin added to ivermectin treatment. Exp Parasitol 2024; 265:108823. [PMID: 39187057 DOI: 10.1016/j.exppara.2024.108823] [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: 08/17/2023] [Revised: 04/20/2024] [Accepted: 08/08/2024] [Indexed: 08/28/2024]
Abstract
Trichinosis is a common parasitic disease that affects the striated skeletal muscles, causing apoptotic and degenerative changes associated with myogenin expression in the affected myocytes. Hence, this study aimed to assess the ameliorative effects of stem cells and atorvastatin added to ivermectin on the infected myocytes during the muscular phase of murine trichinosis. 120 laboratory Swiss albino male mice were divided into 10 groups, and each group was subdivided into intestinal and muscular phases (each n = 6); uninfected control; untreated infected control; infected received ivermectin monotherapy; infected received atorvastatin monotherapy; infected received stem cells monotherapy; infected received ivermectin and atorvastatin dual therapy; infected received ivermectin and stem cells dual therapy; infected received atorvastatin and stem cells dual therapy; infected received ivermectin 0.2, atorvastatin 40, and stem cells triple therapy; and infected received ivermectin 0.1, atorvastatin 20, and stem cells triple therapy. Intestinal phase mice were sacrificed on the 5th day post-infection, while those of the muscular phase were sacrificed on the 35th day post-infection. Parasitological, histopathological, ultrastructural, histochemical, biochemical, and myogenin gene expression assessments were performed. The results revealed that mice that received ivermectin, atorvastatin, and stem cell triple therapies showed the maximum reduction in the adult worm and larvae burden, marked improvement in the underlying muscular degenerative changes (as was noticed by histopathological, ultrastructural, and histochemical Feulgen stain assessment), lower biochemical levels of serum NK-κB and tissue NO, and lower myogenin expression. Accordingly, the combination of stem cells, atorvastatin, and ivermectin affords a potential synergistic activity against trichinosis with considerable healing of the underlying degenerative sequel.
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Affiliation(s)
- Zeinab R Hassan
- Departments of Parasitology, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt; Departments of Parasitology, Benha National University (BNU), Qalyubia, Egypt.
| | - Samar El-Sayed
- Departments of Parasitology, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
| | - Kareman M Zekry
- Departments of Parasitology, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
| | - Samah G Ahmed
- Histology, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
| | | | - Doaa E A Salama
- Pathology, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt; Departments of Pathology, School of Medicine, Badr University in Cairo (BUC), Cairo, Egypt
| | - Azza Kamal Taha
- Pathology, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
| | - Nihal A Mahmoud
- Physiology, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
| | | | - Mona M Amin
- Pharmacology, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
| | | | - Ayat M S Eraque
- Biochemestry, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
| | - Shimaa A Mohamed
- Biochemestry, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
| | - Ranya M Abdelgalil
- Anatomy, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
| | | | - Nermeen Talaat Fahmy
- Molecular Biology and Genomics, Egypt Center for Research and Regenerative Medicine (ECRRM), Cairo, Egypt
| | - Mohamed S Badr
- Molecular Biology and Genetic-Bioinformatics Nano-Robot Diagnostics, Medical Research Centre, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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Su W, Yin Y, Cheng Y, Yu S, Hu R, Zhang H, Hu J, Ren R, Zhang Y, Zhao J, Wang A, Lyu Z, Mu Y, Gao J. The phenotype and related gene expressions of macrophages in adipose tissue of T2D mice following MSCs infusion. Immunobiology 2024; 229:152788. [PMID: 38309141 DOI: 10.1016/j.imbio.2024.152788] [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: 10/25/2023] [Revised: 12/28/2023] [Accepted: 01/24/2024] [Indexed: 02/05/2024]
Abstract
BACKGROUND Infusion of mesenchymal stem cells (MSCs) induces polarization of M2 macrophages in adipose tissue of type 2 diabetes (T2D) mice. Studies have shown that M2 macrophages were divided into four sub-phenotypes (M2a, M2b, M2c and M2d) with different functions, and manuscripts have also confirmed that macrophages co-cultured with MSCs were not matched with known four phenotype macrophages. Therefore, our study explored the phenotype and related gene expressions of macrophages in the adipose tissue of T2D mice with/without MSCs infusion. METHODS We induced a T2D mouse model by using high-fat diets and streptozotocin (STZ) injection. The mice were divided into three groups: the control group, the T2D group, and the MSCs group. MSCs were systemically injected once a week for 6 weeks. The phenotype of macrophages in adipose tissue was detected via flow cytometric analysis. We also investigated the gene expression of macrophages in different groups via SMART-RNA-sequencing and quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR). RESULTS The present study found that the macrophages of adipose tissue in the MSCs group were polarized to the M2 phenotype mixed with four sub-phenotypes. Besides, M2a and M2c held a dominant position, while M2b and M2d (tumor-associated macrophages, TAMs) exhibited a decreasing trend after infusion of MSCs. Moreover, the MSCs group did not appear to express higher levels of tumor-associated, inflammation-associated, or fibrosis-associated genes in comparison to the T2D group. CONCLUSION The present results unveiled that the macrophage phenotype was inclined to be present in a hybridity state of four M2 sub-phenotypes and the genes related to tumor-promoting, pro-inflammation and pro-fibrosis were not increased after MSCs injection.
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Affiliation(s)
- Wanlu Su
- School of Medicine, Nankai University, No. 94 Weijin Road, Tianjin 300071, China; Department of Endocrinology, Chinese People's Liberation Army General Hospital, No. 28 Fuxing Road, Beijing 100853, China
| | - Yaqi Yin
- Department of Endocrinology, Chinese People's Liberation Army General Hospital, No. 28 Fuxing Road, Beijing 100853, China
| | - Yu Cheng
- Department of Endocrinology, Chinese People's Liberation Army General Hospital, No. 28 Fuxing Road, Beijing 100853, China
| | - Songyan Yu
- Department of Endocrinology, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
| | - Ruofan Hu
- Department of Endocrinology, Chinese People's Liberation Army General Hospital, No. 28 Fuxing Road, Beijing 100853, China
| | - Haixia Zhang
- Department of Endocrinology, Chinese People's Liberation Army General Hospital, No. 28 Fuxing Road, Beijing 100853, China
| | - Jia Hu
- Department of Endocrinology, Chinese People's Liberation Army General Hospital, No. 28 Fuxing Road, Beijing 100853, China
| | - Rui Ren
- Department of Endocrinology, Chinese People's Liberation Army General Hospital, No. 28 Fuxing Road, Beijing 100853, China
| | - Yue Zhang
- Department of Endocrinology, Chinese People's Liberation Army General Hospital, No. 28 Fuxing Road, Beijing 100853, China
| | - Jian Zhao
- Department of Endocrinology, Chinese People's Liberation Army General Hospital, No. 28 Fuxing Road, Beijing 100853, China
| | - Anning Wang
- Department of Endocrinology, Chinese People's Liberation Army General Hospital, No. 28 Fuxing Road, Beijing 100853, China
| | - Zhaohui Lyu
- Department of Endocrinology, Chinese People's Liberation Army General Hospital, No. 28 Fuxing Road, Beijing 100853, China.
| | - Yiming Mu
- School of Medicine, Nankai University, No. 94 Weijin Road, Tianjin 300071, China; Department of Endocrinology, Chinese People's Liberation Army General Hospital, No. 28 Fuxing Road, Beijing 100853, China.
| | - Jieqing Gao
- Department of Endocrinology, Beijing Rehabilitation Hospital of Capital Medical University, Beijing, China.
