Publications by authors named "Seyed Mahmoud Hashemi"

106 Publications

Nationwide population-based surveys of Iranian COVID-19 Serological Surveillance (ICS) program: The surveys protocol.

Med J Islam Repub Iran 2021 12;35:61. Epub 2021 May 12.

Osteoporosis Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.

Serological surveillance of COVID-19 through conducting repetitive population-based surveys can be useful in estimating and monitoring changes in the prevalence of infection across the country. This paper presents the protocol of nationwide population-based surveys of the Iranian COVID-19 Serological Surveillance (ICS) program. The target population of the surveys is all individuals ≥6 years in Iran. Stratified random sampling will be used to select participants from those registered in the primary health care electronic record systems in Iran. The strata are the 31 provinces of the country, in which sampling will be done through simple random sampling. The sample size is estimated 858 individuals for each province (except for Tehran province, which is 2574) at the first survey. It will be recalculated for the next surveys based on the findings of the first survey. The participants will be invited by the community health workers to the safe blood sampling centers at the district level. After obtaining written informed consent, 10 mL of venous blood will be taken from the participants. The blood samples will be transferred to selected reference laboratories in order to test IgG and IgM antibodies against COVID-19 using an Iranian SARS-CoV-2 ELISA Kit (Pishtaz Teb). A serologically positive test is defined as a positive IgG, IgM, or both. After adjusting for the measurement error of the laboratory test, nonresponse bias, and sampling design, the prevalence of COVID-19 will be estimated at the provincial and national levels. Also, the approximate incidence rate of infection will be calculated based on the data of both consecutive surveys. The implementation of these surveys will provide a comprehensive and clear picture of the magnitude of COVID-19 infection and its trend over time for health policymakers at the national and subnational levels.
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http://dx.doi.org/10.47176/mjiri.35.61DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278025PMC
May 2021

Transfer of miRNA in tumor-derived exosomes suppresses breast tumor cell invasion and migration by inducing M1 polarization in macrophages.

Life Sci 2021 Oct 7;282:119800. Epub 2021 Jul 7.

Medical Nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address:

Aims: Macrophage repolarization from M1 to M2 phenotype is one of the hallmarks of malignancy. M2 macrophages are the most represented population in the tumor microenvironment and play an active role in tumor progression. In recent years, microRNAs (miRNAs) have been identified as a regulator of macrophage polarization.

Main Methods: In this study, miR-130 was delivered to M2 macrophages using tumor-derived exosomes. Then, we evaluated the macrophage polarization status by assessment of specific markers and cytokines for M1 and M2 phenotype. The phagocytosis ability of macrophages was also investigated. Additionally, we performed migration and invasion assays to detect the effect of macrophage reprogramming on breast cancer cells migration and invasion.

Key Findings: The findings of the current study indicated that exosomes efficiently delivered miR-130 into macrophages. Delivery of miR-130 into macrophages resulted in upregulation of M1 specific markers and cytokines, including CD86, Irf5, Nos2, TNF-α, and IL-1β and downregulation of M2 specific markers and cytokines, including CD206, Ym1, Arg, TGF-β, and IL-10. The phagocytosis ability of macrophages also enhanced after treatment with miRNA-loaded exosomes. Furthermore, migration and invasion assays demonstrated reduced ability of 4T1 breast cancer cells for migration and invasion after macrophages reprogramming.

Significance: These observations suggest that repolarization of M2 macrophages to M1 phenotype using miRNA-containing exosomes can be a therapeutic strategy against tumor invasion and metastasis in breast cancer.
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http://dx.doi.org/10.1016/j.lfs.2021.119800DOI Listing
October 2021

Prevalence of COVID-19 in Iran: results of the first survey of the Iranian COVID-19 Serological Surveillance programme.

Clin Microbiol Infect 2021 Jun 7. Epub 2021 Jun 7.

Osteoporosis Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Objectives: This study aims to estimate the prevalence of coronavirus disease 2019 (COVID-19) in the general population of Iran.

Methods: The target population was all Iranian people aged 6 years and older in the country. A stratified random sampling design was used to select 28 314 people from among the individuals registered in the electronic health record systems used in primary health care in Iran. Venous blood was taken from each participant and tested for the IgG antibody against COVID-19. The prevalence of COVID-19 was estimated at provincial and national levels after adjusting for the measurement error of the laboratory test, non-response bias and sampling design.

Results: Of the 28 314 Iranians selected, 11 256 (39.75%) participated in the study. Of these, 5406 (48.0%) were male and 6851 (60.9%) lived in urban areas. The mean (standard deviation) participant age was 35.89 (18.61) years. The adjusted prevalence of COVID-19 until 20 August 2020 was estimated as 14.2% (95% uncertainty interval 13.3%-15.2%), which was equal to 11 958 346 (95% CI 11 211 011-12 746 776) individuals. The adjusted prevalences of infection were 14.6%, 13.8%, 16.6%, 11.7% and 19.4% among men, women, urban population, rural population and individuals aged 60 years or more, respectively. Ardabil, Golestan and Khuzestan provinces had the highest prevalence and Alborz, Hormozgan and Kerman provinces had the lowest.

Conclusions: Based on the study results, a large proportion of the Iranian population had not yet been infected by COVID-19. The observance of hygienic principles and social restrictions should therefore continue until the majority of the population has been vaccinated.
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http://dx.doi.org/10.1016/j.cmi.2021.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8226066PMC
June 2021

Conditioned medium derived from seminal extracellular vesicles-exposed endometrial stromal cells induces inflammatory cytokine secretion by macrophages.

Eur J Obstet Gynecol Reprod Biol 2021 Jul 11;262:174-181. Epub 2021 May 11.

Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Men's Health and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address:

Objective: Seminal plasma (SP) contains large numbers of sub-cellular structures called extracellular vesicles (EV) which have been postulated to have immunological functions due to their bioactive contents including proteins and small non-coding RNAs. Although the response of endometrial cells to seminal EV (SEV) is recently being elucidated, the impact of these signaling vesicles on stroma-immune crosstalk is still unknown. Herein, we aimed to investigate the effect of conditioned medium (CM) derived from SEV-exposed endometrial stromal cells (eSC) on cytokine secretion by macrophages.

Study Design: SEV were isolated from SP samples of healthy donors and characterized by common methods needed for EV characterization, including size determination by dynamic light scattering (DLS), transmission electron microscopy (TEM), and western blot analysis of EV markers. Endometrial biopsies were obtained from healthy individuals and eSC were isolated and characterized. EV internalization assay was performed by labeling the SEV with PKH67 green fluorescent dye. Then, the eSC were exposed to SEV and the CM was collected. Finally, the CM from SEV-exposed eSC was added to the macrophage culture and the level of inflammatory (interleukin (IL)-1α and IL-6) and anti-inflammatory (IL-10) cytokines were measured in the culture supernatant of macrophages.

