Therapeutic approaches of cell therapy based on stem cells and terminally differentiated cells: Potential and effectiveness.

Cell-based therapy, as a promising regenerative medicine approach, has been a promising and effective strategy to treat or even cure various kinds of diseases and conditions. Generally, two types of cells are used in cell therapy, the first is the stem cell, and the other is a fully differentiated cell. Initially, all cells in the body are derived from stem cells. Based on the capacity, potency and differentiation potential of stem cells, there are four types: totipotent (produces all somatic cells plus perinatal tissues), pluripotent (produces all somatic cells), multipotent (produces many types of cells), and unipotent (produces a particular type of cells). All non-totipotent stem cells can be used for cell therapy, depending on their potency and/or disease state/conditions. Adult fully differentiated cell is another cell type for cell therapy that is isolated from adult tissues or obtained following the differentiation of stem cells. The cells can then be transplanted back into the patient to replace damaged or malfunctioning cells, promote tissue repair, or enhance the targeted organ's overall function. With increasing science and knowledge in biology and medicine, different types of techniques have been developed to obtain efficient cells to use for therapeutic approaches. In this study, the potential and opportunity of use of all cell types, both stem cells and fully differentiated cells, are reviewed.

Association between the copper/selenium ratio and the immune response to SARS-CoV-2 infection.

Aim: To assess the association serum levels of selenium (Se) and copper (Cu) with symptoms and IgG immune response to SARS-CoV-2. Patients & methods/materials: Blood samples and nasopharyngeal swabs were obtained from 126 COVID-19 patients with mild and severe symptoms. The serum levels of Cu and Se were measured by atomic-absorption spectrophotometry. Results & conclusion: Mean Se was higher in patients with mild symptoms and IgG nonresponders, whereas mean Cu was higher in patients with severe symptoms and IgG responders. The Cu/Se ratio was lower in patients with no IgG responses to infection and mild symptoms versus IgG responders with severe symptoms. These results suggest the Cu/Se ratio as a nutritional biomarker of severity and IgG immune response in COVID-19 patients.

The association between the strong immune response to infections and trace elements such as copper (Cu) and selenium (Se) is well documented. Se and Cu are changed under infectious conditions. Since SARS-CoV-2 causes inflammation in the body, this study was conducted to evaluate the association between serum levels of Se and Cu changes with the symptoms and immune response to SARS-CoV-2, and then assess the Cu/Se ratio. Blood samples and nasopharyngeal swabs were obtained from 126 SARS-CoV-2 participants with mild and severe clinical symptoms. The SARS-CoV-2 infection and immune response to the virus were confirmed in the laboratory. Next, the Se and Cu serum levels were measured. Finally, we analyzed our findings. The median Se levels were higher in patients with mild symptoms (115 µg/l) in comparison with the severe symptoms group (99 µg/l), and the mean Se levels were higher in immune nonresponders (110.33 ± 3.38 µg/l) in comparison with the immune responders' group (102.42 ± 1.83 µg/l). However, the median Cu was higher in participants with severe symptoms (124 µg/dl) compared with the mild symptoms group (103 µg/dl), and the mean Cu levels were higher in immune responders (112 ± 9.98 µg/dl) in comparison with the immune nonresponders' group (105.1 ± 9.4 µg/dl). The Cu/Se ratio was lower (ratio <1) in participants with no responses to infection and mild symptoms versus responders with severe symptoms. Our results suggest that the Cu/Se ratio may act as a nutritional biomarker of severity and immune response in SARS-CoV-2-infected patients.

Effects of MRI on stemness properties of Wharton's jelly-derived mesenchymal stem cells.

