Benefits Of Mesenchymal Stem Cells Research Articles

Novel Therapeutic Opportunities for Neurodegenerative Diseases with Mesenchymal Stem Cells: The Focus on Modulating the Blood-Brain Barrier.

Neurodegenerative disorders encompass a broad spectrum of profoundly disabling situations that impact millions of individuals globally. While their underlying causes and pathophysiology display considerable diversity and remain incompletely understood, a mounting body of evidence indicates that the disruption of blood-brain barrier (BBB) permeability, resulting in brain damage and neuroinflammation, is a common feature among them. Consequently, targeting the BBB has emerged as an innovative therapeutic strategy for addressing neurological disorders. Within this review, we not only explore the neuroprotective, neurotrophic, and immunomodulatory benefits of mesenchymal stem cells (MSCs) in combating neurodegeneration but also delve into their recent role in modulating the BBB. We will investigate the cellular and molecular mechanisms through which MSC treatment impacts primary age-related neurological conditions like Alzheimer's disease, Parkinson's disease, and stroke, as well as immune-mediated diseases such as multiple sclerosis. Our focus will center on how MSCs participate in the modulation of cell transporters, matrix remodeling, stabilization of cell-junction components, and restoration of BBB network integrity in these pathological contexts.

Physiological oxygen conditions enhance the angiogenic properties of extracellular vesicles from human mesenchymal stem cells

BackgroundFollowing an ischemic injury to the brain, the induction of angiogenesis is critical to neurological recovery. The angiogenic benefits of mesenchymal stem cells (MSCs) have been attributed at least in part to the actions of extracellular vesicles (EVs) that they secrete. EVs are membrane-bound vesicles that contain various angiogenic biomolecules capable of eliciting therapeutic responses and are of relevance in cerebral applications due to their ability to cross the blood–brain barrier (BBB). Though MSCs are commonly cultured under oxygen levels present in injected air, when MSCs are cultured under physiologically relevant oxygen conditions (2–9% O2), they have been found to secrete higher amounts of survival and angiogenic factors. There is a need to determine the effects of MSC-EVs in models of cerebral angiogenesis and whether those from MSCs cultured under physiological oxygen provide greater functional effects.MethodsHuman adipose-derived MSCs were grown in clinically relevant serum-free medium and exposed to either headspace oxygen concentrations of 18.4% O2 (normoxic) or 3% O2 (physioxic). EVs were isolated from MSC cultures by differential ultracentrifugation and characterized by their size, concentration of EV specific markers, and their angiogenic protein content. Their functional angiogenic effects were evaluated in vitro by their induction of cerebral microvascular endothelial cell (CMEC) proliferation, tube formation, and angiogenic and tight junction gene expressions.ResultsCompared to normoxic conditions, culturing MSCs under physioxic conditions increased their expression of angiogenic genes SDF1 and VEGF, and subsequently elevated VEGF-A content in the EV fraction. MSC-EVs demonstrated an ability to induce CMEC angiogenesis by promoting tube formation, with the EV fraction from physioxic cultures having the greatest effect. The physioxic EV fraction further upregulated the expression of CMEC angiogenic genes FGF2, HIF1, VEGF and TGFB1, as well as genes (OCLN and TJP1) involved in BBB maintenance.ConclusionsEVs from physioxic MSC cultures hold promise in the generation of a cell-free therapy to induce angiogenesis. Their positive angiogenic effect on cerebral microvascular endothelial cells demonstrates that they may have utility in treating ischemic cerebral conditions, where the induction of angiogenesis is critical to improving recovery and neurological function.

Promising effects of exosomes from menstrual blood-derived mesenchymal stem cells on endometriosis

Endometriosis as a non-malignant gynecological disease leads to dysregulation of numerous cellular functions including apoptosis, angiogenesis, migration, proliferation, and inflammation. Accumulating evidence has shed light on the importance of endometrial stem cells within the menstrual blood which are involved in the establishment and progression of endometriotic lesions in a retrograde manner. According to the fact that the therapeutic benefits of mesenchymal stem cells are provided through paracrine functions, we used exosomes from menstrual blood-derived stem cells (MenSCs) for treating endometriotic stem cells to inhibit their lesion formation tendency. Menstrual blood samples from healthy and endometriosis women were collected. Isolated MenSCs by the density-gradient centrifugation method were characterized by flow cytometry. Secreted exosomes were isolated from healthy MenSCs (NE-MenSCs) and used to treat endometriotic cells (E-MenSCs). 72 h after treatment, different mechanisms and pathways including inflammation, proliferation, apoptosis, migration, and angiogenesis were analyzed using Real-Time PCR, ELISA, immunocytochemistry, annexin V/PI, and scratching assay. Exosome treatment significantly reduce the expression level of markers related to inflammation, proliferation, migration, and angiogenesis in E-MenSCs which are aberrantly expressed in endometriosis. Moreover, apoptosis was induced in E-MenSCs after treatment which was evaluated in both gene and protein levels. In this study, we give preliminary evidence for the potential of MenSCs-Exo in ameliorating endometriosis. Regarding our results, we suggest that after relevant clinical trial, MenSCs-derived exosomes can be considered as a better treatment option to improve endometriosis compared to common and conventional treatments and show their potential as a cell-free product in endometriosis repair.

