Impact Of Mesenchymal Stem Cells Research Articles

Impact of Mesenchymal Stem Cells on the Gut Microbiota and Microbiota Associated Functions in Inflammatory Bowel Disease: A Systematic Review of Preclinical Evidence on Animal Models.

Inflammatory bowel disease (IBD) is a global health problem in which gut microbiota dysbiosis plays a pivotal pathogenic role. Mesenchymal stem cells (MSCs) therapy has shown promising application prospects for its powerful immune regulation and tissue repair ability. Recent experimental data suggest that MSCs also regulate the composition of gut microbiota. The current review analyzed, for the first time, the research data linking MSCs and gut microbiota modulation in IBD models aiming at assessing the role of gut microbiota in MSCs repair of IBD. A comprehensive and structured literature search was performed up to January 2023 on the PubMed, Web of Science, and Scopus databases. The quality and risk of bias assessment followed the PRISMA guidelines and SYRCLE's tool. A total of nine pre-clinical studies on animal models were included. Although the dose and route of MSCs applied were quite heterogeneous, results showed that MSCs displayed protective effects on intestinal inflammation, including mice general assessment, immunoregulation, and intestinal barrier integrity. Meanwhile, studies showed positive effects on the composition of gut flora with MSCs administration, which had been characterized by restoration of Firmicutes/ Bacteroides balance and reduction of Proteobacteria. The beneficial bacteria Akkermansia, Bifidobacterium, and Lactobacillus were also distinctly enriched, and the pathogenic bacteria Escherichia-Shigella was conversely decreased. The alpha and beta diversity were also regulated to resemble those of healthy mice. Microbial metabolic functions, such as biosynthesis of secondary bile acid and sphingolipid metabolism, and some biological behaviors related to cell regeneration were also up-regulated, while cancer function and poorly characterized cellular function were down-regulated. Current data support the remodeling effect on gut microbiota with MSC administration, which provides a potential therapeutic mechanism for MSCs in the treatment of IBD. Additional studies in humans and animal models are warranted to further confirm the role of gut microflora in MSCs repairing IBD.

Mesenchymal Stem Cell Therapy for Bone Repair of Human Hip Osteonecrosis with Bilateral Match-Control Evaluation: Impact of Tissue Source, Cell Count, Disease Stage, and Volume Size on 908 Hips.

We investigated the impact of mesenchymal stem cell (MSC) therapy on treating bilateral human hip osteonecrosis, analyzing 908 cases. This study assesses factors such as tissue source and cell count, comparing core decompression with various cell therapies. This research emphasizes bone repair according to pre-treatment conditions and the specificities of cell therapy in osteonecrosis repair, indicating a potential for improved bone repair strategies in hips without femoral head collapse. This study utilized a single-center retrospective analysis to investigate the efficacy of cellular approaches in the bone repair of osteonecrosis. It examined the impact on bone repair of tissue source (autologous bone marrow concentrate, allogeneic expanded, autologous expanded), cell quantity (from none in core decompression alone to millions in cell therapy), and osteonecrosis stage and volume. Excluding hips with femoral head collapse, it focused on patients who had bilateral hip osteonecrosis, both pre-operative and post-operative MRIs, and a follow-up of over five years. The analysis divided these patients into seven groups based on match control treatment variations in bilateral hip osteonecrosis, primarily investigating the outcomes between core decompression, washing effect, and different tissue sources of MSCs. Younger patients (<30 years) demonstrated significantly better repair volumes, particularly in stage II lesions, than older counterparts. Additionally, bone repair volume increased with the number of implanted MSCs up to 1,000,000, beyond which no additional benefits were observed. No significant difference was observed in repair outcomes between different sources of MSCs (BMAC, allogenic, or expanded cells). The study also highlighted that a 'washing effect' was beneficial, particularly for larger-volume osteonecrosis when combined with core decompression. Partial bone repair was the more frequent event observed, while total bone repair of osteonecrosis was rare. The volume and stage of osteonecrosis, alongside the number of injected cells, significantly affected treatment outcomes. In summary, this study provides comprehensive insights into the effectiveness and variables influencing the use of mesenchymal stem cells in treating human hip osteonecrosis. It emphasizes the potential of cell therapy while acknowledging the complexity and variability of results based on factors such as age, cell count, and disease stage.