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Wang X, Wang Q, Meng L, Tian R, Guo H, Tan Z, Tan Y. Biodistribution-based Administration of cGMP-compliant Human Umbilical Cord Mesenchymal Stem Cells Affects the Therapeutic Effect of Wound Healing. Stem Cell Rev Rep 2024; 20:329-346. [PMID: 37889447 DOI: 10.1007/s12015-023-10644-9] [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] [Accepted: 10/12/2023] [Indexed: 10/28/2023]
Abstract
BACKGROUND Although mesenchymal stem cells (MSCs) are used as therapeutic agents for skin injury therapy, few studies have reported the effects of dosing duration and delivery frequency on wound healing. In addition, before the clinical application of MSCs, it is important to assess whether their usage might influence tumor occurrence. METHODS We described the metabolic patterns of subcutaneous injection of hUC-MSCs using fluorescence tracing and qPCR methods and applied them to the development of drug delivery strategies for promoting wound healing. RESULTS (i) We developed cGMP-compliant hUC-MSC products with critical quality control points for wound healing; (ii) The products did not possess any tumorigenic or tumor-promoting/inhibiting ability in vivo; (iii) Fluorescence tracing and qPCR analyses showed that the subcutaneous application of hUC-MSCs did not result in safety-relevant biodistribution or ectopic migration; (iv) Reinjecting hUC-MSCs after significant consumption significantly improved reepithelialization and dermal regeneration. CONCLUSIONS Our findings provided a reference for controlling the quality of MSC products used for wound healing and highlighted the importance of delivery time and frequency for designing in vivo therapeutic studies.
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Affiliation(s)
- Xin Wang
- Qilu Cell Therapy Technology Co., Ltd, Gangyuan 6th Road, Licheng District, Ji'nan, Shandong, 250000, People's Republic of China
| | - Qiuhong Wang
- Qilu Cell Therapy Technology Co., Ltd, Gangyuan 6th Road, Licheng District, Ji'nan, Shandong, 250000, People's Republic of China
| | - Lingjiao Meng
- Qilu Cell Therapy Technology Co., Ltd, Gangyuan 6th Road, Licheng District, Ji'nan, Shandong, 250000, People's Republic of China
| | - Ruifeng Tian
- Qilu Cell Therapy Technology Co., Ltd, Gangyuan 6th Road, Licheng District, Ji'nan, Shandong, 250000, People's Republic of China
| | - Huizhen Guo
- Qilu Cell Therapy Technology Co., Ltd, Gangyuan 6th Road, Licheng District, Ji'nan, Shandong, 250000, People's Republic of China
| | - Zengqi Tan
- School of Medicine, Northwest University, Xi'an, China
| | - Yi Tan
- Qilu Cell Therapy Technology Co., Ltd, Gangyuan 6th Road, Licheng District, Ji'nan, Shandong, 250000, People's Republic of China.
- Shandong Yinfeng Life Science Research Institute, Ji'nan, People's Republic of China.
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Jafari MM, Azimzadeh Tabrizi Z, Dayer MS, Kazemi-Sefat NA, Mohtashamifard M, Mohseni R, Bagheri A, Bahadory S, Karimipour-Saryazdi A, Ghaffarifar F. Immune system roles in pathogenesis, prognosis, control, and treatment of Toxoplasma gondii infection. Int Immunopharmacol 2023; 124:110872. [PMID: 37660595 DOI: 10.1016/j.intimp.2023.110872] [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: 04/19/2023] [Revised: 08/25/2023] [Accepted: 08/27/2023] [Indexed: 09/05/2023]
Abstract
Toxoplasma gondii is the protozoan causative agent of toxoplasmosis in humans and warm-blooded animals. Recent studies have illustrated that the immune system plays a pivotal role in the pathogenesis of toxoplasmosis by triggering immune cytokines like IL-12, TNF-α, and IFN-γ and immune cells like DCs, Th1, and Th17. On the other hand, some immune components can serve as prognosis markers of toxoplasmosis. In healthy people, the disease is often asymptomatic, but immunocompromised people and newborns may suffer severe symptoms and complications. Therefore, the immune prognostic markers may provide tools to measure the disease progress and help patients to avoid further complications. Immunotherapies using monoclonal antibody, cytokines, immune cells, exosomes, novel vaccines, and anti-inflammatory molecules open new horizon for toxoplasmosis treatment. In this review article, we discussed the immunopathogenesis, prognosis, and immunotherapy of Toxoplasma gondii infection.
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Affiliation(s)
- Mohammad Mahdi Jafari
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Zahra Azimzadeh Tabrizi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mohammad Saaid Dayer
- Department of Parasitology and Medical Entomology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | | | - Mahshid Mohtashamifard
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Rahimeh Mohseni
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Atefeh Bagheri
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Saeed Bahadory
- Department of Parasitology and Medical Entomology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Amir Karimipour-Saryazdi
- Department of Parasitology and Medical Entomology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Fatemeh Ghaffarifar
- Department of Parasitology and Medical Entomology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
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Masalova OV, Lesnova EI, Kalsin VA, Klimova RR, Fedorova NE, Kozlov VV, Demidova NA, Yurlov KI, Konoplyannikov MA, Nikolaeva TN, Pronin AV, Baklaushev VP, Kushch AA. Human Mesenchymal Stem Cells Modified with the NS5A Gene of Hepatitis C Virus Induce a Cellular Immune Response Exceeding the Response to DNA Immunization with This Gene. BIOLOGY 2023; 12:792. [PMID: 37372076 PMCID: PMC10295215 DOI: 10.3390/biology12060792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 05/22/2023] [Accepted: 05/27/2023] [Indexed: 06/29/2023]
Abstract
Hepatitis C virus (HCV) is one of the basic culprits behind chronic liver disease, which may result in cirrhosis and hepatocarcinoma. In spite of the extensive research conducted, a vaccine against HCV has not been yet created. We have obtained human mesenchymal stem cells (hMSCs) and used them for expressing the HCV NS5A protein as a model vaccination platform. Sixteen hMSC lines of a different origin were transfected with the pcNS5A-GFP plasmid to obtain genetically modified MSCs (mMSCs). The highest efficiency was obtained by the transfection of dental pulp MSCs. C57BL/6 mice were immunized intravenously with mMSCs, and the immune response was compared with the response to the pcNS5A-GFP plasmid, which was injected intramuscularly. It was shown that the antigen-specific lymphocyte proliferation and the number of IFN-γ-synthesizing cells were two to three times higher after the mMSC immunization compared to the DNA immunization. In addition, mMSCs induced more CD4+ memory T cells and an increase in the CD4+/CD8+ ratio. The results suggest that the immunostimulatory effect of mMSCs is associated with the switch of MSCs to the pro-inflammatory phenotype and a decrease in the proportion of myeloid derived suppressor cells. Thus, the possibility of using human mMSCs for the creation of a vaccine against HCV has been shown for the first time.
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Affiliation(s)
- Olga V. Masalova
- Gamaleya National Research Center for Epidemiology and Microbiology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia; (E.I.L.); (R.R.K.); (N.E.F.); (V.V.K.); (N.A.D.); (K.I.Y.); (T.N.N.); (A.V.P.); (A.A.K.)
| | - Ekaterina I. Lesnova
- Gamaleya National Research Center for Epidemiology and Microbiology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia; (E.I.L.); (R.R.K.); (N.E.F.); (V.V.K.); (N.A.D.); (K.I.Y.); (T.N.N.); (A.V.P.); (A.A.K.)
| | - Vladimir A. Kalsin
- Federal Research Clinical Center of Specialized Medical Care and Medical Technologies, Federal Medical-Biological Agency of the Russian Federation, 115682 Moscow, Russia; (V.A.K.); (M.A.K.); (V.P.B.)
| | - Regina R. Klimova
- Gamaleya National Research Center for Epidemiology and Microbiology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia; (E.I.L.); (R.R.K.); (N.E.F.); (V.V.K.); (N.A.D.); (K.I.Y.); (T.N.N.); (A.V.P.); (A.A.K.)