Mesenchymal stem cells (MSCs), derived from various tissues, are served as a promising source of cells in clinic and regenerative medicine. Umbilical cord-Wharton's jelly (WJ-MSCs)-derived MSCs exhibit advantages over those from adult tissues, such as no ethical concerns, shorter population doubling time, broad differentiation potential, readily available non-invasive source, prolonged maintenance of stemness properties. The aim of this study was to evaluate the effect of MRI (1.5 T, 10 min) on stemness gene expression patterns (OCT-4, SOX-2, NANOG) of WJ-MSCs. Additionally, we assessed cell viability, growth kinetics and apoptosis of WJ-MSCs after MRI treatment. The quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) data showed that transcript levels of SOX-2, NANOG in MRI-treated WJ-MSCs were increased 32- and 213-fold, respectively. MTT assay was performed at 24, 48, and 72 h post-treatment and the viability was not significantly different between the two groups. The doubling time of the MRI group was markedly higher than the control group. In addition, the colony formation ability of WJ-MSCs after MRI treatment significantly increased. Furthermore, no change in apoptosis was seen before or after MRI treatment. Our results suggest that the use of MRI can improve the quality of MSCs and enhance the efficacy of mesenchymal stem cell-based therapies.

Breastfeeding Increases the Expression of TLR4, TNF-α, CCL2, and CCL3 in the Prepuce Tissue of Neonates.

INTRODUCTION: Innate immunity plays a significant role in the tissue repair process. It is well documented that breastfeeding may alter immune responses. Thus, this study was designed to evaluate the effects of breastfeeding on the levels of TLR1-4, TNF-α, TGF-ß, CCL2, and CCL3 in the prepuce tissue of neonates. MATERIAL AND METHODS: This study was conducted on 90 samples of prepuce tissue obtained from neonates (45 neonates who were breastfed with human milk [HM] and 45 neonates who were not breastfed and received non-human milk [NHM]). The tissues were homogenized and mRNA levels of TLR1-4 and protein levels of TNF-α, TGF-ß, CCL2, and CCL3 were analyzed using Real-Time PCR and ELISA techniques, respectively. RESULTS: Protein levels of TNF-α, CCL2 and CCL3, and mRNA levels of TLR4 were significantly lower in the NHM neonates than in the HM neonates. There was a significant negative correlation between duration of pregnancy and mRNA levels of TLR1 in the NHM neonates. CONCLUSION: These results indicate that breastfeeding may be associated with the regulated expression of TLR4 and its related cytokines/chemokines and that it may improve wound healing and aid in the fight against pathogens.

Involvement of T-bet and GATA3 transcription factors in Mesenchymal stem cells and royal jelly combination treatment in brain stroke.

INTRODUCTION: Mesenchymal stem cells (MSC) therapy is a promising therapeutic strategy to overcome the brain stroke side effects. However, it may be associated with long-term complications, including induction of inflammation. This project was designed to examine the effects of MSC administration and its combination with royal jelly (RJ) on the differentiation of T helper subsets. MATERIAL AND METHODS: In this project, the mice were divided to the six groups, including control (healthy without stroke), stroke (mice model of middle cerebral artery occlusion (MCAO)), treated with mouse MSC (mMSC), royal jelly (RJ), combination of mMSC and RJ (mMSC + RJ) and MSC conditioned medium (SUP). Thereafter, sticky test, brain mRNA levels of T-bet (transcription factor for Th1 subset), GATA3 (transcription factor for Th2 subset), and ROR-γ (transcription factor for Th17 subset) and percentage of myeloperoxidase (MPO) activities were explored in the groups. RESULTS: Administration of mMSC and mMSC + RJ improved the sticky test times and decreased the MPO activities. Using mMSCs and RJ was associated with increased expression of T-bet and GATA3 transcription factors. Transplantation of mMSCs in combination with RJ reduced expression of T-bet in the infarcted tissue. CONCLUSION: Using mMSC may be associated with Th1-related inflammation in the long term. RJ co-administration significantly reduced the risks, hence, to decrease the plausible side effects of MSCs, it can be proposed to use RJ in combination with MSC to reduce stroke complications.

Aqueous extract of Achillea millefolium significantly affects mesenchymal stem cell renewal and differentiation in a dose dependent manner.