Comparative evaluation of bone marrow and dental pulp mesenchymal stem cells for motor functional recovery in rat sciatic nerve injury.

This study delves into the impact of mesenchymal stem cells derived from bone marrow (BM-MSCs) and those sourced from dental pulp (DP-MSCs) on the recovery of motor function and morphological aspects of the rat's sciatic nerve after crush injuries. The findings highlight that the groups treated with BM-MSCs, DP-MSCs or a combination of both (BM + DP-MSCs) displayed enhanced sciatic functional index values when juxtaposed with the sham group. This points to bettered motor functionalities. A deeper morphological analysis showed that all the groups had retained perineurium structure and fascicular arrangement. Notably, the sham and BM-MSCs groups had very few inconsistencies. All groups showed standard vascular density. Remarkably, the combined treatment group (BM + DP-MSCs) presented diminished oedema and a lower count of inflammatory cells. Through immunohistochemical methods, the presence of S100 expression was noted in the groups that underwent treatment. In summation, the study suggests that both BM-MSCs and DP-MSCs, whether used singly or in combination, can significantly aid in motor function restoration and morphological enhancements. An interesting observation from our research and earlier studies is that stem cells from dental pulp, which are sourced with less discomfort from milk and wisdom teeth, show a heightened propensity to evolve into nerve cells. This is in contrast to the more uncomfortably acquired BM-MSCs.

Effects of Mesenchymal Stem Cell-conditioned Media with Natural Immunomodulatory Agent Resveratrol on Type 1 Diabetes.

Type 1 diabetes mellitus (T1DM) is a condition marked by elevated blood sugar levels and primarily recognized by the destruction of beta cells caused by an autoimmune attack, which is a significant characteristic of T1DM. Recent studies have demonstrated the regenerative potential of conditioned medium therapy. In light of this, the current research sought to assess the impact of Mesenchymal Stem Cell conditioned media (CM) and CM with resveratrol (CM+ Resveratrol) on the management of T1DM in Swiss albino mice. By leveraging and modifying existing conditioned medium therapy, this study aims to evaluate its effectiveness in treating T1DM. Diabetes was induced in animals using the diabetes-inducing agent streptozotocin (STZ). The animals were then divided into five groups: Normal control, Disease Control, Resveratrol, Condition Media, and CM + Resveratrol. Treatments were given to the animals accordingly. The study period was 28 days. During this time, the animals were monitored for foodwater intake twice a week, blood glucose levels, and body weight. At the conclusion of the 28-day study period, biochemical estimations were performed for serum insulin levels, C-peptide levels, anti-inflammatory cytokines levels and pro-inflammatory cytokines levels. Additionally, histopathology of the pancreas was performed. The test groups showed a significant decrease in blood glucose levels, an increase in Cpeptide levels, and a decrease in pro-inflammatory cytokine levels compared to the disease group. However, no statistically significant change within groups was observed in terms of serum insulin and anti-inflammatory cytokine levels. The improvement in diabetic symptoms, such as polyphagia, polydipsia, and weight loss, was observed in the treatment group, along with pancreatic regeneration, which indicated improved insulin secretion. In the current investigation, we concluded that CM and CM+ Resveratrol, as natural immunomodulators, have the capacity to regenerate injured pancreatic beta cells and have antidiabetic action, together with immunomodulating impact. Nonetheless, future studies on this therapy appear to be promising.