Results: The results demonstrated that the CM derived from SEV-exposed eSC induce IL-1α and IL-6 secretion by the macrophages, while the secretion of IL-10 was reduced.

Conclusion: Our results support the idea that the stroma-immune interaction is affected by SEV. This effect may be a part of immunoregulatory function of SP inside upper female genital tract and have an obvious impact during peri-implantation period.
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http://dx.doi.org/10.1016/j.ejogrb.2021.05.019DOI Listing
July 2021

Tumor-Derived Exosomes Enriched by miRNA-124 Promote Anti-tumor Immune Response in CT-26 Tumor-Bearing Mice.

Front Med (Lausanne) 2021 27;8:619939. Epub 2021 Apr 27.

Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Exosomes have been introduced as a new alternative delivery system for the transmission of small molecules. Tumor-derived exosomes (TEXs) not only contain tumor-associated antigens to stimulate antitumor immune responses but also act as natural carriers of microRNAs. The aim of the current study was to evaluate the efficacy of miR-124-3p-enriched TEX (TEXomiR) as cell-free vaccine in the induction of antitumor immune responses in a mouse model of colorectal cancer. Briefly, the exosomes were isolated from cultured CT-26 cell line, and modified calcium chloride method was used to deliver miR-124-3p mimic into the exosomes. We used a CT-26-induced BALB/c mouse model of colorectal cancer and analyzed the effect of TEXomiR on survival, tumor size, spleen and tumor-infiltrated lymphocytes, and splenocyte proliferation. Furthermore, intra-tumor regulatory T cells, cytotoxic activity of the splenocytes, and cytokine secretion was also evaluated to describe the anti-tumor immune response. When the tumor size reached 100 mm, the mice were injected with TEXomiR, TEX, and/or phosphate-buffered saline (PBS) subcutaneously three times with 3-day interval, and then tumor size was monitored every 2 days. The results indicated that TEXs could efficiently deliver functional miR-124-3p mimic. The evaluation in tumor-bearing mice showed that treatment with TEXomiR can elicit a stronger anti-tumor immune response than unloaded TEX and PBS. Significant tumor growth inhibition and increased median survival time was achieved in tumor-bearing mice treated with TEXomiR. A significant decrease in CD4/CD8 and Treg/CD8 ratio in tumor tissue was demonstrated. Moreover, increased cytotoxicity and proliferation of splenocytes in the TEXomiR group compared to the TEX and PBS groups were identified. Taken together, our data demonstrated that tumor-derived exosomes efficiently deliver miR-124-3p mimic, and TEXomiR promotes anti-tumor immune responses.
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http://dx.doi.org/10.3389/fmed.2021.619939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110712PMC
April 2021

Hyperglycemia results in decreased immune cell infiltration and increased viral load in the lung in a mouse model of RSV infection.

Cytokine 2021 Jul 21;143:155539. Epub 2021 Apr 21.

Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Respiratory Syncytial virus (RSV) infection is a feared disease in vulnerable populations with impaired immune responses. There is currently no vaccine against RSV and young children along with elderly people are at increased risk of severe or sometimes life-threatening RSV infection. Hyperglycemia with immunomodulatory patterns can impact on infectious disease outcomes and immune system responses in diabetic patients. Even though research continues to uncover the complex mechanisms underlying RSV immunopathogenesis and diabetes mellitus disease separately, limited information is available about interaction between these two phenomena. Here, we evaluated the influence of hyperglycemia as the hallmark of diabetes mellitus disease on the pathogenesis and immunopathogenesis of RSV in a mouse model. In this experiment, hyperglycemia was induced by intraperitoneal injection of Streptozotocin (STZ), and after diabetes confirmation, mice were infected with RSV-A2, and the immune responses were followed for 5 days until the mice were sacrificed. Analyses on airway immune cell influx, T-Lymphocyte subtypes, cytokines secretion, lung histopathology, and viral load were conducted. Our results showed that hyperglycemia resulted in reduced lung immune cells infiltration totally and it was associated with decreased pathological damage of the lung. Following RSV infection in hyperglycemic mice, the ratio of CD4/CD8 T-Lymphocytes due to CD8 depletion, increased. Furthermore, the level of IFN-γ and IL-17A cytokines decreased, whereas IL-10 showed an upward trend and the viral load increased in hyperglycemic mice compared with normoglycemic mice. In conclusion, these findings indicate that hyperglycemia can ameliorate and downregulate RSV-induced inflammatory and antiviral responses, and result in increment of viral load.
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http://dx.doi.org/10.1016/j.cyto.2021.155539DOI Listing
July 2021

Correction to: Stem Cell-Derived Exosomes as Treatment for Stroke: a Systematic Review.

Stem Cell Rev Rep 2021 Apr;17(2):439

Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

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http://dx.doi.org/10.1007/s12015-021-10153-7DOI Listing
April 2021

Adipose-derived mesenchymal stem cell-secreted exosome alleviates dextran sulfate sodium-induced acute colitis by Treg cell induction and inflammatory cytokine reduction.

J Cell Physiol 2021 Aug 16;236(8):5906-5920. Epub 2021 Mar 16.

Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is an inflammatory condition that results in gastrointestinal tract damage. Various factors, including environmental and genetic agents, disrupt the function of the intestinal immune system that can lead to IBD. Mesenchymal stem cells (MSCs) display an immunoregulatory function and demonstrate regenerative potential by paracrine action. In this study, we evaluated the immunomodulatory effects of MSCs' derived exosomes in the acute form of dextran sulfate sodium (DSS)-induced colitis. Exosomes were isolated from adipose-derived MSCs. Acute colitis was induced by DSS. The exosome was used by intraperitoneal injection into mice with acute colitis. Stool consistency, body weight changes, bleeding severity, colon length, and weight were examined. At the experimental endpoint (Day 7), the changes in the colon tissue were evaluated. The level of cytokines of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-17 (IL-17), IL-4, IL-12, transforming growth factor-β (TGF-β) and, IL-10, and Treg cells percentage were assayed. Results showed that exosome administration diminished colon shortening, bodyweight loss, bleeding, and colon injury. The levels of IFN-γ, TNF-α, IL-12, and IL-17 were decreased, and the level of TGF-β, IL-4, and IL-10 were increased in lymph node and spleen of mice treated with exosome.  Percentages of CD4 CD25 Foxp3 Treg cells were grown in the lymph node and spleen of mice treated with exosomes. Overall, current data suggest that MSC-derived exosome could regulate the Treg population and improves inflammation in DSS-induced acute colitis.
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http://dx.doi.org/10.1002/jcp.30275DOI Listing
August 2021

Cross-linked acellular lung for application in tissue engineering: Effects on biocompatibility, mechanical properties and immunological responses.