Introduction: Achillea millefolium is an Iranian herbal medicine with various effects on the human cells. The aim of this study was to investigate the effects of the aqueous extract of Achillea millefolium (AEAM) on the proliferation and differentiation of mesenchymal stem cells (MSCs). Methods: In this study, bone marrow-MSCs (BM-MSCs) were obtained from Wister rat bone morrow and then cultured in Dulbecco's modified Eagle's medium /Nutrient Ham's Mixture F-12 (DMEM/F12) media. Then, the isolated MSCs were cultured in either osteocyte or adipocyte differentiation media containing 0.2 or 2 mg/mL AEAM and assessed using specific staining method. Results: The isolated BM-MSCs exhibited fibroblast-like morphology and were positive for CD73, and CD90, while negative for CD34 and CD45. AEAM significantly increased self-renewal of BM-MSCs at low dose (0.2 mg/ml, P= 0.001) and increased the pool stem cells in both osteocyte and adipocyte differentiation media. Conclusion: AEAM at low doses may be used in cases where there is a need for large number of stem cells, via increased numbers of MSCs, and help tissue repair and immunomodulation.

Ionizing radiation and toll like receptors: A systematic review article.

Ionizing radiation, including X and gamma rays, are used for various purposes such as; medicine, nuclear power, research, manufacturing, food preservation and construction. Furthermore, people are also exposed to ionizing radiation from their workplace or the environment. Apart from DNA fragmentation resulting in apoptosis, several additional mechanisms have been proposed to describe how radiation can alter human cell functions. Ionizing radiation may alter immune responses, which are the main cause of human disorders. Toll like receptors (TLRs) are important human innate immunity receptors which participate in several immune and non-immune cell functions including, induction of appropriate immune responses and immune related disorders. Based on the role played by ionizing radiation on human cell systems, it has been hypothesized that radiation may affect immune responses. Therefore, the main aim of this review article is to discuss recent information regarding the effects of ionizing radiation on TLRs and their related disorders.

Tissue-engineered nerve graft using silk-fibroin/polycaprolactone fibrous mats decorated with bioactive cerium oxide nanoparticles.

The main aim of this study was to evaluate the efficacy of cerium oxide nanoparticles (CNPs) encapsulated in fabricated hybrid silk-fibroin (SF)/polycaprolactone (PCL) nanofibers as an artificial neural guidance conduit (NGC) applicable for peripheral nerve regeneration. The NGC was prepared by PCL and SF filled with CNPs. The mechanical properties, contact angle, and cell biocompatibility experiments showed that the optimized concentration of CNPs inside SF and SF/PCL wall of conduits was 1% (wt/wt). The SEM image analysis showed the nanoscale texture of the scaffold in different topologies depend on composition with fiber diameters at about 351 ± 54 nm and 420 ± 73 nm respectively for CNPs + SF and CNPs + SF/PCL fibrous mats. Furthermore, contact angle measurement confirmed the hydrophilic behavior of the membranes, ascribable to the SF content and surface modification through modified methanol treatment. The balance of morphological and biochemical properties of hybrid CNPs 1% (wt/wt) + SF/PCL construct improves cell adhesion and proliferation in comparison with lower concentrations of CNPs in nanofibrous scaffolds. The release of CNPs 1% (wt/wt) from both CNPs + SF and CNPs+ SF/PCL fibrous mats was highly controlled and very slow during the extended time of incubation until 60 days. Fabricated double-layered NGC using CNPs + SF and CNPs + SF/PCL fibers was consistent for application in nervous tissue engineering and regenerative medicine from a structural and biocompatible perspective.

Mesenchymal Stem Cells: The Potential Therapeutic Cell Therapy to Reduce Brain Stroke Side Effects.