MSCs-derived exosomes containing miR-486-5p attenuate cerebral ischemia and reperfusion (I/R) injury

ObjectivesThis study aims to investigate the impact of mesenchymal stem cell (MSC)-derived exosomes (Exo) on cerebral ischemia and reperfusion (I/R) injury, along with the underlying mechanism. MethodsAn animal model of cerebral ischemia was induced using middle cerebral artery occlusion (MCAO), and a cell model utilizing Neuro‐2a cells was established through oxygen-glucose deprivation/reoxygenation (OGD/R). Exosomes isolated from mouse MSCs were administered to mice or used to stimulate Neuro‐2a cells. Exosomes from MSCs transfected with miR-NC, miR-486-5p mimics, miR-486-5p inhibitor, or phosphatase and tensin homolog (PTEN) short hairpin RNAs (sh-PTEN) were employed to stimulate Neuro‐2a cells. The regulatory axis of miR-486-5p and PTEN was confirmed through rescue experiments. ResultsExo-miR-486-5p mimics alleviated cerebral I/R injury, improving neurological deficits and reducing the infarct ratio. Furthermore, Exo-miR-486-5p mimics attenuated OGD/R-induced defects in cell viability and inhibited apoptosis in Neuro‐2a cells. These mimics also reduced levels of lactate dehydrogenase (LDH) and malondialdehyde (MDA) while enhancing superoxide dismutase (SOD) activity, both in brain tissue homogenates of mice and cell supernatants. Mechanistically, PTEN was identified as a target of miR-486-5p, and the downregulation of PTEN notably elevated Exo-miR-486-inhibitor-induced reductions in cell viability while mitigating cell apoptosis. ConclusionThe results of this study demonstrate the potential of exosomes derived from MSCs to protect against cerebral I/R injury via the miR-486-5p and PTEN axis.

THE INFLUENCE OF MESENCHYMAL STEM CELLS ON THE DYNAMICS OF REGULATOR OF ENDOTHELIAL PROLIFERATION EXPRESSIONS IN THE BRAIN STRUCTURES OF RATS WITH EXPERIMENTAL ALZHEIMER-TYPE DEMENTIA

Background. Despite numerous studies, the assessment of the functional state of the vascular endothelium by determining the localization of cells, producers of the endothelial proliferation factor, and measuring the intensity of its production in the brain of rats with dementia of Alzheimer type is of great relevance.&#x0D; Objective: to investigate the impact of mesenchymal stem cells on the functional state of the endothelium of brain vessel in rats with Alzheimer-type dementia by assessing the optical density of brain structures expressing the endothelial proliferation factor.&#x0D; Results. In neurons of the CA1 zone of the hippocampus in gr. SС-14 and in In SС-28, SС-28-MSC, the optical density of cytoplasm marked by endothelial proliferation factor, compared to the control, was 3.6, 1.5, and 2.0 times lower, respectively, and in cortical neurons it did not differ from the control level. After injections of mesenchymal stem cells in all studied groups, there was a decrease in the optical density of labeled factor proliferation of the endothelium of the cytoplasm of cortical neurons and more significantly - in hippocampus neurons (especially in the SС-14-MSC group).&#x0D; Conclusions. In rats with scopolamine-induced dementia of the Alzheimer's type, after 14 days of the "regeneration" period, compared to controls the expression level of vascular factor in hippocampal neurons was significantly lower than that in cortical neurons, which is associated with their greater degree of damage depending on the duration of scopolamine administration, Less active production and more significant reception of endothelial proliferation factor by endotheliocytes was accompanied by a decrease in the optical density of the correspondingly labeled plasma. The introduction of mesenchymal stem cells, probably due to stimulation by the growth factors in them, leads to the activation of the proliferation of the vascular endothelium and a decrease in the synthesis of the own factor of endothelial proliferation.

Human Mesenchymal Stem Cell Derived from Bone Marrow and Umbilical Cord Display Anti-Cancer Activity in Cancer Cell Lines in Vitro