Mater Sci Eng C Mater Biol Appl 2021 Mar 5;122:111938. Epub 2021 Feb 5.

Cellular and Molecular Research Centre, Iran University of Medical Sciences, Tehran, Iran; Department of Tissue Engineering & Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran; Department of Medical Biotechnology, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran. Electronic address:

The concept of providing tissue engineering scaffolds with natural physical properties and minimal immunogenicity has not been systematically approached for the lungs yet. Here, the rat acellular lung tissue (ALT) was cross-linked to provide either EDC/NHS cross-linked tissue (EDC/NHS-CLT) or tannic acid cross-linked tissue (TA-CLT). Young's modulus revealed that EDC/NHS-CLT had mechanical properties similar to the native lung and culture of lung mesenchymal cells showed a higher potential of cell proliferation on EDC/NHS-CLT versus TA-CLT and ALT. The in vitro immunogenicity tests showed a strong induction of T-cell proliferation by TA-CLT and an attenuated macrophage induction by TA-CLT. Processed rat lungs were implanted xenogenically into the mouse peritoneal cavity and the host-implant interactions showed that tannic acid is not released from TA-CLT in a physiologically effective dose. The profile of peritoneal fluid proinflammatory (TNFα, IL-1β, IL-12p70 and IL-17) and anti-inflammatory (IL-10 and TGFβ1) cytokines, and CD3 T-lymphocytes and CD11b macrophages revealed that apart from induction of high levels of IL-17 during the first week and IL-10 during the second to third weeks after implantation by TA-CLT, other indicators of immune reactions to cross-linked tissues were not significantly different from ALT. Also, a high fibrotic reaction to TA-CLT was observed on the weeks 2-3, but alveolar structures were preserved in EDC/NHS-CLT. Our findings show that by controlled EDC/NHS cross-linking, an acellular lung scaffold could be provided with mechanical properties similar to native lung, which promotes mesenchymal lung cells proliferation and does not stimulate recipient's immune system more than a non-cross-linked tissue.
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http://dx.doi.org/10.1016/j.msec.2021.111938DOI Listing
March 2021

Imipenem alters systemic and liver inflammatory responses in CLP- induced sepsis mice in a dose-dependent manner.

Int Immunopharmacol 2021 Apr 4;93:107421. Epub 2021 Feb 4.

Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Background: Considering the role of inflammation in the outcome of sepsis and the widespread use of imipenem in the disease, this study was designed to assess the effect of imipenem on the dynamics of inflammatory responses in the sepsis mouse model.

Methods: Cecal Ligation and Puncture (CLP) model was used to induce sepsis in mice. C57BL/6 mice were divided into sham, CLP-induced sepsis mice, CLP-induced sepsis mice receiving 25 mg/kg, and 125 mg/kg imipenem. Blood and liver samples were obtained and bacterial load, endotoxin level, and liver enzymes were evaluated. The concentration and mRNA expression of cytokines were also determined.

Results: Sepsis mice treated with a high dose (125 mg/kg) of imipenem showed a significant reduction in bacterial load, while increased liver enzymes, endotoxin level, and inflammatory cytokine production in plasma and liver. In contrast, significant reduction in the liver enzymes, bacterial load, endotoxin levels, and inflammatory cytokine levels was observed in the mice treated with a low dose (25 mg/kg) of imipenem compared with other mice groups. Liver tissue pathology of mice indicated little tissue destruction in the sepsis mice treated with 25 mg/kg of imipenem compared to other groups. Mice receiving 25 mg/kg of imipenem had better survival rate.

Conclusions: Our results demonstrated the dose-dependent effect of subcutaneous administration of imipenem on the inflammatory responses in sepsis mice. A dose of 25 mg/kg imipenem resulted in better pathology, lower inflammatory mediators, and increased survival rate in sepsis mice.
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http://dx.doi.org/10.1016/j.intimp.2021.107421DOI Listing
April 2021

Exosome-mediated delivery of functionally active miRNA-375-3p mimic regulate epithelial mesenchymal transition (EMT) of colon cancer cells.

Life Sci 2021 Mar 13;269:119035. Epub 2021 Jan 13.

Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Aims: EMT is the process by which a polarized epithelial cell undergoes several changes leading to highly invasive and fibroblast-like morphology. It has been described that miR-375 is inversely associated with EMT in cancerous patients and can effectively inhibit invasion and migration of tumor cells. Here, we investigate whether miR-375 mimic delivered by tumor-derived exosomes could reverse EMT process.

Main Methods: The exosomes were isolated from HT-29 and SW480. Subsequently, exosomes were loaded with miR-375-3p mimic applying modified calcium chloride method. Quantitative real-time PCR was used for evaluation of the loading efficiency of miR-375 mimic in the exosomes. The effects of miR-375 loaded tumor exosomes (TEXomiR) on EMT process investigated using flow cytometry, cell morphology, and invasion and migration assay.

Key Findings: The in vitro results showed that the tumor derived exosomes can efficiently deliver miR-375 mimic to reduce the expression of β-catenin, vimentin, ZEB1, and snail. In contrast, TEXomiR significantly increased the expression of E- cadherin in EMT process. Furthermore, the migration and invasion abilities of HT-29 and SW480 cells were inhibited by TEXomiR. The expression of CD44 and CD133 are increased in EMT process. Flow cytometry evaluation demonstrated that treatment with TEXomiR significantly decreased the expression of CD44 and CD133 in SW480 cell line.

Significance: Our results imply that colon cancer cells-derived exosomes could be used as an effective nonvehicle to deliver miR-375-3p mimic. Moreover, TEXomiR may be a potent therapeutic agent for the treatment of metastatic colorectal cancer.
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http://dx.doi.org/10.1016/j.lfs.2021.119035DOI Listing
March 2021

Delivery of miR-381-3p Mimic by Mesenchymal Stem Cell-Derived Exosomes Inhibits Triple Negative Breast Cancer Aggressiveness; an In Vitro Study.

Stem Cell Rev Rep 2021 Jun 6;17(3):1027-1038. Epub 2021 Jan 6.

Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Recent investigations have emphasized the role of aberrant expression of microRNAs (miRNAs) in progression of almost all types of cancers. Exosomes, membrane-enclosed natural nanovesicles, transport cellular contents, including proteins, mRNAs, and miRNAs, between cells. Unique features of exosomes make them an appropriate carrier for drug delivery. miRNA-381 is one of the downregulated miRNAs in several cancers including triple-negative breast cancer (TNBC) and restoration of its expression in TNBC cells can restrict their migratory ability through targeting several signaling pathways. In current study, we exploited the exosomes isolated from adipose-derived mesenchymal stem cells (ADMSC-exosomes) to deliver miR-381 mimic to MDA-MB-231 cells to elucidate their effects on TNBC cells. The effects of miR-381 loaded ADMSC-exosomes on proliferation, apoptosis, migration, and invasion of MDA-MB-231 cells were analyzed. Our results indicated that ADMSC-exosomes were successfully isolated and internalized by MDA-MB-231 cells. miR-381 mimic was efficiently delivered to MDA-MB-231 cells by ADMSC-exosomes. miR-381 loaded ADMSC-exosomes significantly downregulated the expression of epithelial to mesenchymal transition (EMT) related genes and proteins. Notably, miR-381 loaded ADMSC-exosomes inhibited proliferation, migration, and invasion capacity of MDA-MB-231 and promoted their apoptosis in vitro. Taken together, we showed that ADMSC-exosomes could be used as efficient nanocarriers for RNA-based therapies. Graphical abstract.
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http://dx.doi.org/10.1007/s12015-020-10089-4DOI Listing
June 2021

Intranasal administration of small extracellular vesicles derived from mesenchymal stem cells ameliorated the experimental autoimmune encephalomyelitis.

Int Immunopharmacol 2021 Jan 4;90:107207. Epub 2020 Dec 4.

Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address:

Experimental autoimmune encephalomyelitis (EAE) is a mouse model for the human multiple sclerosis, which is characterized by inflammation in the central nervous system (CNS), de-myelination of axonal neurons, and loss of motor coordination. The aim of the current study was to evaluate the effect of intranasal administration of mesenchymal stem cells (MSCs) and small extracellular vesicle (SEV) derived from the MSC (MSC-SEV) on disease activity and antigen-specific responses in the EAE mouse model. MSCs (5 × 10) were administered intranasally to EAE mice (n = 5) on the 15th and 24th days after immunization. In addition, the intranasal administration of MSC-SEV (10 μg) was used to treat EAE mice (n = 5) on a daily basis from the 15th to the 27th day after induction of the disease. The outcomes of therapies were evaluated using studying clinical symptoms and histological analysis of CNS lesions. Moreover, T cell proliferation, the frequency of regulatory T cells, the expression of transcription factors of T-helper subsets, and the levels of their corresponded cytokines were evaluated in splenocytes culture that was stimulated with specific-antigen. The results of treatment of EAE mice with MSC- SEV and MSC showed a significant decrease in the clinical scores, and it was found that treatment with MSC-SEV was more effective in alleviating clinical scores than MSC. In addition, the decrease in clinical symptoms was associated with an increase in immunomodulatory responses, including an increase in the frequency of Foxp3+ CD25+ regulatory T cells. Moreover, the level of TGF-β was increased by both treatments; however, interleukin-10 was increased only by MSC treatment. Ultimately, it was achieved that the intranasal administration of MSC-SEV to EAE mice was more effective than the administration of MSC to reduce clinical scores and histological lesions of the CNS tissue.
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http://dx.doi.org/10.1016/j.intimp.2020.107207DOI Listing
January 2021

Exosome-mediated miR-33 transfer induces M1 polarization in mouse macrophages and exerts antitumor effect in 4T1 breast cancer cell line.

Int Immunopharmacol 2021 Jan 25;90:107198. Epub 2020 Nov 25.

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. Electronic address:

Macrophages are the most abundant tumor-infiltrating immune cells. Macrophages are conventionally classified as M1 or M2 types. M2 type is the dominant phenotype of macrophages in the tumor microenvironment. M2 macrophages support different aspects of tumor development, including tumor formation, growth, and metastasis. MicroRNAs (miRNAs) have been demonstrated to regulate numerous cellular processes, including macrophage polarization. To determine whether miR-33 containing exosomes can alter macrophage polarization, we used the exosomes isolated from 4T1 breast cancer cells to deliver miR-33 mimic into IL-4 induced M2 macrophages and treated macrophages with 4T1-conditioned media. Then, we assayed the expression of M1 specific markers and the production of cytokines using real-time PCR and ELISA, respectively. Additionally, we performed MTT, migration, and invasion assays to detect the effect of miRNA-mediated macrophage repolarization on cancer cell proliferation, migration, and invasion. The results of this study showed that miR-33 containing exosomes could convert M2 to M1 phenotype as indicated by an increase in expression of M1 markers, including Irf5, Nos2, and CD86, and a decrease in M2 markers including Arg, Ym1, and CD206. Furthermore, the secretion of TNF-α and IL-1β as M1 specific cytokines increased, while the secretion of IL-10 and TGF-β as M2 specific cytokines decreased. Incubation of 4T1 cells with conditioned media of treated macrophages showed reduced proliferation, invasion, and migration of these cells. So, our data suggests that exosomes can be used as an efficient nanocarrier for miR-33 delivery into macrophages. Also, miR-33 is capable of inducing M1 polarization in macrophages, which is essential for suppressing tumor growth and metastasis.
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http://dx.doi.org/10.1016/j.intimp.2020.107198DOI Listing
January 2021

Synergistic therapeutic effect of mesenchymal stem cells and tolerogenic dendritic cells in an acute colitis mouse model.

Int Immunopharmacol 2020 Nov 23;88:107006. Epub 2020 Sep 23.

Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address:

Cell-based therapy with tolerizing cells has been applied for the treatment of inflammatory bowel disease (IBD) in previous experimental and clinical studies with promising results. In the current study, we utilized the dextran sulfate sodium (DSS)-induced colitis model, to investigate if tolerogenic dendritic cell-mesenchymal stem cell (tDC-MSC) combination therapy can augment the therapeutic effects of single transplantation of each cell type. The effect of MSC and tDC co-transplantation on the severity of colitis was assessed by daily monitoring of body weight, stool consistency, and rectal bleeding, and compared with control groups. Moreover, the colon length, colon weight, myeloperoxidase (MPO) activity were measured and evaluated with histological analysis of colon tissues. The Treg cell percentage and cytokine levels in spleens and mesenteric lymph nodes (MLNs) were measured by flow cytometry and ELISA, respectively. The results showed co-transplantation of MSCs and tDCs was more effective in alleviating the clinical and histological manifestations of colitis than monotherapy, especially when compared with MSC alone. The protective effects of tDC-MSC were accompanied by the induction of Treg cells and increased the production of anti-inflammatory cytokines in spleens and mesenteric lymph nodes. Together, co-transplantation of MSCs and tDCs could be a promising and effective therapeutic approach in the treatment of IBD.
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http://dx.doi.org/10.1016/j.intimp.2020.107006DOI Listing
November 2020

In vitro and in vivo evaluation of anti-tumoral effect of M1 phenotype induction in macrophages by miR-130 and miR-33 containing exosomes.