| | - Natalya E. Fedorova
- Gamaleya National Research Center for Epidemiology and Microbiology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia; (E.I.L.); (R.R.K.); (N.E.F.); (V.V.K.); (N.A.D.); (K.I.Y.); (T.N.N.); (A.V.P.); (A.A.K.)
| | - Vyacheslav V. Kozlov
- Gamaleya National Research Center for Epidemiology and Microbiology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia; (E.I.L.); (R.R.K.); (N.E.F.); (V.V.K.); (N.A.D.); (K.I.Y.); (T.N.N.); (A.V.P.); (A.A.K.)
| | - Natalya A. Demidova
- Gamaleya National Research Center for Epidemiology and Microbiology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia; (E.I.L.); (R.R.K.); (N.E.F.); (V.V.K.); (N.A.D.); (K.I.Y.); (T.N.N.); (A.V.P.); (A.A.K.)
| | - Kirill I. Yurlov
- Gamaleya National Research Center for Epidemiology and Microbiology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia; (E.I.L.); (R.R.K.); (N.E.F.); (V.V.K.); (N.A.D.); (K.I.Y.); (T.N.N.); (A.V.P.); (A.A.K.)
| | - Mikhail A. Konoplyannikov
- Federal Research Clinical Center of Specialized Medical Care and Medical Technologies, Federal Medical-Biological Agency of the Russian Federation, 115682 Moscow, Russia; (V.A.K.); (M.A.K.); (V.P.B.)
- Institute for Regenerative Medicine, Sechenov First Moscow State Medical University, 119435 Moscow, Russia
| | - Tatyana N. Nikolaeva
- Gamaleya National Research Center for Epidemiology and Microbiology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia; (E.I.L.); (R.R.K.); (N.E.F.); (V.V.K.); (N.A.D.); (K.I.Y.); (T.N.N.); (A.V.P.); (A.A.K.)
| | - Alexander V. Pronin
- Gamaleya National Research Center for Epidemiology and Microbiology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia; (E.I.L.); (R.R.K.); (N.E.F.); (V.V.K.); (N.A.D.); (K.I.Y.); (T.N.N.); (A.V.P.); (A.A.K.)
| | - Vladimir P. Baklaushev
- Federal Research Clinical Center of Specialized Medical Care and Medical Technologies, Federal Medical-Biological Agency of the Russian Federation, 115682 Moscow, Russia; (V.A.K.); (M.A.K.); (V.P.B.)
| | - Alla A. Kushch
- Gamaleya National Research Center for Epidemiology and Microbiology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia; (E.I.L.); (R.R.K.); (N.E.F.); (V.V.K.); (N.A.D.); (K.I.Y.); (T.N.N.); (A.V.P.); (A.A.K.)
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7
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Kian M, Mirzavand S, Sharifzadeh S, Kalantari T, Ashrafmansouri M, Nasri F. Efficacy of Mesenchymal Stem Cells Therapy in Parasitic Infections: Are Anti-parasitic Drugs Combined with MSCs More Effective? Acta Parasitol 2022; 67:1487-1499. [DOI: 10.1007/s11686-022-00620-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 09/20/2022] [Indexed: 11/01/2022]
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8
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Lin JC, Chen XD, Xu ZR, Zheng LW, Chen ZH. Association of the Circulating Supar Levels with Inflammation, Fibrinolysis, and Outcome in Severe Burn Patients. Shock 2021; 56:948-955. [PMID: 34779798 PMCID: PMC8579993 DOI: 10.1097/shk.0000000000001806] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 03/19/2021] [Accepted: 04/28/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Hyperfibrinolysis and pro/anti-inflammatory imbalance usually occur in the early stage of severe burns. Soluble urokinase-type plasminogen activator receptor (suPAR) is involved in fibrinolysis and inflammation. To date, the levels of circulating suPAR in non-survivors with severe burns remain unknown. This study aimed to investigate the early association between circulating suPAR levels and biomarkers of fibrinolysis, pro/anti-inflammatory, and prognosis. METHODS Sixty-four consecutive Chinese patients with severe burns and 26 healthy volunteers were enrolled in a prospective observational cohort. Clinical characteristics and laboratory data were collected prospectively. Blood samples were collected at 48 h post-burn, and suPAR and biomarkers of pro/anti-inflammatory and fibrinolysis were detected by enzyme-linked immunosorbent assays. Important indicators between non-survivors and survivors were compared. Linear regression analysis was performed to screen variables associated with suPAR. Logistic regression analysis and receiver operating characteristic curve (ROC) analysis were performed to evaluate the prognostic value of suPAR. RESULT Compared with the control group, the circulating suPAR levels in the survivors (P < 0.001) and non-survivors (P = 0.017) were higher. Compared with survivors, non-survivors had lower circulating suPAR levels at 48 h post-burn, and they showed a higher degree of fibrinolysis (higher D-dimer) and a lower TNF-α/IL-10 ratio. According to linear regression analysis, the variables independently associated with a lower suPAR level were lower platelet factor 4 (PF-4), urokinase-type plasminogen activator (uPA), and TNF-α/IL-10 levels and a higher D-dimer level. Logistic regression and ROC analyses indicated that a suPAR level ≤ 4.70 μg/L was independently associated with 30-day mortality. CONCLUSION Low circulating suPAR levels at 48 h post-burn in severe burn patients may reflect decreased TNF-α/IL-10 ratio and increased hyperfibrinolysis. suPAR can predict 30-day mortality in patients with severe burn.
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Affiliation(s)
- Jian-Chang Lin
- Fujian Provincial Key Laboratory of Burn and Trauma, Fujian Burn Institute, Fujian Burn Medical Center, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
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9
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Tavasolian F, Hosseini AZ, Rashidi M, Soudi S, Abdollahi E, Momtazi-Borojeni AA, Sathyapalan T, Sahebkar A. The Impact of Immune Cell-derived Exosomes on Immune Response Initiation and Immune System Function. Curr Pharm Des 2021; 27:197-205. [PMID: 33290196 DOI: 10.2174/1381612826666201207221819] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Accepted: 08/16/2020] [Indexed: 11/22/2022]
Abstract
Exosomes are small extracellular vesicles that pass genetic material between various cells to modulate or alter their biological function. The role of exosomes is to communicate with the target cell for cell-to-cell communication. Their inherent characteristics of exosomes, such as adhesion molecules, allow targeting specifically to the receiving cell. Exosomes are involved in cell to cell communication in the immune system including antigen presentation, natural killer cells (NK cells) and T cell activation/polarisation, immune suppression and various anti-inflammatory processes. In this review, we have described various functions of exosomes secreted by the immune cells in initiating, activating and modulating immune responses; and highlight the distinct roles of exosomal surface proteins and exosomal cargo. Potential applications of exosomes such as distribution vehicles for immunotherapy are also discussed.
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Affiliation(s)
- Fataneh Tavasolian
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ahmad Z Hosseini
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mohsen Rashidi
- Department of Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Sara Soudi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Elham Abdollahi
- Department of Medical Immunology and Allergy, Student Research Committee, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir A Momtazi-Borojeni
- Nanotechnology Research Center, Department of Medical Biotechnology, Student Research Committee, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Thozhukat Sathyapalan
- Department of Academic Diabetes, Endocrinology and Metabolism, Hull York Medical School, University of Hull, Hull HU3 2JZ, United Kingdom
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
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The potential therapeutic effect of adipose-derived mesenchymal stem cells in the treatment of cutaneous leishmaniasis caused by L. major in BALB/c mice. Exp Parasitol 2021; 222:108063. [PMID: 33412170 DOI: 10.1016/j.exppara.2020.108063] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 12/12/2020] [Accepted: 12/23/2020] [Indexed: 12/14/2022]
Abstract
Leishmaniasis is one of the most neglected tropical infectious diseases in the world. The emergence of drug resistance and toxicity and the high cost of the available drugs with a lack of new anti-leishmanial drugs highlight the need to search for newer therapies with anti-leishmanial activities. Due to the mesenchymal stem cell (MSC) immunomodulatory capacity, they have been applied in a wide variety of disorders. In this study, the potential effects of adipose-derived MSC (AD-MSCs) therapy and its combination with glucantime were evaluated in a murine model of cutaneous leishmaniasis induced by L. major. The results showed that AD-MSCs improved wound healing and decreased parasite burden. The real-time PCR results obtained from mice treated with AD-MSCs showed that IL-12 and TNF-α genes were upregulated. IL-10, arginase, and FOXP3 genes were downregulated whereas no differences in expression of the IL-4 gene were found. Overall, it seems that AD-MSCs therapy enhances Th1 immune response in L. major infected BALB/c mice. Unexpectedly, our results showed that the association of glucantime to AD-MSCs treatments did not lead to an increment in the anti-leishmanial activity.