The anti-tumour efficacy of engineered mesenchymal stem cell (MSCs) in cancers have been well documented by several reports. However, the impact of MSCs on the pathogenesis of solid cancers remains elusive. The study aims to elucidate the role of MSCs from bone marrow (BMMSCs) and umbilical cord (UCMSCs) on the proliferation, apoptosis and clonogenicity of cancer cell including H2170 (squamous cell carcinoma), LN18 (glioblastoma) and MCF7 (breast cancer) in vitro. Highest concentration of conditioned medium derived from the UCMSCs was significantly (p&lt;0.001) effective to inhibit the proliferation of H2170 (25.8 ± 3.5%), LN18 (17.6 ± 6.5%) and MCF7 (33.2 ± 6.8%) as compared to 100% viability in basal. Both MSCs and its conditioned medium were able to significantly (p&lt;0.001) induce apoptosis (early and late) to the H2170 and LN18 cells. However, for MCF7 cells, co-cultured with both MSCs had higher impact on the apoptosis as compared to their condition medium. Furthermore, conditioned medium from UCMSCs were able to significantly reduced the number of colonies in H2170 (609.5 ± 4.9) and LN18 (171.3 ± 12.6) as compared to control (H2170; 1196.3 ±12.8 and LN18; 253.3 ± 12.3), suggesting that these two cancer cells are sensitive to the MSCs. Notably, by co-culturing of all three cancer cell lines with the MSCs’ conditioned medium, we found that there was an increased expression of more than two-fold in BAX, BAD, and APAF1 genes showing the ability of MSCs’ conditioned medium to induce the intrinsic apoptosis pathway in the cancer cells. Collectively, our findings demonstrated that the MSCs could induce apoptosis and inhibit both H2170 and LN18 cancer cell proliferation. Furthermore, this study did not find evidence of MSCs in enhancing tumorigenic characteristics of these cancer cells, and thus we postulate that MSCs are basically safe as a cell-based therapy in cancer treatment.

Potential impact of mesenchymal stem cells on nephrotoxicity induced by gamma irradiation and antiepileptic drugs cotherapy in rats.

The goal of this study was to assess the influence of bone marrow-derived mesenchymal stem cells (BM-MSCs) on the nephrotoxicity induced by fractionated doses of gamma irradiation (Rad) and the cotherapy of levetiracetam and oxcarbazepine in male rats. Adult rats were randomly divided into four groups. Group I: Control, Group II: antiepileptic drugs (AEDs), Group III: AEDs +Rad and Group IV: AEDs + Rad + MSCs. Rats treated with AEDs and exposed to fractionated doses of γ-irradiation displayed a discernible increase in serum urea, creatinine, kidney injury marker, kidney malondialdehyde, transforming growth factor beta (TGF-β) and the relative expression of Smad3 along with a decrease in the relative expression of Smad7 and glutathione level. Alternatively, groups treated with BM-MSCs with AEDs and Rad showed a substantial modification in the majority of the evaluated parameters and looked to be successful in reducing the hazards of the combination therapy of AEDs and radiation. The reno-histopathological study supports the biochemical analysis. In conclusion, BM-MSCs exhibited therapeutic potential against nephrotoxicity induced by fractionated doses of γ-irradiation and AEDs. The outcome was brought about by the downregulation of the TGF-β/Smad pathway. BM-MSCs might be suggested as a valuable therapeutic strategy to overcome kidney injury induced by gamma irradiation during AEDs cotherapy.

Therapeutic potential of bone marrow mesenchymal stem cells in cyclophosphamide-induced infertility.

Cancer is a deadly disease characterized by abnormal cell proliferation. Chemotherapy is one technique of cancer treatment. Cyclophosphamide (CYP) is the most powerful chemotherapy medication, yet it has serious adverse effects. It is an antimitotic medicine that regulates cell proliferation and primarily targets quickly dividing cells, and it has been related to varying levels of infertility in humans. In the current study, we assessed the biochemical, histological, and microscopic evaluations of testicular damage following cyclophosphamide administration. Further, we have explored the potential protective impact of mesenchymal stem cell (MSCs) transplantation. The biochemical results revealed that administration of cyclophosphamide increased serum concentrations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), while it decreased serum concentrations of free testosterone hormone (TH), testicular follicle-stimulating hormone, luteinizing hormone, and free testosterone hormone concentrations, testicular total antioxidant capacity (TAC), and testicular activity of superoxide dismutase (SOD) enzyme. The histology and sperm examinations revealed that cyclophosphamide induced destruction to the architectures of several tissues in the testes, which drastically reduced the Johnsen score as well as the spermatogenesis process. Surprisingly, transplantation of mesenchymal stem cell after cyclophosphamide administration altered the deterioration effect of cyclophosphamide injury on the testicular tissues, as demonstrated by biochemical and histological analysis. Our results indicated alleviation of serum and testicular sex hormones, as well as testicular oxidative stress markers (total antioxidant capacity and superoxide dismutase activity), and nearly restored the normal appearance of the testicular tissues, Johnsen score, and spermatogenesis process. In conclusion, our work emphasizes the protective pharmacological use of mesenchymal stem cell to mitigate the effects of cyclophosphamide on testicular tissues that impair the spermatogenesis process following chemotherapy. These findings indicate that transferring mesenchymal stem cell to chemotherapy patients could significantly improve spermatogenesis.