Cancer Immunol Immunother 2021 May 3;70(5):1323-1339. Epub 2020 Nov 3.

Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

In the tumor microenvironment, macrophages polarize into the M2 phenotype to facilitate tumorigenesis. Tumor-derived exosomes can act as mediators between the tumor microenvironment and stromal cells by transporting proteins, mRNAs, and miRNAs. Exosomal miRNAs play a pivotal role in modulating tumor microenvironment and macrophage polarization. Here, we overexpressed miR-130 and miR-33 in exosomes of MDA-MB-231 cells and investigated their effect on macrophage polarization and tumor progression. For this purpose, exosomes were extracted from MDA-MB-231 cells and characterized using dynamic light scattering, electron microscopy, and western blotting of exosomal markers. Then, miR-130 or miR-33 containing exosomes were used to treat IL4-induced M2 or tumor-associated macrophages (TAMs). After treatment, the polarization status of macrophages, including the expression of M1 specific genes, and the secretion of cytokines were evaluated. Finally, the conditioned medium from exosome-treated macrophages was incubated with cancer cells to evaluate its effect on the migration and invasion ability of cancer cells and, in vivo experiments investigated the effect of exosome-treated macrophages on breast cancer progression. Exosomes characterization results approved the range of size and homogeneity of extracted exosomes. Overexpression of miR-130 and miR-33 in exosomes increased the expression of M1 signature genes (IRF5, MCP1, CD80) and secretion of cytokines (IL-1β and TNF-α) as well as yeast phagocytic activity of macrophages. Besides, the conditioned medium of macrophages treated with miRNA containing exosomes declined the migration and invasion ability of cancer cells. The in vivo results indicated the inhibitory effect of exosome-treated macrophages on tumor growth. Furthermore, the results showed that in response to exosome-treated macrophages, the production of TNF-α by spleen cells increased, while the production of IL-10 and TGF-β by these cells decreased. These findings suggest that overexpression of miR-130 and miR-33 in exosomes can decrease tumor progression by shifting macrophage polarization from M2 to M1 phenotype and can be a potential therapeutic strategy for tumor interventions.
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http://dx.doi.org/10.1007/s00262-020-02762-xDOI Listing
May 2021

MicroRNA-218 competes with differentiation media in the induction of osteogenic differentiation of mesenchymal stem cell by regulating β-catenin inhibitors.

Mol Biol Rep 2020 Nov 13;47(11):8451-8463. Epub 2020 Oct 13.

Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Osteoporosis, a systemic skeletal disorder specified by low bone mass, is associated with bone fragility and the raised risk of fractures. Activation of the Wnt/β-catenin signaling pathway has been directly demonstrated as a prominent biological event in the prevention of osteoporosis. Recently, critical roles of microRNAs (miRNAs) were further revealed in Wnt/β-catenin signaling activation and thereby contributing to the development and maintenance of the human skeleton. In this study, we investigated whether miR-218 can significantly promote the osteogenic differentiation of mesenchymal stem cells in conditional media by regulating β-catenin signaling inhibitors. The pre-miRNA nucleotide sequence of miR-218 was cloned into the pEGP-miR vector. Next, human adipose tissue-derived mesenchymal stem cells (AD-MSCs) were isolated, characterized, and transfected using pEGP-miR-218.Subsequently, the osteogenic potential of AD-MSCs was investigated in different treated groups using alkaline phosphatase (ALP)activity, calcium mineral deposition, and the expression of osteogenesis-related genes. Finally, negative regulators of Wnt signaling targeted by miR-218 were bioinformatically predicted. Our results indicated a significant increase in the ALP activity, mineralization, and osteogenesis-related genes expression in the AD-MSCs transfected with pEGP-miR-218. Also, the bioinformatic surveys and gene expression results showed that adenomatosis polyposis coli (APC) and glycogen synthase kinase 3 (GSK3-β) were downregulated in the transfected AD-MSCs in both differential and conditional media. This study provided evidence that miR-218 can promote osteogenic differentiation of AD-MSCs even in conditional media. Therefore, our findings suggest miR-218 as a putative novel therapeutic candidate in the context of osteoporosis and other bone metabolism-related diseases.
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http://dx.doi.org/10.1007/s11033-020-05885-7DOI Listing
November 2020

Mesenchymal stem cell therapies for COVID-19: Current status and mechanism of action.

Life Sci 2020 Dec 23;262:118493. Epub 2020 Sep 23.

Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address:

The outbreak of COVID-19 in December 2019, has become an urgent and serious public health emergency. At present, there is no effective treatment or vaccine for COVID-19. Therefore, there is a crucial unmet need to develop a safe and effective treatment for COVID-19 patients. Mesenchymal stem cells (MSCs) are widely used in basic science and in a variety of clinical trials. MSCs are able to engraft to the damaged tissues after transplantation and promote tissue regeneration, besides MSCs able to secrete immunomodulatory factors that suppress the cytokine storms. Moreover, the contribution of MSCs to prevent cell death and inhibit tissue fibrosis is well established. In the current review article, the potential mechanisms by which MSCs contribute to the treatment of COVID-19 patients are highlighted. Also, current trials that evaluated the potential of MSC-based treatments for COVID-19 are briefly reviewed.
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http://dx.doi.org/10.1016/j.lfs.2020.118493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510562PMC
December 2020

Stem Cell-Derived Exosomes as Treatment for Stroke: a Systematic Review.

Stem Cell Rev Rep 2021 Apr;17(2):428-438

Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Background: The therapeutic potential of stem cells may largely be mediated by paracrine factors contained in exosomes released from intracellular endosomes. A systematic review was performed to identify the effects of stem cell-derived exosomes for their ability to induce restorative effects in animal models of stroke.

Methods: PubMed, Scopus, and ISI Web of Science databases were searched for all available articles testing stem cell-derived exosomes as therapeutic interventions in animal models of stroke until April 2020. The STAIR scale was used to assess the quality of the included studies.