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Navard SH, Rezvan H, Haddad MHF, Ali SA, Nourian A, Eslaminejad MB, Behmanesh MA. Therapeutic effects of mesenchymal stem cells on cutaneous leishmaniasis lesions caused by Leishmania major. J Glob Antimicrob Resist 2020; 23:243-250. [PMID: 32977079 DOI: 10.1016/j.jgar.2020.09.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 08/25/2020] [Accepted: 09/14/2020] [Indexed: 02/08/2023] Open
Abstract
OBJECTIVES Leishmania major (L. major) is a cutaneous leishmaniasis causative agent. Current chemotherapeutic methods are not totally effective in treatment of this disease. The immunomodulation and tissue repairing capability of mesenchymal stem cells (MSCs), ease of isolation, detection and in vitro culture, have encouraged biologists to use MSCs for cell therapy in different infections such as cutaneous leishmaniasis. METHODS BALB/c mice (6-8 weeks old) were infected with L. major then divided into four groups and treated with MSCs, Glucantime, Glucantime + MSCs, or PBS. Regression of lesions, potency of macrophages for phagocytosis, proliferation of immune cells against Leishmania soluble antigen, reduction of spleen parasite burden and healing of the lesions were evaluated on days 10, 20 and 30 of treatment. RESULTS The results indicated that the mice intralesionally injected with MSCs showed significant regression in the lesions produced by L. major by day 30. Proliferation of splenocytes stimulated with SLA (soluble leishmania antigen) in vitro in MSC-treated mice on day 20 was significantly higher than in the other groups. The potency of phagocytosis in macrophages of mice treated with MSCs was significantly higher by day 30 and healing of the lesions in this group of mice showed more progress on histopathological examinations. Spleen parasite burden showed significant reduction in the mice treated with Glucantime + MSCs by day 30. CONCLUSIONS The results showed that including MSCs in treatment of cutaneous leishmaniasis caused by L. major is a promising approach.
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Affiliation(s)
- Sahar Hamoon Navard
- Department of Pathobiology, School of Veterinary Science, Bu-Ali Sina University, Hamedan, Iran
| | - Hossein Rezvan
- Department of Pathobiology, School of Veterinary Science, Bu-Ali Sina University, Hamedan, Iran
| | - Mohammad Hossein Feiz Haddad
- Leishmaniasis Disease Registry Committee, Dezful University of Medical Sciences, Dezful, Iran; Infectious and Tropical Diseases Research Centre, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
| | - S A Ali
- Interdisciplinary Biomedical Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, UK
| | - Alireza Nourian
- Department of Pathobiology, School of Veterinary Science, Bu-Ali Sina University, Hamedan, Iran
| | - Mohamadreza Baghaban Eslaminejad
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Mohammad Amin Behmanesh
- Department of Histology, School of Medicine, Dezful University of Medical Sciences, Dezful, Iran
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12
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Ramos TD, Silva JD, da Fonseca-Martins AM, da Silveira Pratti JE, Firmino-Cruz L, Maciel-Oliveira D, Dos-Santos JS, Tenorio JIN, de Araujo AF, Freire-de-Lima CG, Diaz BL, Cruz FF, Rocco PRM, de Matos Guedes HL. Combined therapy with adipose tissue-derived mesenchymal stromal cells and meglumine antimoniate controls lesion development and parasite load in murine cutaneous leishmaniasis caused by Leishmania amazonensis. Stem Cell Res Ther 2020; 11:374. [PMID: 32867857 PMCID: PMC7457509 DOI: 10.1186/s13287-020-01889-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 08/06/2020] [Accepted: 08/17/2020] [Indexed: 12/13/2022] Open
Abstract
Background Leishmaniasis is a neglected disease caused by Leishmania spp. One of its characteristics is an imbalance of host immune responses to foster parasite survival. In this setting, mesenchymal stromal cells (MSCs) may be a viable therapeutic alternative, given their well-established immunomodulatory potential. In this study, we compared the effects of therapy with bone marrow (BM)- and adipose tissue (AD)-derived MSCs in leishmaniasis caused by Leishmania amazonensis in C57BL/6 mice. After determining the most effective MSC source, we then combined these cells with meglumine antimoniate (a pentavalent antimonial commonly used for the treatment of leishmaniasis) to treat the infected mice. Methods In vitro, co-culture of AD-MSCs and BM-MSCs with Leishmania amazonensis-infected macrophages was performed to understand the influence of both MSC sources in infected cells. In vivo, infected C57BL/6 mice were treated with phosphate-buffered saline (PBS), AD-MSCs and BM-MSCs, and then meglumine antimoniate was combined with MSCs from the most effective source. Results In vitro, co-culture of Leishmania amazonensis-infected macrophages with BM-MSCs, compared to AD-MSCs, led to a higher parasite load and lower production of nitric oxide. Fibroblasts grown in conditioned medium from co-cultures with AD-MSCs promoted faster wound healing. Despite a non-significant difference in the production of vascular endothelial growth factor, we observed higher production of tumor necrosis factor-α and interleukin (IL)-10 in the co-culture with AD-MSCs. In vivo, treatment of infected mice with BM-MSCs did not lead to disease control; however, the use of AD-MSCs was associated with partial control of lesion development, without significant differences in the parasite load. AD-MSCs combined with meglumine antimoniate reduced lesion size and parasite load when compared to PBS and AD-MSC groups. At the infection site, we detected a small production of IL-10, but we were unable to detect production of either IL-4 or interferon-γ, indicating resolution of infection without effect on the percentage of regulatory T cells. Conclusion Combination treatment of cutaneous leishmaniasis with AD-MSCs and meglumine antimoniate may be a viable alternative.
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Affiliation(s)
- Tadeu Diniz Ramos
- Grupo de Imunologia e Vacinologia, Laboratório de Imunofarmacologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil.,Laboratório de Imunomodulação, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
| | - Johnatas Dutra Silva
- Laboratório de Investigação Pulmonar, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
| | - Alessandra Marcia da Fonseca-Martins
- Grupo de Imunologia e Vacinologia, Laboratório de Imunofarmacologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
| | - Juliana Elena da Silveira Pratti
- Grupo de Imunologia e Vacinologia, Laboratório de Imunofarmacologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
| | - Luan Firmino-Cruz
- Grupo de Imunologia e Vacinologia, Laboratório de Imunofarmacologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
| | - Diogo Maciel-Oliveira
- Grupo de Imunologia e Vacinologia, Laboratório de Imunofarmacologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
| | - Julio Souza Dos-Santos
- Grupo de Imunologia e Vacinologia, Laboratório de Imunofarmacologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
| | - João Ivo Nunes Tenorio
- Laboratório de Inflamação, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
| | - Almair Ferreira de Araujo
- Laboratório de Inflamação, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
| | - Célio Geraldo Freire-de-Lima
- Laboratório de Imunomodulação, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
| | - Bruno Lourenço Diaz
- Laboratório de Inflamação, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
| | - Fernanda Ferreira Cruz
- Laboratório de Investigação Pulmonar, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
| | - Patricia Rieken Macedo Rocco
- Laboratório de Investigação Pulmonar, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil. .,National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Rio de Janeiro, Brazil.
| | - Herbert Leonel de Matos Guedes
- Grupo de Imunologia e Vacinologia, Laboratório de Imunofarmacologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil. .,UFRJ Campus Duque de Caxias Professor Geraldo Cidade, Duque de Caxias, Rio de Janeiro, Brazil. .,Laboratório Interdisciplinar de Pesquisas Médicas, Instituto Oswaldo Cruz/FIOCRUZ, Rio de Janeiro, Brazil.