Stem cells as a potential therapeutic trend for experimental trichinosis

Background: Trichinella spiralis causes trichinosis through ingestion of pork contaminated by its infectivelarvae, resulting in intestinal and muscular phases of infection in the same host. Stem cells (SCs) treatsome diseases due to their capacity for trans-differentiation and immunomodulation.Objective: To assess the therapeutic impact of mesenchymal stem cells (MSCs) during intestinal andmuscular stages in T. spiralis-experimentally infected mice; used alone as monotherapy or combined withmebendazole (MBZ).Material and Methods: Forty albino mice were used to obtain bone marrow MSCs. Another 100 albinomice were divided into 2 groups 50 mice each simulating intestinal (a) and muscular (b) phases. Eachgroup was further subdivided into 5 subgroups, 10 mice each as follows: G1a and G1b: negative noninfected control; G2a and G2b: positive infected control; G3a and G3b: infected and MBZ treated; G4aand G4b: infected and MSCs tested; and G5a and G5b: infected and combined MBZ and MSCs therapytested. Mice of intestinal phase were sacrificed on 7th day post-infection (PI) while mice of muscularphase were sacrificed on 49th day PI. Assessment was done by parasitological assessment (the number ofadult worms in the intestine in groups (a) and the number of encysted larvae in the diaphragm in groups(b); histopathological and histochemical assessment of all groups using hematoxylin and eosin (HE it showed the highest significant reduction in the numberof intestinal worms and encysted muscular larvae with preservation of the different tissues elements asinvestigated by different stains and TEM.Conclusion: MSCs can be used as additive/synergistic therapy in the treatment of trichinosis.

Oxidative Stress, Inflammation, and Autophagy: Potential Targets of Mesenchymal Stem Cells-Based Therapies in Ischemic Stroke.

Ischemic stroke is a leading cause of death worldwide; currently available treatment approaches for ischemic stroke are to restore blood flow, which reduce disability but are time limited. The interruption of blood flow in ischemic stroke contributes to intricate pathophysiological processes. Oxidative stress and inflammatory activity are two early events in the cascade of cerebral ischemic injury. These two factors are reciprocal causation and directly trigger the development of autophagy. Appropriate autophagy activity contributes to brain recovery by reducing oxidative stress and inflammatory activity, while autophagy dysfunction aggravates cerebral injury. Abundant evidence demonstrates the beneficial impact of mesenchymal stem cells (MSCs) and secretome on cerebral ischemic injury. MSCs reduce oxidative stress through suppressing reactive oxygen species (ROS) and reactive nitrogen species (RNS) generation and transferring healthy mitochondria to damaged cells. Meanwhile, MSCs exert anti-inflammation properties by the production of cytokines and extracellular vesicles, inhibiting proinflammatory cytokines and inflammatory cells activation, suppressing pyroptosis, and alleviating blood–brain barrier leakage. Additionally, MSCs regulation of autophagy imbalances gives rise to neuroprotection against cerebral ischemic injury. Altogether, MSCs have been a promising candidate for the treatment of ischemic stroke due to their pleiotropic effect.