Results: A total of 994 published articles were identified in the systematic search. After screening for eligibility, a total of 16 datasets were included. Type of cerebral ischemia was transient in majority studies and most studies used rat or mice adipose tissue-derived stem cells/bone marrow-derived stem cells. Eight studies indicated improved functional recovery while 8 were able to show reduced infarct volume as a result of exosome therapy. The beneficial effects were mainly attributed to reduced inflammation and oxidative stress, enhanced neurogenesis, angiogenesis, and neurite remodeling. Also, 4 studies demonstrated that exosomes hold great promise as an endogenous drug delivery nano-system.

Conclusion: In preclinical studies, use of stem cell-derived exosomes is strongly associated with improved neurological recovery and reduced brain infarct volume following stroke. Improved preclinical study quality in terms of treatment allocation reporting, randomization and blinding will accelerate needed progress towards clinical trials that should assess feasibility and safety of this therapeutic approach in humans. Graphical abstract.
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http://dx.doi.org/10.1007/s12015-020-10024-7DOI Listing
April 2021

Ethics of research on stem cells and regenerative medicine: ethical guidelines in the Islamic Republic of Iran.

Stem Cell Res Ther 2020 09 14;11(1):396. Epub 2020 Sep 14.

Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Banihashem Sq., Banihashem St., Ressalat highway,1665659911, P.O. Box: 16635-148, Tehran, Iran.

Background: Regenerative medicine plays a major role in biomedicine, and given the ever-expanding boundaries of this knowledge, numerous ethical considerations have been raised.

Main Text: Rapid advancement of regenerative medicine science and technology in Iran, emerged the Iranian National Committee for Ethics in Biomedical Research to develop a comprehensive national ethical guideline. Therefore, the present ethical guideline which comprises eleven chapters was developed in 2019 and approved in early 2020. The titles of these chapters were selected based on the ethical considerations of various aspects of the field of regenerative medicine: (1) ethical principles of research on stem cells and regenerative medicine; (2) ethical considerations for research on stem cells (embryonic stem cells, epiblast stem cells, tissue-specific stem cells, stem cells derived from transdifferentiation, induced pluripotent stem cells [iPSCs], germline pluripotent stem cells, germline stem cells, and somatic cell nuclear transfer [SCNT] stem cells); (3) ethical considerations for research on somatic cells in regenerative medicine (adult somatic cells, fetal tissue somatic cells, and somatic cells derived from pregnancy products [other than fetus]); (4) ethical considerations for research on gametes in regenerative medicine; (5) ethical considerations for research related to genetic manipulation (human and animal) in regenerative medicine; (6) ethical considerations for research on tissue engineering in regenerative medicine; (7) ethical considerations for pre-clinical studies in regenerative medicine; (8) ethical considerations for clinical trials in regenerative medicine; (9) ethical considerations for stem cells and regenerative medicine bio-banks; (10) ethical considerations for privacy and confidentiality; and (11) ethical considerations for obtaining informed consent.

Conclusion: This article discusses the process of developing the present ethical guidelines and its practical points. We hope that it can play an important worldwide role in advancing ethics of research on stem cells and regenerative medicine.
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http://dx.doi.org/10.1186/s13287-020-01916-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489032PMC
September 2020

Improving the function of neutrophils from chronic granulomatous disease patients using mesenchymal stem cells' exosomes.

Hum Immunol 2020 Oct - Nov;81(10-11):614-624. Epub 2020 Sep 3.

Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Sheffield, UK. Electronic address:

In chronic granulomatous disease (CGD) patients, reactive oxygen species (ROS) production by neutrophils is impaired. So, they are susceptible to infections. Studies showed that, mesenchymal stem cells (MSCs) have protective effects on the function of neutrophils and an approach that MSCs use to apply their effects, is secreting soluble factors and exosomes. So, we investigated the effects of MSC-exosomes and MSC-conditioned media (MSC-CM) on the function and apoptosis of neutrophils in CGD patients. In this study, neutrophils were isolated from healthy donors and CGD patients and then incubated with exosomes or CM that were prepared from MSCs. Then, neutrophil respiratory burst, apoptosis and phagocytosis capacity were evaluated by NBT assay, Annexin V-PI method and Giemsa staining. It was demonstrated that both MSC-exosomes and CM could improve the phagocytosis capacity and ROS production of neutrophils in CGD patients and healthy donors. In contrast to the healthy group, in CGD patients, exosomes significantly reduced the percentage of viable neutrophils. This report indicated that MSC exosomes and CM could increase the function of the neutrophils isolated from CGD patients. But decreasing the number of the living cells is one of the limitations of them. However, it is hoped that this intervention will be developed in future studies to minimize its limitations.
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http://dx.doi.org/10.1016/j.humimm.2020.05.009DOI Listing
June 2021

Immunomodulatory and Therapeutic Effects of Mesenchymal Stem Cells on Organ Dysfunction in Sepsis.

Shock 2021 Apr;55(4):423-440

Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Abstract: Sepsis is a life-threatening disorder that is caused by a dysregulated inflammatory response during an infection. The disease mostly affects pregnant women, newborns, and patients in intensive care units. Sepsis treatment is a significant part of a country's health budgets. Delay in the therapy causes irreversible failure of various organs due to the lack of blood supply and reduction of oxygen in the tissues and eventually increased mortality. The involvement of four or five organs by sepsis has been attributed to an increased risk of death to over 90%. Although antibiotics are at the first line of sepsis treatment, they do not possess enough potency to control the disease and prevent subsequent organ failure. The immunomodulatory, anti-inflammatory, anti-apoptotic, and anti-microbial properties of mesenchymal stem cells (MSCs) have been reported in various studies. Therefore, the application of MSCs has been considered a potentially promising therapeutic strategy. In preclinical studies, the administration of MSCs has been associated with reduced bacterial load and decreased levels of pro-inflammatory factors as well as the improved function of the different vital organs, including heart, kidney, liver, and lungs. The current study provides a brief review of sepsis and its pathophysiology, and then highlights recent findings in the therapeutic effects of MSCs and MSC-derived secretome in improving sepsis-induced organ dysfunction. Besides, eligible sepsis candidates for MSC-therapy and the latest clinical findings in these areas have been reviewed.
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http://dx.doi.org/10.1097/SHK.0000000000001644DOI Listing
April 2021

Adipose derived mesenchymal stem cell exosomes loaded with miR-10a promote the differentiation of Th17 and Treg from naive CD4 T cell.

Life Sci 2020 Oct 9;259:118218. Epub 2020 Aug 9.

Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address:

Aims: The balance between various CD4 T cell subsets through highly regulated differentiation of naïve T cells is critical to ensure proper immune response, disruption of which may cause autoimmunity and cancers. miR-10a has been reported to regulate the fate of naïve T cells. Mesenchymal stem cells (MSC) derived exosomes are known effective immunomodulators and ideal vehicles for delivery of microRNAs. This study was aimed to examine the impacts of miR-10a on CD4 cell fate upon exosomal delivery in combination with immunomodulatory effects of MSCs.

Main Methods: Exosomes isolated form adipose tissue derived mesenchymal stem cells (AD-MSC-Exo) were transfected with miR-10a and added to naïve T cells purified from mouse spleen. AD-MSC-Exos were characterized and the efficacy of miR-10a delivery was evaluated. The expression levels of T-bet, GATA3, RORγt, and Foxp3 and the secreted levels of IFN-γ, IL-4, IL-17, and TGF-β respectively specific to Th1, Th2, Th17 and Treg, were assessed by qPCR and ELISA.

Key Findings: Being transferred by AD-MSC-Exo, miR-10a was effectively induced in CD4 T cells. Upon treatment with miR-10a loaded exosomes, the expression levels of RORγt and Foxp3 were enhanced and that of T-bet was reduced. Similarly, the secreted levels of IL-17, and TGF-β were increased and that of IFN-γ was decreased.

Significance: Our data indicate that miR-10a loaded exosomes, promote Th17 and Tregs response while reduce that of Th1. Promotion of both Th17 and Tregs in concert, mediated by the combined effect of miR-10a and MSC-Exo, indicate new therapeutic potentials, particularly in line with novel anti-tumor immunotherapeutic strategies.
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http://dx.doi.org/10.1016/j.lfs.2020.118218DOI Listing
October 2020

Wharton's Jelly Mesenchymal Stem Cells Exosomes and Conditioned Media Increased Neutrophil Lifespan and Phagocytosis Capacity.

Immunol Invest 2020 Aug 11:1-16. Epub 2020 Aug 11.

Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Neutrophils are the first cells involved in inflammation and pathogen elimination, but they have a short lifespan. So, strategies for enhancing neutrophil lifespan and activities can be useful in many situations such as patients with immunodeficiencies. Previous researches demonstrated that mesenchymal stem cell (MSC) has anti-apoptotic effects on neutrophils. These multipotent cells have immunomodulatory properties and can be isolated from different tissues. MSCs isolated from Wharton's jelly (WJ-MSCs), a mucosal connective tissue of the umbilical cord, may be better candidates than MSCs obtained from bone marrow or adipose tissue, because WJ-MSCs are younger and protected from damages that are resulted from aging, environmental toxins, and diseases. In addition, they have high proliferative capacity, easier accessibility, and more abundance. It was shown that following in vitro expansion, they are more effective than other sources of MSCs. Cell to cell contact or secretion of soluble factors and exosomes are the main approaches of MSCs in applying their effects. Exosomes and conditioned media (CM) were prepared from WJ-MSCs. Then, neutrophils were isolated and cultured with medium, CM, or exosomes. Then, neutrophil respiratory burst, apoptosis, and phagocytosis capacity were assessed by NBT assay, Annexin V-PI method, and Giemsa staining, respectively. Both treatments improved neutrophil lifespan and phagocytosis. Only MSC-CM could enhance neutrophil respiratory burst. This research demonstrated that MSC-exosomes and CM have protective effects on neutrophil function and lifespan. It can be concluded that MSC mediators can be responsible factors for protective functions of MSCs on neutrophils.
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http://dx.doi.org/10.1080/08820139.2020.1801720DOI Listing
August 2020

Inhibition of miR-34a reduces cellular senescence in human adipose tissue-derived mesenchymal stem cells through the activation of SIRT1.

Life Sci 2020 Sep 4;257:118055. Epub 2020 Jul 4.

Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address:

Aims: Human adipose derived mesenchymal stem cells (hAD-MSCs) as the most promising target for cell therapy and regenerative medicine, face senescence as a major drawback resulting in their limited proliferation and differentiation potentials. To evaluate the efficacy of miR-34a silencing as an anti-senescence strategy in hAD-MSCs, in this study common hallmarks of senescence were assessed after transient inhibition of miR-34a in hAD-MSCs.

Materials And Methods: The expression levels of miR-34a in hAD-MSCs at different passages were evaluated by real-time quantitative PCR. hAD-MSCs at passage 2 and passage 7 were transfected with miR-34a inhibitor. Doubling time assay, colony forming assay, and cell cycle analysis were performed to evaluate cell proliferation rate. The activity of senescence associated β-galactosidase (SA-β-gal) was assessed by histochemical staining. Moreover, the senescence associated molecular alterations including that of pro-senescence (P53, P21 and P16) and anti-senescence (SIRT1, HTERT and CD44) genes were examined by quantitative RT-PCR and western blot assays. To evaluate the differentiation potentials of MSCs, following adipogenic and osteogenic induction, the expression levels of lineage specific markers were analyzed by qPCR.

Key Findings: Our results showed that inhibition of miR-34a enhances the proliferation, promotes the adipogenic and osteogenic differentiation potency, reduces the senescence associated-β gal activity, and reverses the senescence associated molecular alterations in hAD-MSCs.

Significance: In this study, we showed that inhibition of miR-34a reduces the cellular senescence through the activation of SIRT1. Our findings support the silencing of miR-34a as an anti-senescence approach to improve the therapeutic potentials of hAD-MSCs.
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http://dx.doi.org/10.1016/j.lfs.2020.118055DOI Listing
September 2020

Biological function and molecular properties of Pyrenaican SF-1 as biological macromolecule extracted from Daldinia pyrenaica.

Int J Biol Macromol 2020 Nov 27;163:298-308. Epub 2020 Jun 27.

Department of Biotechnology, Engineering School of Lorena, University of São Paulo, São Paulo, Brazil (Under São Paulo Research Foundation - FAPESP, Processo No. 2018/14095-7; 2016/10636-8).