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Zanganeh E, Soudi S, Zavaran Hosseini A. Intralesional Injection of Mouse Mesenchymal Stem Cells Reduces IL-10 Production and Parasite Burden in L. major Infected BALB/c Mice. CELL JOURNAL 2020; 22:11-18. [PMID: 32779429 PMCID: PMC7481897 DOI: 10.22074/cellj.2020.6838] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Accepted: 09/04/2019] [Indexed: 12/25/2022]
Abstract
Objective Leishmaniasis is of public health problems, especially in endemic areas. The activation of macrophages,
as the main host of leishmania and promotion of the TH1 immune responses, are the main goal of im-munotherapy
methods. Recently, the immunomodulatory role of mesenchymal stem cells (MSCs) in infectious disease has been
considered. Different in vitro studies demonstrated the immunostimulatory effect of MSCs on macrophages in response
to L.major. In this study, the effect of MSCs on cutaneous leishmaniasis in BALB/c mice was assessed.
Materials and Methods To do this experimental research, BALB/c mice infected with L. major that was followed by
multiple subcutaneous injections of MSCs at infection site at different intervals. Footpad thickness, spleen parasite
burden, lymph node, and spleen cytokine production were measured to determine the efficacy of cell therapy.
Results Significant (P<0.05) reduction in footpad thickness and delayed wound formation was observed in MSCs
treated group. The spleen of the MSCs-treated group indicated a two-fold reduction in parasite burden compared with
non-treated infected mice. In addition, nitric oxide (NO), interleukin-10 (IL-10), and tumor necrosis factor-alpha (TNF-α)
production of lymph node isolated cells and splenocytes changed to the benefit of macrophage activation in response
to L. major in MSCs treated group. A two-fold increase in interferon-gamma (IFN-γ) production in the lymph node was
determined in the MSCs-treated group.
Conclusion Although MSCs therapy could not clear the parasite, the results confirm the ability of MSCs to enhance
immune responses against leishmania by induction of inflammatory responses and slowing down the spread of
parasites. However, further studies needed to improve the efficacy of this method and provide a therapeutic protocol.
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Affiliation(s)
- Elham Zanganeh
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Sara Soudi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran. Electronic Address:
| | - Ahmad Zavaran Hosseini
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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14
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Masalova OV, Lesnova EI, Klimova RR, Momotyuk ED, Kozlov VV, Ivanova AM, Payushina OV, Butorina NN, Zakirova NF, Narovlyansky AN, Pronin AV, Ivanov AV, Kushch AA. Genetically Modified Mouse Mesenchymal Stem Cells Expressing Non-Structural Proteins of Hepatitis C Virus Induce Effective Immune Response. Vaccines (Basel) 2020; 8:62. [PMID: 32024236 PMCID: PMC7158691 DOI: 10.3390/vaccines8010062] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 01/29/2020] [Accepted: 01/31/2020] [Indexed: 02/08/2023] Open
Abstract
Hepatitis C virus (HCV) is one of the major causes of chronic liver disease and leads to cirrhosis and hepatocarcinoma. Despite extensive research, there is still no vaccine against HCV. In order to induce an immune response in DBA/2J mice against HCV, we obtained modified mouse mesenchymal stem cells (mMSCs) simultaneously expressing five nonstructural HCV proteins (NS3-NS5B). The innate immune response to mMSCs was higher than to DNA immunization, with plasmid encoding the same proteins, and to naïve unmodified MSCs. mMSCs triggered strong phagocytic activity, enhanced lymphocyte proliferation, and production of type I and II interferons. The adaptive immune response to mMSCs was also more pronounced than in the case of DNA immunization, as exemplified by a fourfold stronger stimulation of lymphocyte proliferation in response to HCV, a 2.6-fold higher rate of biosynthesis, and a 30-fold higher rate of secretion of IFN-γ, as well as by a 40-fold stronger production of IgG2a antibodies to viral proteins. The immunostimulatory effect of mMSCs was associated with pronounced IL-6 secretion and reduction in the population of myeloid derived suppressor cells (MDSCs). Thus, this is the first example that suggests the feasibility of using mMSCs for the development of an effective anti-HCV vaccine.
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Affiliation(s)
- Olga V. Masalova
- Gamaleya National Research Center of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, Moscow 123098, Russia; (E.I.L.); (R.R.K.); (E.D.M.); (V.V.K.); (A.M.I.); (A.N.N.); (A.V.P.); (A.A.K.)
| | - Ekaterina I. Lesnova
- Gamaleya National Research Center of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, Moscow 123098, Russia; (E.I.L.); (R.R.K.); (E.D.M.); (V.V.K.); (A.M.I.); (A.N.N.); (A.V.P.); (A.A.K.)
| | - Regina R. Klimova
- Gamaleya National Research Center of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, Moscow 123098, Russia; (E.I.L.); (R.R.K.); (E.D.M.); (V.V.K.); (A.M.I.); (A.N.N.); (A.V.P.); (A.A.K.)
| | - Ekaterina D. Momotyuk
- Gamaleya National Research Center of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, Moscow 123098, Russia; (E.I.L.); (R.R.K.); (E.D.M.); (V.V.K.); (A.M.I.); (A.N.N.); (A.V.P.); (A.A.K.)
| | - Vyacheslav V. Kozlov
- Gamaleya National Research Center of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, Moscow 123098, Russia; (E.I.L.); (R.R.K.); (E.D.M.); (V.V.K.); (A.M.I.); (A.N.N.); (A.V.P.); (A.A.K.)
| | - Alla M. Ivanova
- Gamaleya National Research Center of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, Moscow 123098, Russia; (E.I.L.); (R.R.K.); (E.D.M.); (V.V.K.); (A.M.I.); (A.N.N.); (A.V.P.); (A.A.K.)
| | - Olga V. Payushina
- Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow 119991, Russia;
| | - Nina N. Butorina
- Koltzov Institute of Developmental Biology of Russian Academy of Sciences, Moscow 119334, Russia;
| | - Natalia F. Zakirova
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia;
| | - Alexander N. Narovlyansky
- Gamaleya National Research Center of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, Moscow 123098, Russia; (E.I.L.); (R.R.K.); (E.D.M.); (V.V.K.); (A.M.I.); (A.N.N.); (A.V.P.); (A.A.K.)
| | - Alexander V. Pronin
- Gamaleya National Research Center of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, Moscow 123098, Russia; (E.I.L.); (R.R.K.); (E.D.M.); (V.V.K.); (A.M.I.); (A.N.N.); (A.V.P.); (A.A.K.)
| | - Alexander V. Ivanov
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia;
| | - Alla A. Kushch
- Gamaleya National Research Center of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, Moscow 123098, Russia; (E.I.L.); (R.R.K.); (E.D.M.); (V.V.K.); (A.M.I.); (A.N.N.); (A.V.P.); (A.A.K.)