Functionality of immune cells in COVID-19 infection: development of cell-based therapeutics.

Introduction: In late December 2019, a sudden severe respiratory illness of unknown origin was reported in China. In early January 2020, the cause of COVID-19 infection was announced a new coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Examination of the SARS-CoV-2 genome sequence revealed a close resemblance to the previously reported SARS-CoV and coronavirus Middle East respiratory syndrome (MERS-CoV). However, initial testing of drugs used against SARS-CoV and MERS-CoV has been ineffective in controlling SARS-CoV-2. One of the key strategies to fight the virus is to look at how the immune system works against the virus, which has led to a better understanding of the disease and the development of new therapies and vaccine designs. Methods: This review discussed the innate and acquired immune system responses and how immune cells function against the virus to shed light on the human body's defense strategies. Results: Although immune responses have been revealed critical to eradicating infections caused by coronaviruses, dysregulated immune responses can lead to immune pathologies thoroughly investigated. Also, the benefit of mesenchymal stem cells, NK cells, Treg cells, specific T cells, and platelet lysates have been submitted as promising solutions to prevent the effects of infection in patients with COVID-19. Conclusion: It has been concluded that none of the above has undoubtedly been approved for the treatment or prevention of COVID-19, but clinical trials are underway better to understand the efficacy and safety of these cellular therapies.

Critical roles of cytokine storm and bacterial infection in patients with COVID-19: therapeutic potential of mesenchymal stem cells.

The severe acute respiratory syndrome coronavirus 2 has been a shocking disaster for healthcare systems worldwide since December 2019. This virus can affect all systems of the body and its symptoms vary from a simple upper respiratory infection to fatal complications including end-organ damage. On the other hand, the normal immune system plays a pivotal role in the recovery of infectious diseases such as COVID-19. However, occasionally, exaggerated immune system inflammation and an excessive synthesis of cytokines, known as a "cytokine storm," can deteriorate the patient's clinical condition. Secondary bacterial co-infection is another problem in COVID-19 which affects the prognosis of patients. Although there are a few studies about this complication, they suggest not using antibiotics commonly, especially broad-spectrum ones. During this pandemic, various approaches and therapeutics were introduced for treating COVID-19 patients. However, available treatments are not helpful enough, especially for complicated cases. Hence, in this era, cell therapy and regenerative medicine will create new opportunities. Therefore, the therapeutic benefits of mesenchymal stem cells, especially their antimicrobial activity, will help us understand how to treat COVID-19. Herein, mesenchymal stem cells may stop the immune system from becoming overactive in COVID-19 patients. On the other side, the stem cells' capacity for repair could encourage natural healing processes.

Mesenchymal Stem Cell-Derived Extracellular Vesicles: New Soldiers in the War on Immune-Mediated Diseases.

Inflammatory diseases are a group of debilitating disorders with varying degrees of long-lasting functional impairment of targeted system. New therapeutic agents that will attenuate on-going inflammation and, at the same time, promote regeneration of injured organ are urgently needed for the treatment of autoimmune and inflammatory disorders. During the last decade numerous studies have demonstrated that crucial therapeutic benefits of mesenchymal stem cells (MSCs) in inflammatory diseases are based on the effects of MSC-produced paracrine mediators and not on the activity of engrafted cells themselves. Thus, to overcome the limitations of stem cell transplantation, MSC-derived extracellular vesicles (MSC-EVs) have been rigorously investigated, as a promising cell-free pharmaceutical component. In this review, we focus on the mechanisms of MSC-EV covering the current knowledge on their potential therapeutic applications for immune-mediated diseases.

Therapeutic Benefits of Mesenchymal Stem Cells in Acute Respiratory Distress Syndrome: Potential Mechanisms and Challenges.

Acute respiratory distress syndrome (ARDS) presents as a form of acute respiratory failure resulting from non-cardiogenic pulmonary edema due to excessive alveolocapillary permeability, which may be pulmonary or systemic in origin. In the last 3 years, the coronavirus disease 2019 pandemic has resulted in an increase in ARDS cases and highlighted the challenges associated with this syndrome, as well as the unacceptably high mortality rates and lack of effective treatments. Currently, clinical treatment remains primarily supportive, including mechanical ventilation and drug-based therapy. Mesenchymal stem cell (MSC) therapies are emerging as a promising intervention in patients with ARDS and have promising therapeutic effects and safety. The therapeutic mechanisms include modifying the immune response and assisting with tissue repair. This review provides an overview of the general properties of MSCs and outlines their role in mitigating lung injury and promoting tissue repair in ARDS. Finally, we summarize the current challenges in the study of translational MSC research and identify avenues by which the discipline may progress in the coming years.