Tissue plasminogen activator (tPA) is the gold standard treatment for ischemic stroke in the time window of 3-4.5 hours after the onset of symptoms. However, tPA administration is associated with inflammation and neurotoxic effects. Mesenchymal stem cells (MSC)-based therapy is emerging as a promising therapeutic strategy to control different inflammatory conditions. This project was designed to examine the protective role of MSC administration alone or in combination with royal jelly (RJ) five hours after stroke onset. The mice model of middle cerebral artery occlusion (MCAO) was established and put to six groups, including intact (healthy mice without stroke), control (untreated stroke), treated with mouse MSC (mMSC), Sup (conditioned medium), RJ and combination of mMSC and RJ (mMSC/RJ). Thereafter, behavioral functions, serum and brain (in both infarcted and non-infarcted tissues) levels of interleukin (IL)-1ß, IL-4, IL-10, tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) the sizes of brain infarction have been determined in the groups. Administration of mMSC and mMSC/RJ significantly improved the behavioral functions when compared to the controls. mMSC, RJ and mMSC/RJ significantly decreased the infarcted volumes. RJ and mMSC/RJ, but not mMSC, significantly decreased the brain edema. The infarction increased the serum levels of the cytokines, except TNF-α, and treatment with mMSC, Sup and RJ reduced serum levels of the pro-inflammatory cytokines. mMSC reduced IL-1ß in the non-infarcted brain tissue. To conclude, data revealed that using mMSC/RJ combination significantly reduced stroke side effects, including brain edema and serum levels of pro-inflammatory cytokines, and suggested that combination therapy of MSCs with RJ may be considered as an effective stroke therapeutic strategy.

Therapeutic effects of combination of platelet lysate and sulfasalazine administration in TNBS-induced colitis in rat.

Inflammatory bowel disease (IBD) is a chronic and idiopathic disease with gastrointestinal dysfunction. Current therapeutic approaches in IBD have several limitations such as, harmful side effects and high price for biologic drugs. It sounds that finding of an effective, safe and inexpensive strategy to overcome IBD is critical. Platelet derivatives, as biological pool of wide range of growth factors and cytokines, are widely used in regenerative medicine for treatment of soft and hard tissue lesions. We sought to determine whether platelet lysate (PL) alone or in combination with sulfasalazine (reference drug) can be a valuable strategy for overcoming IBD. In the present study, we investigated and compared the daily and alternate-day administration of PL alone or combined with sulfasalazine for treating colitis in a rat model of IBD. Histological damage scores of TNBS-induced colitis were reduced by co-administration of every alternate day PL and sulfasalazine. Pro-inflammatory cytokines TNF-α, IL-1 and IL-6 were decreased and anti-inflammatory cytokines IL-10 and TGF-ß were increased after treatment with PL compared to that in the TNBS group. Furthermore, combined treatment with PL and sulfasalazine decreased apoptosis and inhibited the NF-κB signaling pathway. In conclusion, the combined administration of PL with conventional IBD therapy is able to effectively ameliorate IBD through modulation of inflammatory status.

The roles played by TLR4 in the pathogenesis of multiple sclerosis; A systematic review article.

Multiple sclerosis (MS) is a world-wide pro-inflammatory based disease, which is prevalent among young individuals. The etiology of the disease and its related complications are yet to be clarified. It has been hypothesized that environmental factors, including pathogen-associated molecular patterns (PAMPs) and the internal factors such as damage-associated molecular patterns (DAMPs), may be the most important inducers/stimulators of the disorder and its related complications. Previous investigations proved that pathogen recognition receptors (PRRs) are the main sensors for the PAMPs and DAMPs. Therefore, it seems that the PRRs have been considered to be the plausible molecules participating in the etiology of MS. Toll-like receptors (TLRs) have been the widely studied PRRs and their roles have been documented in human-related diseases. TLR4 is the main PRR expressed on the cell surface of several immune cells including macrophages and dendritic cells. Several investigations reported that TLR4 to be the main molecule involved in the pathogenesis of pro-inflammatory based diseases. Thus, it has been hypothesized that TLR4 may be a part of the MS puzzle. This review article discusses the role of TLR4 in the MS pathogenesis using recent in vitro and in vivo investigations.

MicroRNA-4731-5p delivered by AD-mesenchymal stem cells induces cell cycle arrest and apoptosis in glioblastoma.