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15
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Hamoon Navard S, Rezvan H, Feiz Haddad MH, Baghaban Eslaminejad M, Azami S. Expression of Cytokine Genes in Leishmania major-Infected BALB/c Mice Treated with Mesenchymal Stem Cells. JOURNAL OF MEDICAL MICROBIOLOGY AND INFECTIOUS DISEASES 2020. [DOI: 10.29252/jommid.8.1.7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
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Matthews H, Noulin F. Unexpected encounter of the parasitic kind. World J Stem Cells 2019; 11:904-919. [PMID: 31768219 PMCID: PMC6851008 DOI: 10.4252/wjsc.v11.i11.904] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 08/10/2019] [Accepted: 09/13/2019] [Indexed: 02/06/2023] Open
Abstract
Both parasitology and stem cell research are important disciplines in their own right. Parasites are a real threat to human health causing a broad spectrum of diseases and significant annual rates morbidity and mortality globally. Stem cell research, on the other hand, focuses on the potential for regenerative medicine for a range of diseases including cancer and regenerative therapies. Though these two topics might appear distant, there are some “unexpected encounters”. In this review, we summarise the various links between parasites and stem cells. First, we discuss how parasites’ own stem cells represent interesting models of regeneration that can be translated to human stem cell regeneration. Second, we explore the interactions between parasites and host stem cells during the course of infection. Third, we investigate from a clinical perspective, how stem cell regeneration can be exploited to help circumvent the damage induced by parasitic infection and its potential to serve as treatment options for parasitic diseases in the future. Finally, we discuss the importance of screening for pathogens during organ transplantation by presenting some clinical cases of parasitic infection following stem cell therapy.
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Affiliation(s)
- Holly Matthews
- Centre for Applied Entomology and Parasitology, School of Life Sciences, Keele University, Keele ST5 5BG, United Kingdom
| | - Florian Noulin
- Centre for Applied Entomology and Parasitology, School of Life Sciences, Keele University, Keele ST5 5BG, United Kingdom
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Zutshi S, Kumar S, Chauhan P, Bansode Y, Nair A, Roy S, Sarkar A, Saha B. Anti-Leishmanial Vaccines: Assumptions, Approaches, and Annulments. Vaccines (Basel) 2019; 7:vaccines7040156. [PMID: 31635276 PMCID: PMC6963565 DOI: 10.3390/vaccines7040156] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 09/24/2019] [Accepted: 10/08/2019] [Indexed: 12/17/2022] Open
Abstract
Leishmaniasis is a neglected protozoan parasitic disease that occurs in 88 countries but a vaccine is unavailable. Vaccination with live, killed, attenuated (physically or genetically) Leishmania have met with limited success, while peptide-, protein-, or DNA-based vaccines showed promise only in animal models. Here, we critically assess several technical issues in vaccination and expectation of a host-protective immune response. Several studies showed that antigen presentation during priming and triggering of the same cells in infected condition are not comparable. Altered proteolytic processing, antigen presentation, protease-susceptible sites, and intracellular expression of pathogenic proteins during Leishmania infection may vary dominant epitope selection, MHC-II/peptide affinity, and may deter the reactivation of desired antigen-specific T cells generated during priming. The robustness of the memory T cells and their functions remains a concern. Presentation of the antigens by Leishmania-infected macrophages to antigen-specific memory T cells may lead to change in the T cells' functional phenotype or anergy or apoptosis. Although cells may be activated, the peptides generated during infection may be different and cross-reactive to the priming peptides. Such altered peptide ligands may lead to suppression of otherwise active antigen-specific T cells. We critically assess these different immunological issues that led to the non-availability of a vaccine for human use.
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Affiliation(s)
| | - Sunil Kumar
- National Centre for Cell Science, Ganeshkhind, Pune 411007, India.
| | - Prashant Chauhan
- National Centre for Cell Science, Ganeshkhind, Pune 411007, India.
| | - Yashwant Bansode
- National Centre for Cell Science, Ganeshkhind, Pune 411007, India.
| | - Arathi Nair
- National Centre for Cell Science, Ganeshkhind, Pune 411007, India.
| | - Somenath Roy
- Department of Human Physiology with Community Health, Vidyasagar University, Midnapore 721102, India.
| | - Arup Sarkar
- Department of Biotechnology, Trident Academy of Creative Technology, Bhubaneswar 751024, India.
| | - Bhaskar Saha
- National Centre for Cell Science, Ganeshkhind, Pune 411007, India.
- Department of Biotechnology, Trident Academy of Creative Technology, Bhubaneswar 751024, India.
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Zanganeh E, Soudi S, Zavaran Hosseini A, Khosrojerdi A. Repeated intravenous injection of adipose tissue derived mesenchymal stem cells enhances Th1 immune responses in Leishmania major-infected BALB/c mice. Immunol Lett 2019; 216:97-105. [PMID: 31622634 DOI: 10.1016/j.imlet.2019.10.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2019] [Revised: 10/09/2019] [Accepted: 10/13/2019] [Indexed: 12/26/2022]
Abstract
Mesenchymal stem cell (MSCs) therapy are among new strategies that are used to combat infections through immunomodulation. Cell number, route and frequency of injection and the duration of exposure to the infectious agent are of the main factors to determine the effectiveness of cell therapy. The current study was aimed to assess the effect of multiple intravenous (i.v.) injection of adipose tissue derived (AD)-MSCs on immune response of Leishmania (L.) major-infected BALB/c mice. Therefore, infected mice received AD-MSCs four times during the early phase of infection through i.v. route. They were then monitored weekly for footpad swelling and lesion development. Parasite burden, nitric oxide (NO) and cytokine production were measured in the spleen and lymph node 90 days post-infection. Delayed lesion development, significant reduction in footpad swelling and lower parasite burden in the spleen of AD-MSCs-treated mice showed the relative effect of AD-MSCs therapy in the control of L. major dissemination. In addition, MSCs were able to manage direct cytokine responses toward T-helper 1 (Th1). Although the level of interleukin (IL)-10 was still higher than the associated level of tumor necrosis factor (TNF)-α, a shift towards higher level of TNF-α was also observed.
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Affiliation(s)
- Elham Zanganeh
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Sara Soudi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Ahmad Zavaran Hosseini
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Arezou Khosrojerdi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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Perspectives for Clinical Translation of Adipose Stromal/Stem Cells. Stem Cells Int 2019; 2019:5858247. [PMID: 31191677 PMCID: PMC6525805 DOI: 10.1155/2019/5858247] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 02/26/2019] [Accepted: 03/07/2019] [Indexed: 12/15/2022] Open
Abstract
Adipose stromal/stem cells (ASCs) are an ideal cell type for regenerative medicine applications, as they can easily be harvested from adipose tissue in large quantities. ASCs have excellent proliferation, differentiation, and immunoregulatory capacities that have been demonstrated in numerous studies. Great interest and investment have been placed in efforts to exploit the allogeneic use and immunomodulatory and anti-inflammatory effects of ASCs. However, bridging the gap between in vitro and in vivo studies and moving into clinical practice remain a challenge. For the clinical translation of ASCs, several issues must be considered, including how to characterise such a heterogenic cell population and how to ensure their safety and efficacy. This review explores the different phases of in vitro and preclinical ASC characterisation and describes the development of appropriate potency assays. In addition, good manufacturing practice requirements are discussed, and cell-based medicinal products holding marketing authorisation in the European Union are reviewed. Moreover, the current status of clinical trials applying ASCs and the patent landscape in the field of ASC research are presented. Overall, this review highlights the applicability of ASCs for clinical cell therapies and discusses their potential.