Impact of mesenchymal stem cells derived conditioned media on neural progenitor cells

Neurodegenerative diseases are common problem for companion animals. Due to the limited ability of injured axons to regenerate, innovative therapies combined with rehabilitation have been applied and evaluated. Among them, stem cells and their conditioned media implantation, which can ameliorate damaged tissue has been suggested as a promising treatment strategy. The main goal of our study was to characterize mesenchymal stem cells (MSC) derived from canine adipose tissue (AT-MSC) and umbilical cord (UC-MSC) and analyse effect of their conditioned media (CM) on neurite outgrowth of neural progenitor cells isolated from the brain cortex of neonatal rats. MSC from both sources showed high osteogenic and chondrogenic potential and expression of CD90 and CD29. Furthermore, both UC-MSCCM and AT-MSCCM stimulated neurite growth. Interestingly, this effect was more pronounced with UC-MSCCM when compared to AT-MSCCM in vitro, which may be related to the different content of neurotrophic factors included in the CM.

Impact of Mesenchymal Stem Cell on High Mobility Group AT-Hook 2 Gene and Tubular Epithelial Cell Epithelial-Mesenchymal Transitions in Diabetic Nephropathy

The present study aims to probe the impact of mesenchymal stem cells (MSCs) on the HMGA2 gene and renal tubular epithelial cell EMT in diabetic nephropathy (DN). The advanced glycation end product (AGE) in the later period was used to interfere with the HK-2 cell modeling of humans in vitro, while STZ was used for the modeling of mice DN in vivo. Allogeneic MSCs were used to interfere with the model to detect the concentration of the correlation factor in cells and mice kidney tissues and HMGA2 expression level. The following aspects were prompted after treatment with MSCs in vitro and in vivo: (1) TGF-β1 concentration, Smad2, HMGA2, vimentin and α-SMA expression levels were significantly reduced, when compared to the model group (P &lt;0.05), while Smad7 and E-cadherin expression levels significantly increased, when compared to the model group (P &lt;0.05); (2) The proteinuria and serum creatinine level of mice were alleviated, and the ultrastructure damage condition of kidneys also improved, when compared to the model group. MSCs can restrain the high expression of HMGA2 in DN, EMT and kidney fibrosis, and postpone renal function progression.

The impact of mesenchymal stem cells on host immunity and disease outcome in bacterial lung infection

Bacterial pneumonia is the most common infectious cause of death worldwide, disease burden is increasing and antibiotic resistance continues to escalate.[1,2][1] Novel therapies are needed. Mesenchymal stem cells (MSCs) are a heterogeneous subset of stromal stem cells which reside in bone marrow and

Mesenchymal stem cells maintain the stemness of colon cancer stem cells via interleukin-8/mitogen-activated protein kinase signaling pathway.

Mesenchymal stem cells (MSCs) can act as a carrier in tumor therapy, and tumor suppressor gene-modified MSCs can reach and suppress the tumor. However, in the colon cancer microenvironment, MSCs could promote tumor growth and create the environment that is conducive to the survival of cancer stem cells (CSCs). This study discovered MSCs from three sources (bone marrow, adipose, placenta) could induce the stemness and epithelial–mesenchymal transition (EMT) of HCT116 in vitro, meanwhile adipose- and placenta-derived MSCs increase the proportion of CD133+/CD44+ HCT116. Then, we explored the interaction mechanism between CD133+/CD44+ HCT116 and MSCs by the bioinformatics and in vitro assays. After CD133+/CD44+ HCT116 were co-cultured with MSCs, many cytokines in MSCs were stimulated, including interleukin-8 (IL-8). The binding of IL-8/CXCR2 activates the downstream mitogen-activated protein kinase (MAPK) signaling pathway in colon CSCs, thereby promoting the stemness and EMT. However, inhibition of IL-8/CXCR2/Erk1/2 could reverse the effect of MSCs on CSC stemness. In addition, MSCs co-cultured with CD133+/CD44+ HCT116 produce a carcinoma-associated fibroblast phenotype via intracellular FGF10–PKA–Akt–β-catenin signaling, which can be attenuated by IL-8 peptide inhibitor. To conclude, IL-8 promotes the interaction between colon CSCs and MSCs, and activates the MAPK signaling pathway in colon CSCs, which provides a theoretical basis for the application of MSCs in clinical practice. Impact statement MSCs have the property of chemotaxis and they can migrate to the tumor site by paracrine pathway in the tumor environment, and then interact with tumor cells. Although a mass of studies have been conducted about the impact of MSCs on tumors, it is still controversial whether the exogenous MSCs promote or inhibit tumor growth. In this work, we evaluated the effects of MSCs from three sources (bone marrow, adipose, placenta) on the proliferation, stemness, and metastasis of the colon cancer cells both in vitro and in vivo. Then, we proved the IL-8/CXCR2/MAPK and FGF10–PKA–Akt–β-catenin signaling pathway which mediate the interplay between MSC and CD133+/CD44+ colon cancer cell. This research aims to provide a theoretical basis for the safe application of MSCs in the clinical treatment of colon cancer.