Glioblastoma multiforme (GBM) exhibits the most malignant brain tumor with very poor prognosis. MicroRNAs (miRNAs) are regulatory factors that can downregulate the expression of multiple genes. Several miRNAs acting as tumor-suppressor genes have been identified so far. The delivery of miRNA by mesenchymal stem cell (MSC) due to their ability to specifically target tumors is a new, hopeful therapeutic approach for glioblastoma. The objective of our study is the investigation of the effect of lentivirus-mediated microRNA-4731 (miR-4731) genetic manipulated adipose-derived (AD)-MSC on GBM. The downregulation of miR-4731 in human GBM tumor was detected using the GEO dataset. To evaluate the function of miR-4731, we overexpressed miR-4731 using lentiviral vectors in U-87 and U-251 GBM cell lines. The effects of miR-4731 on cell proliferation and cell cycle of glioma cells were analyzed by wound test and flow-cytometry assay. miR-4731 inhibited the proliferation of GBM cancer cells. Coculturing was used to study the antiproliferative effect of miR-4731-AD-MSCs on GBM cell lines. Direct and indirect coculture of GBM cell lines with miR-4731-AD-MSCs induced cell cycle arrest and apoptosis. Our findings suggest that AD-MSCs expressing miR-4731 have favorable antitumor characteristics and should be further explored in future glioma therapy.

Thalidomide attenuates the hyporesponsiveness of isolated atria to chronotropic stimulation in BDL rats: The involvement of TNF-α, IL-6 inhibition, and SOCS1 activation.

OBJECTIVES: Cirrhotic cardiomyopathy is a complication of uncured cirrhosis which is associated with hyporesponsiveness of the heart to sympathetic stimulation. The enhancement of portal pressure, nitric oxide (NO) level, pro-inflammatory mediators and down-regulation of Suppressor of Cytokine Signaling 1 (SOCS1) are involved in this situations. The present study seeks to examine the beneficial effect of thalidomide on cirrhotic cardiomyopathy. MATERIALS AND METHODS: The male rats were grouped as: Sham/saline, Sham/Thalidomide, Bile Duct Ligation (BDL)/saline and BDL/Thalidomide. BDL model of cirrhosis was used. In the treatment groups, thalidomide (200 mg/kg/day) was administrated by intragastrial gavage for 28 consecutive days, the chronotropic response was assessed in isolated atria by isoproterenol stimulation. Serum levels of NO, IL-6 and TNF-α hepatic level were evaluated. The intrasplenic pulp pressure (ISPP) as the portal pressure and histopathologic assessment were assessed. Real time RT-PCR was used for the evaluation of SOCS1 gene expression. RESULTS: Our results showed that thalidomide administration could significantly increase the atrial chronotropic response in BDL animals. The increased level of portal pressure decreased by thalidomide in BDL animals. Thalidomide could ameliorate the histopathological conditions of BDL rats. Furthermore, the chronic treatment by this drug diminished the elevated levels of NO, TNF-α and IL-6 in BDL animals. On the other hand, hepatic SOCS1 expression was up-regulated by thalidomide treatment in this group. CONCLUSION: Thalidomide improves the chronotropic hyporesponsiveness of isolated atria in BDL. This effect is probably mediated by the inhibiting NO, TNF-α and IL-6 production, reducing portal pressure and increasing the expression of SOCS1.

Combination therapy of mesenchymal stromal cells and sulfasalazine attenuates trinitrobenzene sulfonic acid induced colitis in the rat: The S1P pathway.