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20
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Ghahremani Piraghaj M, Soudi S, Ghanbarian H, Bolandi Z, Namaki S, Hashemi SM. Effect of efferocytosis of apoptotic mesenchymal stem cells (MSCs) on C57BL/6 peritoneal macrophages function. Life Sci 2018; 212:203-212. [DOI: 10.1016/j.lfs.2018.09.052] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2018] [Revised: 09/16/2018] [Accepted: 09/30/2018] [Indexed: 01/20/2023]
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21
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Tomiotto-Pellissier F, Bortoleti BTDS, Assolini JP, Gonçalves MD, Carloto ACM, Miranda-Sapla MM, Conchon-Costa I, Bordignon J, Pavanelli WR. Macrophage Polarization in Leishmaniasis: Broadening Horizons. Front Immunol 2018; 9:2529. [PMID: 30429856 PMCID: PMC6220043 DOI: 10.3389/fimmu.2018.02529] [Citation(s) in RCA: 140] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Accepted: 10/15/2018] [Indexed: 01/14/2023] Open
Abstract
Leishmaniasis is a vector-borne neglected tropical disease that affects more than 700,000 people annually. Leishmania parasites cause the disease, and different species trigger a distinct immune response and clinical manifestations. Macrophages are the final host cells for the proliferation of Leishmania parasites, and these cells are the key to a controlled or exacerbated response that culminates in clinical manifestations. M1 and M2 are the two main macrophage phenotypes. M1 is a pro-inflammatory subtype with microbicidal properties, and M2, or alternatively activated, is an anti-inflammatory/regulatory subtype that is related to inflammation resolution and tissue repair. The present review elucidates the roles of M1 and M2 polarization in leishmaniasis and highlights the role of the salivary components of the vector and the action of the parasite in the macrophage plasticity.
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Affiliation(s)
- Fernanda Tomiotto-Pellissier
- Biosciences and Biotechnology Postgraduate Program, Carlos Chagas Institute (ICC), Fiocruz, Curitiba, Brazil.,Laboratory of Immunoparasitology, Department of Pathological Sciences, State University of Londrina, Londrina, Brazil
| | - Bruna Taciane da Silva Bortoleti
- Biosciences and Biotechnology Postgraduate Program, Carlos Chagas Institute (ICC), Fiocruz, Curitiba, Brazil.,Laboratory of Immunoparasitology, Department of Pathological Sciences, State University of Londrina, Londrina, Brazil
| | - João Paulo Assolini
- Laboratory of Immunoparasitology, Department of Pathological Sciences, State University of Londrina, Londrina, Brazil
| | - Manoela Daiele Gonçalves
- Laboratory of Biotransformation and Phytochemistry, Department of Chemistry, State University of Londrina, Universitary Hospital, Londrina, Brazil
| | | | | | - Ivete Conchon-Costa
- Laboratory of Immunoparasitology, Department of Pathological Sciences, State University of Londrina, Londrina, Brazil
| | - Juliano Bordignon
- Biosciences and Biotechnology Postgraduate Program, Carlos Chagas Institute (ICC), Fiocruz, Curitiba, Brazil.,Laboratory of Molecular Virology, Carlos Chagas Institute (ICC), Fiocruz, Curitiba, Brazil
| | - Wander Rogério Pavanelli
- Biosciences and Biotechnology Postgraduate Program, Carlos Chagas Institute (ICC), Fiocruz, Curitiba, Brazil.,Laboratory of Immunoparasitology, Department of Pathological Sciences, State University of Londrina, Londrina, Brazil
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22
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Advances of Stem Cell Therapeutics in Cutaneous Wound Healing and Regeneration. Mediators Inflamm 2017; 2017:5217967. [PMID: 29213192 PMCID: PMC5682068 DOI: 10.1155/2017/5217967] [Citation(s) in RCA: 144] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2017] [Revised: 08/14/2017] [Accepted: 09/13/2017] [Indexed: 12/15/2022] Open
Abstract
Cutaneous wound healing is a complex multiple phase process, which overlaps each other, where several growth factors, cytokines, chemokines, and various cells interact in a well-orchestrated manner. However, an imbalance in any of these phases and factors may lead to disruption in harmony of normal wound healing process, resulting in transformation towards chronic nonhealing wounds and abnormal scar formation. Although various therapeutic interventions are available to treat chronic wounds, current wound-care has met with limited success. Progenitor stem cells possess potential therapeutic ability to overcome limitations of the present treatments as it offers accelerated wound repair with tissue regeneration. A substantial number of stem cell therapies for cutaneous wounds are currently under development as a result of encouraging preliminary findings in both preclinical and clinical studies. However, the mechanisms by which these stem cells contribute to the healing process have yet to be elucidated. In this review, we emphasize on the major treatment modalities currently available for the treatment of the wound, role of various interstitial stem cells and exogenous adult stem cells in cutaneous wound healing, and possible mechanisms involved in the healing process.
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23
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Khosrowpour Z, Hashemi SM, Mohammadi-Yeganeh S, Soudi S. Pretreatment of Mesenchymal Stem Cells With Leishmania majorSoluble Antigens Induce Anti-Inflammatory Properties in Mouse Peritoneal Macrophages. J Cell Biochem 2017; 118:2764-2779. [DOI: 10.1002/jcb.25926] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 02/06/2017] [Indexed: 01/20/2023]
Affiliation(s)
- Zahra Khosrowpour
- Department of Immunology; School of Medicine; Shahid Beheshti University of Medical Sciences; Tehran Iran
| | - Seyed Mahmoud Hashemi
- Department of Immunology; School of Medicine; Shahid Beheshti University of Medical Sciences; Tehran Iran
- Department of Applied Cell Sciences; School of Advanced Technologies in Medicine; Shahid Beheshti University of Medical Sciences; Tehran Iran
| | - Samira Mohammadi-Yeganeh
- Cellular and Molecular Biology Research Center; Shahid Beheshti University of Medical Sciences; Tehran Iran
- Department of Biotechnology; School of Advanced Technologies in Medicine; Shahid Beheshti University of Medical Sciences; Tehran Iran
| | - Sara Soudi
- Department of Immunology; Faculty of Medical Sciences; Tarbiat Modares University; Tehran Iran
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24
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Pereira JC, Ramos TD, Silva JD, de Mello MF, Pratti JES, da Fonseca-Martins AM, Firmino-Cruz L, Kitoko JZ, Chaves SP, Gomes DCDO, Diaz BL, Rocco PRM, de Matos Guedes HL. Effects of Bone Marrow Mesenchymal Stromal Cell Therapy in Experimental Cutaneous Leishmaniasis in BALB/c Mice Induced by Leishmania amazonensis. Front Immunol 2017; 8:893. [PMID: 28848541 PMCID: PMC5554126 DOI: 10.3389/fimmu.2017.00893] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2017] [Accepted: 07/12/2017] [Indexed: 12/24/2022] Open
Abstract
Cutaneous leishmaniasis remains both a public health and a therapeutic challenge. To date, no ideal therapy for cutaneous leishmaniasis has been identified, and no universally accepted therapeutic regimen and approved vaccines are available. Due to the mesenchymal stromal cell (MSC) immunomodulatory capacity, they have been applied in a wide variety of disorders, including infectious, inflammatory, and allergic diseases. We evaluated the potential effects of bone marrow MSC therapy in a murine model of cutaneous leishmaniasis. In vitro, coculture of infected macrophages with MSC increased parasite load on macrophages in comparison with controls (macrophages without MSCs). In vivo, BALB/c mice were infected with 2 × 106Leishmania amazonensis (Josefa strain) promastigotes in the footpad. 7 and 37 days after infection, animals were treated with 1 × 105 MSCs, either intralesional (i.l.), i.e., in the same site of infection, or intravenously (i.v.), through the external jugular vein. Control animals received the same volume (50 µL) of phosphate-buffered saline by i.l. or i.v. routes. The lesion progression was assessed by its thickness measured by pachymetry. Forty-two days after infection, animals were euthanized and parasite burden in the footpad and in the draining lymph nodes was quantified by the limiting dilution assay (LDA), and spleen cells were phenotyped by flow cytometry. No significant difference was observed in lesion progression, regardless of the MSC route of administration. However, animals treated with i.v. MSCs presented a significant increase in parasite load in comparison with controls. On the other hand, no harmful effect due to MSCs i.l. administered was observed. The spleen cellular profile analysis showed an increase of IL-10 producing T CD4+ and TCD8+ cells in the spleen only in mice treated with i.v. MSC. The excessive production of IL-10 could be associated with the disease-aggravating effects of MSC therapy when intravenously administered. As a conclusion, in the current murine model of L. amazonensis-induced cutaneous disease, MSCs did not control the damage of cutaneous disease and, depending on the administration route, it could result in deleterious effects.