The impact of mesenchymal stem cells on doxorubicin-induced testicular toxicity and progeny outcome of male prepubertal rats.

Many therapies to treat cancer are gonadotoxic and can lead to infertility. New strategies to diminish the side effects and protective plans during and after chemotherapy are needed. Therefore, bone marrow mesenchymal stem cells (BM-MSCs) as a novel solution were investigated against doxorubicin (Dox)-induced toxicity in rat testes. Forty male albino prepubertal rats were divided into four groups, 10 rats per each group. The first was injected intraperitoneally with saline as control. The second group was injected intravenously with a single dose of BM-MSCs (2 × 106 cells). The third was injected intraperitoneally with a single dose of Dox (5 mg/kg b.wt). The fourth was injected with both Dox and BM-MSCs as previously mentioned. Rats were cohabited each separately with an untreated adult female after 8 weeks of treatment to examine Dox effects on male's fertility. BM-MSCs counteract the deleterious effects of Dox on body, testicular weight as well as sperm quality by increasing sperm concentration and reducing the rate of abnormal sperm. BM-MSCs reduced significantly the testicular oxidative stress by reducing the elevated level of malondialdehyde and increasing the antioxidant capacity. Histologically, the testicular atrophy, severe damage of spermatogenesis and the significant reduction of the diameter and germinative cell layer thickness of the seminiferous tubules caused by Dox were significantly recovered after administration of the BM-MSCs. BM-MSCs have a significant role in restoring the structural efficiency of male reproductive system in rats after Dox treatment.

Mesenchymal stem cells decrease blood\u2013brain barrier permeability in rats with severe acute pancreatitis

BackgroundImpairment of the blood–brain barrier (BBB) could result in secondary cerebral edema and life-threatening pancreatic encephalopathy in patients with severe acute pancreatitis (SAP). Mesenchymal stem cells (MSCs) have been widely adopted in clinical research because of their pleiotropic functions. The aim of this study was to investigate the impact of MSCs on BBB permeability in SAP and the potential mechanisms driving these effects.MethodsSprague-Dawley rats were randomly assigned to the control, SAP and SAP+MSCs groups. Pancreatic impairment was assessed. The serum levels of amylase, TNF-α and IL-10, expression levels of claudin-5, Bax, Bcl-2 and MMP-9, and the BBB permeability were measured. Endothelial cell apoptosis was evaluated.ResultsSAP rats showed BBB impairment with increased permeability and secondary cerebral edema, which was confirmed using the Evans blue assay and the calculation of the brain dry/wet ratio. Treatment with MSCs decreased the serum levels of amylase and TNF-α, increased the serum levels of IL-10, attenuated the apoptosis of brain microvascular endothelial cells, upregulated claudin-5 expression and downregulated MMP-9 expression. This treatment attenuated the increased BBB permeability in SAP rats.ConclusionsMSCs attenuated the impairment of the BBB and decreased its permeability, producing protective effects in SAP rats.