Adipose derived mesenchymal stem cells (ASCs) transplantation is a novel immunomodulatory therapeutic tool to ameliorate the symptom of inflammatory bowel disease (IBD). The objective of this study was to investigate the therapeutic effects of combined sufasalazine and ASCs therapy in a rat model of IBD. After induction of colitis in rats, ASCs were cultured and intraperitoneally injected (3 × 106 cells/kg) into the rats on Days 1 and 5 after inducing colitis, in conjunction with daily oral administration of low dose of sulfasalazine (30 mg/kg). The regenerative effects of combination of ASCs and sulfasalazine on ulcerative colitis were assessed by measuring body weight, colonic weight/length ratio, disease activity index, macroscopic scores, histopathological examinations, cytokine, and inflammation markers profiles. In addition, western blot analysis was used to assess the levels of nuclear factor-kappa B (NF-κB) and apoptosis related proteins in colitis tissues. Simultaneous treatment with ASCs and sulfasalazine was associated with significant amelioration of disease activity index, macroscopic and microscopic colitis scores, as well as inhibition of the proinflammatory cytokines in trinitrobenzene sulfonic acid (TNBS)-induced colitis. Moreover, combined ASCs and sulfasalazine therapy effectively inhibited the NF-κB signaling pathway, reduced the expression of Bax and prevented the loss of Bcl-2 proteins in colon tissue of the rats with TNBS-induced colitis. Furthermore, combined treatment with ASCs and sulfasalazine shifted inflammatory M1 to anti-inflammatory M2 macrophages by decreasing the levels of MCP1, CXCL9 and increasing IL-10, Arg-1 levels. In conclusion, combination of ASCs with conventional IBD therapy is potentially a much more powerful strategy to slow the progression of colitis via reducing inflammatory and apoptotic markers than either therapy alone.

Maternal exposure to silver nanoparticles are associated with behavioral abnormalities in adulthood: Role of mitochondria and innate immunity in developmental toxicity.

Silver nanoparticles (Ag-NPs) are currently used in a wide range of consumer products. Considering the small size of Ag-NPs, they are able to pass through variety of biological barriers and exert their effects. In this regard, the unique physicochemical properties of Ag-NPs along with its high application in the industry have raised concerns about their negative effects on human health. Therefore, it investigated whether prenatal exposure to low doses of Ag-NPs is able to induce any abnormality in the cognitive and behavioral performance of adult offspring. We gavaged pregnant NMRI mice with, 1) Deionized water as vehicle, 2) Ag-NPs 10 nm (0.26 mg/kg/day), 3) Ag-NPs 30 nm (0.26 mg/kg/day), and 4) AgNO3 (0.26 mg/kg/day) from gestational day (GD) 0 until delivery day. At the postnatal day (PD) 1, our results showed that high concentration of silver is present in the brain of pups. Further, we observed mitochondrial dysfunction and upregulation of the genes relevant to innate immune system in the brain. At PD 60, results revealed that prenatal exposure to Ag-NPs provoked severe cognitive and behavioral abnormalities in male offspring. In addition, we found that prenatal exposure to Ag-NPs was associated with abnormal mitochondrial function and significant up-regulation of the genes relevant to innate immunity in the brain. Although the Ag-NPs have been considered as safe compounds at low doses, our results indicate that prenatal exposure to low doses of Ag-NPs is able to induce behavioral and cognitive abnormalities in adulthood. Also, we found that these effects are at least partly associated with hippocampal mitochondrial dysfunction and the activation of sterile inflammation during early stages of life.

The extracellular vesicles-derived from mesenchymal stromal cells: A new therapeutic option in regenerative medicine.

Mesenchymal stem cells (MSCs) are adult multipotent cells that due to their ability to homing to damaged tissues and differentiate into specialized cells, are remarkable cells in the field of regenerative medicine. It's suggested that the predominant mechanism of MSCs in tissue repair might be related to their paracrine activity. The utilization of MSCs for tissue repair is initially based on the differentiation ability of these cells; however now it has been revealed that only a small fraction of the transplanted MSCs actually fuse and survive in host tissues. Indeed, MSCs supply the microenvironment with the secretion of soluble trophic factors, survival signals and the release of extracellular vesicles (EVs) such as exosome. Also, the paracrine activity of EVs could mediate the cellular communication to induce cell-differentiation/self-renewal. Recent findings suggest that EVs released by MSCs may also be critical in the physiological function of these cells. This review provides an overview of MSC-derived extracellular vesicles as a hopeful opportunity to advance novel cell-free therapy strategies that might prevail over the obstacles and risks associated with the use of native or engineered stem cells. EVs are very stable; they can pass the biological barriers without rejection and can shuttle bioactive molecules from one cell to another, causing the exchange of genetic information and reprogramming of the recipient cells. Moreover, extracellular vesicles may provide therapeutic cargo for a wide range of diseases and cancer therapy.