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Affiliation(s)
- Joyce Carvalho Pereira
- Laboratório de Inflamação, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Tadeu Diniz Ramos
- Laboratório de Inflamação, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Johnatas Dutra Silva
- Laboratório de Investigação Pulmonar, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Mirian França de Mello
- Laboratório de Inflamação, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Juliana Elena Silveira Pratti
- Laboratório de Inflamação, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | | | - Luan Firmino-Cruz
- Laboratório de Inflamação, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Jamil Zola Kitoko
- Laboratório de Investigação Pulmonar, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Suzana Passos Chaves
- Laboratório Integrado de Imunoparasitologia, Campus Macaé - Universidade Federal do Rio de Janeiro, Macaé, Brazil
| | - Daniel Claudio De Oliveira Gomes
- Laboratório de Imunobiologia, Núcleo de Doenças Infecciosas/Núcleo de Biotecnologia, Universidade Federal do Espírito Santo, Vitória, Brazil
| | - Bruno Lourenço Diaz
- Laboratório de Inflamação, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Patricia R M Rocco
- Laboratório de Investigação Pulmonar, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Herbert Leonel de Matos Guedes
- Laboratório de Inflamação, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.,Núcleo Multidisciplinar de Pesquisa UFRJ - Xerém em Biologia (NUMPEX-BIO), Polo Avançado de Xerém - Universidade Federal do Rio de Janeiro, Duque de Caxias, Brazil.,Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
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25
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Vasandan AB, Jahnavi S, Shashank C, Prasad P, Kumar A, Prasanna SJ. Human Mesenchymal stem cells program macrophage plasticity by altering their metabolic status via a PGE 2-dependent mechanism. Sci Rep 2016; 6:38308. [PMID: 27910911 PMCID: PMC5133610 DOI: 10.1038/srep38308] [Citation(s) in RCA: 286] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Accepted: 11/08/2016] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are speculated to act at macrophage-injury interfaces to mediate efficient repair. To explore this facet in-depth this study evaluates the influence of MSCs on human macrophages existing in distinct functional states. MSCs promoted macrophage differentiation, enhanced respiratory burst and potentiated microbicidal responses in naïve macrophages (Mφ). Functional attenuation of inflammatory M1 macrophages was associated with a concomitant shift towards alternatively activated M2 state in MSC-M1 co-cultures. In contrast, alternate macrophage (M2) activation was enhanced in MSC-M2 co-cultures. Elucidation of key macrophage metabolic programs in Mo/MSC, M1/MSC and M2/MSC co-cultures indicated changes in Glucose transporter1 (GLUT1 expression/glucose uptake, IDO1 protein/activity, SIRTUIN1 and alterations in AMPK and mTOR activity, reflecting MSC-instructed metabolic shifts. Inability of Cox2 knockdown MSCs to attenuate M1 macrophages and their inefficiency in instructing metabolic shifts in polarized macrophages establishes a key role for MSC-secreted PGE2 in manipulating macrophage metabolic status and plasticity. Functional significance of MSC-mediated macrophage activation shifts was further validated on human endothelial cells prone to M1 mediated injury. In conclusion, we propose a novel role for MSC secreted factors induced at the MSC-macrophage interface in re-educating macrophages by manipulating metabolic programs in differentially polarized macrophages.
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Affiliation(s)
- Anoop Babu Vasandan
- School of Regenerative Medicine, Manipal University, Bangalore, 560065, India
| | - Sowmya Jahnavi
- School of Regenerative Medicine, Manipal University, Bangalore, 560065, India
| | - Chandanala Shashank
- School of Regenerative Medicine, Manipal University, Bangalore, 560065, India
| | - Priya Prasad
- School of Regenerative Medicine, Manipal University, Bangalore, 560065, India
| | - Anujith Kumar
- School of Regenerative Medicine, Manipal University, Bangalore, 560065, India
| | - S. Jyothi Prasanna
- School of Regenerative Medicine, Manipal University, Bangalore, 560065, India
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26
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Mahla RS. Stem Cells Applications in Regenerative Medicine and Disease Therapeutics. Int J Cell Biol 2016; 2016:6940283. [PMID: 27516776 PMCID: PMC4969512 DOI: 10.1155/2016/6940283] [Citation(s) in RCA: 337] [Impact Index Per Article: 37.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2016] [Accepted: 06/05/2016] [Indexed: 12/18/2022] Open
Abstract
Regenerative medicine, the most recent and emerging branch of medical science, deals with functional restoration of tissues or organs for the patient suffering from severe injuries or chronic disease. The spectacular progress in the field of stem cell research has laid the foundation for cell based therapies of disease which cannot be cured by conventional medicines. The indefinite self-renewal and potential to differentiate into other types of cells represent stem cells as frontiers of regenerative medicine. The transdifferentiating potential of stem cells varies with source and according to that regenerative applications also change. Advancements in gene editing and tissue engineering technology have endorsed the ex vivo remodelling of stem cells grown into 3D organoids and tissue structures for personalized applications. This review outlines the most recent advancement in transplantation and tissue engineering technologies of ESCs, TSPSCs, MSCs, UCSCs, BMSCs, and iPSCs in regenerative medicine. Additionally, this review also discusses stem cells regenerative application in wildlife conservation.
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Affiliation(s)
- Ranjeet Singh Mahla
- Department of Biological Sciences, Indian Institute of Science Education and Research (IISER), Bhopal, Madhya Pradesh 462066, India
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27
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Yousefi F, Ebtekar M, Soudi S, Soleimani M, Hashemi SM. In vivo immunomodulatory effects of adipose-derived mesenchymal stem cells conditioned medium in experimental autoimmune encephalomyelitis. Immunol Lett 2016; 172:94-105. [PMID: 26930038 DOI: 10.1016/j.imlet.2016.02.016] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Revised: 02/13/2016] [Accepted: 02/25/2016] [Indexed: 12/20/2022]
Abstract
Mesenchymal stem cells (MSCs) are well known to possess neuroprotective and immunomodulatory effects, due to cell-to-cell interaction and their soluble factors. We conducted a comparative analysis of the immunomodulatory properties of adipose tissue mesenchymal stem cells (AT-MSCs) and their conditioned media (CM), derived from C57/BL6 mice, for mitigating the adverse clinical course of experimental autoimmune encephalomyelitis (EAE). We measure IL4, IL17 and IFNɣ production of supernatant from spleen cells. We analyzed brain cell infiltration, splenocyte proliferation and evaluated the percentage of CD4+CD25+FOXP3+splenic cell population in all EAE C57/BL6 mice. AT-MSCs and its conditioned medium induced CD4+CD25+FOXP3+regulatory T cells after in vitro co-culture with naïve T cells. There is no significant difference in the clinical scores and body weight of EAE mice treated with AT-MSCs and CM. The reduction in proliferative responses and brain cell infiltration was more pronounced in mice injected with CM than other groups. It is found that the percentage of splenic CD4+CD25+FOXP3+ population as well as the level of IL4 production in mice administrated with AT-MSCs is increased compared to other animals. Our results suggest that AT-MSCs-derived CM is promising in stem cell therapy, due to their neuroprotective and immunomudulatory properties.
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Affiliation(s)
- Forouzan Yousefi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Massoumeh Ebtekar
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Sara Soudi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Masoud Soleimani
- Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Seyed Mahmoud Hashemi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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