Interaction with hyaluronan matrix and miRNA cargo as contributors for in vitro potential of mesenchymal stem cell-derived extracellular vesicles in a model of human osteoarthritic synoviocytes

BackgroundOsteoarthritis (OA) is the most prevalent joint disease, and to date, no options for effective tissue repair and restoration are available. With the aim of developing new therapies, the impact of mesenchymal stem cells (MSCs) has been explored, and the efficacy of MSCs started to be deciphered. A strong paracrine capacity relying on both secreted and vesicle-embedded (EVs) protein or nucleic acid-based factors has been proposed as the principal mechanism that contributes to tissue repair. This work investigated the mechanism of internalization of extracellular vesicles (EVs) released by adipose-derived MSCs (ASCs) and the role of shuttled miRNAs in the restoration of homeostasis in an in vitro model of human fibroblast-like synoviocytes (FLSs) from OA patients.MethodsASC-EVs were isolated by differential centrifugation and validated by flow cytometry and nanoparticle tracking analysis. ASC-EVs with increased hyaluronan (HA) receptor CD44 levels were obtained culturing ASCs on HA-coated plastic surfaces. OA FLSs with intact or digested HA matrix were co-cultured with fluorescent ASC-EVs, and incorporation scored by flow cytometry and ELISA. ASC-EV complete miRNome was deciphered by high-throughput screening. In inflamed OA FLSs, genes and pathways potentially regulated by ASC-EV miRNA were predicted by bioinformatics. OA FLSs stimulated with IL-1β at physiological levels (25 pg/mL) were treated with ASC-EVs, and expression of inflammation and OA-related genes was measured by qRT-PCR over a 10-day time frame with modulated candidates verified by ELISA.ResultsThe data showed that HA is involved in ASC-EV internalization in FLSs. Indeed, both removal of HA matrix presence on FLSs and modulation of CD44 levels on EVs affected their recruitment. Bioinformatics analysis of EV-embedded miRNAs showed their ability to potentially regulate the main pathways strictly associated with synovial inflammation in OA. In this frame, ASC-EVs reduced the expression of pro-inflammatory cytokines and chemokines in a chronic model of FLS inflammation.ConclusionsGiven their ability to affect FLS behavior in a model of chronic inflammation through direct interaction with HA matrix and miRNA release, ASC-EVs confirm their role as a novel therapeutic option for osteoarthritic joints.

Mesenchymal stem cells: Cancer promoting effects or tumor suppression - A current overview

The multimodal treatment of cancer deals with cancer cells as well as with the cancer surrounding stroma. This stroma contains non-malignant cells like fibroblasts, immune cells as well as mesenchymal stem cells (MSC). MSC have the ability to migrate towards cancer tissue. In the current literature the impact of MSC on cancer cells is discussed divergently. The majority of the current publications reveal an induction of cancer progression by MSC. Four main processes namely the secretion of soluble factors and cell-cell contact, the transdifferentiation of MSC into carcinoma associated fibroblasts, the improvement of neoangiogenesis and the induction of immune suppression are responsible for cancer progression. This publication gives an overview on the current literature.

The impact of Mesenchymal Stem Cells and their secretome as a treatment for gliomas

In recent years, we have witnessed a significant increase in the amount of studies using Mesenchymal Stem Cells (MSCs) for cancer therapy, mostly as vectors for drug or gene delivery strategies. This is because of their intrinsic capacity of homing into tumor niches. However, the interactions between MSCs themselves and tumor cells is not fully understood, with contradictory results frequently being observed regarding their effects on cancer cell invasion and proliferation. This poses an important question of safety in respect to the application of these cells. The source of the MSC population used, as well as the type of cancer cells under study might strongly influence this interaction. Moreover, differences in isolation protocols, culture media compositions, time of culture and conditioned media collection, or even timing and mode of MSCs administration to in vivo models of cancer may also affect the interaction MSC-tumor cells. In this review, we drive our focus into malignant brain tumors, particularly gliomas, one of the deadliest forms of cancer. Moreover, we look with some detail into different studies using MSCs as a treatment for brain tumors and compare them, highlighting the main deviations and similarities among them.