Molecular properties and biological functions of Pyrenaican SF-1 as a novel biological macromolecule extracted from a fungal isolate were studied. The isolate was identified as Daldinia pyrenaica on the basis of 5.8S rDNA sequencing. Pyrenaican SF-1 was obtained from the culture filtrate of the fungal isolate. The partial characterization of biochemical structure of Pyrenaican SF-1 was conducted. The fungal extract was also tested for the treatment of AGS, MDA and HeLa cell lines to assess cells proliferation, cells cycle and apoptosis. Furthermore, Pyrenaican SF-1 extract was tested for its antibacterial and antioxidant activity. Initial chemical analysis revealed that Pyrenaican SF-1 extract was composed of various monosaccharides such as d-glucose, D- mannitol, D-arabinose and β-D-ribopyranose. In vitro study indicated that Pyrenaican SF-1 could effectively elevate percentage of apoptosis and necrosis of cancer cells and block cell cycle phase of the control group. The fungal extract could inhibit proliferation of Hela and MDA cell up to 67% and 56%, respectively. Moreover, Pyrenaican SF-1 represented a strong antioxidant activity compared to that one obtained from vitamin C. On the other hand, Pyrenaican SF-1 exhibited growth inhibitory effects against different Gram-negative and Gram-positive bacterial strains. Pyrenaican SF-1 can be considered as a bioactive macromolecule with promising application in pharmaceutical and medical sectors.
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http://dx.doi.org/10.1016/j.ijbiomac.2020.06.242DOI Listing
November 2020

Hypothesis for the management and treatment of the COVID-19-induced acute respiratory distress syndrome and lung injury using mesenchymal stem cell-derived exosomes.

Med Hypotheses 2020 Nov 22;144:109865. Epub 2020 May 22.

Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address:

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a member of the coronaviridae that causes respiratory disorders. After infection, large amounts of inflammatory cytokines are secreted, known as the cytokine storm. These cytokines can cause pulmonary damage induced by inflammation resulting in acute respiratory distress syndrome (ARDS), and even death. One of the therapeutic approaches for treatment of ARDS is a mesenchymal stem cell (MSC). MSCs suppress inflammation and reduce lung injury through their immunomodulatory properties. MSCs also have the potential to prevent apoptosis of the lung cells and regenerate them. But our suggestion is using MSCs-derived exosomes. Because these exosomes apply the same immunomodulatory and tissue repair effects of MSCs and they don't have problems associated to cell maintenance and injections. For investigation the hypothesis, MSCs should be isolated from tissues and characterized. Then, the exosomes should be isolated from the supernatants and characterized. These exosomes should be injected into a transgenic animal for COVID-19. In the final section, lung function assessment, histological examination, micro-CT, differential leukocyte, viral load analysis, cytokine assay, and CRP level analysis can be investigated. COVID-19 treatment is currently focused on supportive therapies and no vaccine has been developed for it. So, numerous researches are needed to find potential therapies. Since the pathogenesis of this disease was identified in previous studies and can cause lung injury with ARDS, investigation of the therapeutic approaches that can suppress inflammation, cytokine storm and ARDS can be helpful in finding a novel therapeutic approach for this disease.
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http://dx.doi.org/10.1016/j.mehy.2020.109865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242964PMC
November 2020

Dendritic Cell-Based Therapy Using LY6E Peptide with a Putative Role Against Colorectal Cancer.

Immunotargets Ther 2020 22;9:95-104. Epub 2020 May 22.

Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Introduction: Albeit early stage gastrointestinal (GI) carcinomas have a good prognosis if treated with surgery, diagnosis is often confirmed at a late stage and efficacious drugs are lacking. Recent progress in immune-based therapies has focused on dendritic cells (DCs), aiming to elicit tumor-specific responses by inducing immunological memory. Our previous microarray study indicated that a biomarker, termed lymphocyte antigen-6E (LY6E), is commonly overexpressed in two potentially lethal GI cancers: those of colon and stomach. In this study, we examined the antigenic potency of LY6E in stimulating DCs.

Methods: Following isolation, differentiation, and maturation of mononuclear cells, DCs were pulsed with LY6E peptide, a protein related to major histocompatibility complex (MHC) class I/II. Subsequently, DCs were co-cultured with mouse splenocytes to assess antigen-specific T-cell proliferation. Elucidated cytotoxic T-lymphocyte responses were assessed using subcutaneous colorectal murine tumor models.

Results: Our in vitro results suggest that DCs loaded with LY6E peptide antigen are capable of stimulating and inducing proliferation of murine T-cells. Furthermore, our in vivo results demonstrate that LY6E peptide has a substantial impact on provoking immune responses against induced colon cancer in mice.

Discussion: In conclusion, based on the overexpression of LY6E in colorectal, gastric, and pancreatic cancers, the role of this peptide should be further investigated with a goal of developing new therapies for these challenging diseases.
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http://dx.doi.org/10.2147/ITT.S245913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250699PMC
May 2020

Therapeutic potential of bone marrow-derived mesenchymal stem cells and imatinib in a rat model of liver fibrosis.

Eur J Pharmacol 2020 Sep 11;882:173263. Epub 2020 Jun 11.

Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada; Research Institute in Oncology and Hematology, Cancer Care Manitoba, University of Manitoba, ON, Canada; Faculty of Medicine, University of Technology in Katowice, Katowice, Poland. Electronic address:

Considering the global increase in the prevalence of hepatic fibrosis and ineffective disease treatment, novel therapies are urgently needed. The current study is focused on comparing the therapeutic effects of mesenchymal stem cells (MSC)/imatinib combination therapy to single (MSCs or imatinib) therapy, in a rat model of carbon tetrachloride (CCL4)-induced liver fibrosis. Using rats, hepatic fibrosis was induced by injection of CCL4. Rats were divided into 5 groups: CCL4-induced hepatic fibrosis, phosphate buffered saline (PBS) treatment (vehicle control), Bone marrow-MSCs (BM_MSCs), imatinib, and bone marrow-MSCs/imatinib co-treatment. The therapeutic impact of these approaches was determined using histopathology, sirius-red staining, serum markers, and qRT-PCR for over expression of matrix components. IHC and Western blot were conducted for further confirmation of the results. Single treatment with MSCs or imatinib and the combination therapy, all significantly reduced serum levels of ALT, AST, and ALP concomitant with down-regulation of α-SMA, pro-collagen I, pro-collagen III, collagen IV, and laminin. A significant reduction of ECM components deposits and a decrease in α-SMA expression were detected in all treatment groups. Pathological observations demonstrated that 20% and 40% of the rats in the MSC and MSC/imatinib group were in grade F0 respectively, while 80% of the rats of the imatinib group were in grade 2. Even though all treatment strategies studied resulted in an equally potent reduction in the mRNA and protein expression levels of pro-fibrotic markers, in aspect of pathological observations, our results demonstrate the highest therapeutic potential of utilizing combination of BM-MSCs and imatinib.
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http://dx.doi.org/10.1016/j.ejphar.2020.173263DOI Listing
September 2020
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