Human bone marrow-derived mesenchymal stem cells rescue neonatal CPAP-induced airway hyperreactivity

Continuous positive airway pressure (CPAP) is a primary non-invasive mode of respiratory support for preterm infants. However, emerging evidence suggests CPAP could be an underlying contributor to the unintended pathophysiology of wheezing and associated airway hyperreactivity (AHR) in former preterm infants. The therapeutic benefits of mesenchymal stem cells (MSCs) have been demonstrated in a variety of animal models and several clinical trials are currently underway to assess their safety profiles in the setting of prematurity and bronchopulmonary dysplasia (BPD). In the present study, using a mouse model of neonatal CPAP, we investigated whether conditioned medium harvested from cultures of human bone-marrow derived mesenchymal stem cells (hMSC) could rescue the CPAP-induced AHR, based upon previous observations of their anti-AHR properties. Newborn mice (male and female) were fitted with a custom-made mask for delivery of daily CPAP 3 h/day for the first 7 postnatal days. At postnatal day 21 (two weeks after CPAP ended), lungs were removed, precision-cut lung slices were sectioned and incubated for 48 h in vitro in conditioned medium collected from cultures of three different hMSC donors. As expected, CPAP resulted in AHR to methacholine compared to untreated control mice. hMSC conditioned medium from the cultures of all three donors completely reversed AHR. These data reveal potential therapeutic benefits of hMSC therapy, which may be capable of rescuing the long-term adverse effects of neonatal CPAP on human airway function.

Effect of 2D and 3D Culture Microenvironments on Mesenchymal Stem Cell-Derived Extracellular Vesicles Potencies.

Therapeutic benefits of mesenchymal stem cells (MSCs) are now widely believed to come from their paracrine signalling, i.e. secreted factors such as cytokines, chemokines, and extracellular vesicles (EVs). Cell-free therapy using EVs is an active and emerging field in regenerative medicine. Typical 2D cultures on tissue culture plastic is far removed from the physiological environment of MSCs. The application of 3D cell culture allows MSCs to adapt to their cellular environment which, in turn, influences their paracrine signalling activity. In this study we evaluated the impact of 3D MSCs culture on EVs secretion, cargo proteome composition, and functional assessment in immunomodulatory, anti-inflammatory and anti-fibrotic properties.MSC-EVs from 2D and 3D cultures expressed classical EV markers CD81, CD63, and CD9 with particle diameter of <100 nm. There were distinct changes in immunomodulatory potencies where 3D cultures exhibited reduced indoleamine 2,3-dioxygenase (IDO) activity and significantly reduced macrophage phagocytosis. Administration of 2D and 3D EVs following double dose bleomycin challenge in aged mice showed a marked increase of bodyweight loss in 3D group throughout days 7–28. Histopathological observations of lung tissues in 3D group showed increased collagen deposition, myofibroblast differentiation and leukocytes infiltrations. Assessment of lung mechanics showed 3D group did not improve lung function and instead exhibited increased resistance and tissue damping. Proteome profiling of MSC-EV composition revealed molecular enrichment of EV markers (compared to parental cells) and differential proteome between EVs from 2D and 3D culture condition associated with immune-based and fibrosis/extracellular matrix/membrane organization associated function.This study provides insight into distinct variation in EV protein composition dependent on the cellular microenvironment of the parental cells, which could have implications in their therapeutic effect and potency. Overall, this work suggests that EVs produced from 3D MSC cultures did not enhance typical MSC-EV properties expected from 2D cultures (immunomodulation, anti-fibrotic, anti-inflammatory). The outcome highlights critical differences between MSC-EVs obtained from different culture microenvironments, which should be considered when scaling up MSC culture for clinical manufacturing.

Engineering mesenchymal stem cell paracrine activity with 3D culture

Background & Aim Therapeutic benefits of mesenchymal stem cells (MSCs) are now widely believed to come from their paracrine effects, i.e. cytokines, chemokines, and extracellular vesicles (EVs). Consequently, there is growing interest in the use of these factors, rather than whole cells, in regenerative medicine. Typical 2D cultivation of stem cells on tissue culture plastic is far removed from the physiological environment of MSCs. The application of 3D cell culture allows MSCs to adapt to their cellular niche environment which, in turn, influences their paracrine signalling activity. We seek to determine the biological implications of EV production in 3D culture and investigate their anti-fibrotic activity. Methods, Results & Conclusion Bone marrow MSCs were maintained and passaged on tissue culture plastic using DMEM//10% FBS. MSCs were aggregated into 3D spheroids using non-adherent 96-well plates. Both 2D and 3D MSCs were then maintained in serum free media for 4 days. EVs were isolated by ultracentrifugation and characterised on the ExoView platform which allows simultaneous detection of particle size and expression of EV markers CD81/CD63/CD9/CD105. miRNAs were isolated from cell lysates and qRT-PCR was performed to analyse expression of candidate miRNAs. To model the progress of pulmonary fibrosis, human lung fibroblasts (HLFs) were cultured with TGF-β1 to induce fibroblast activation, subsequently exposed to 2D and 3D MSC-EVs, and collagen production by HLF was measured. Further, 2D and 3D MSC-EVs were added into human lung MSCs isolated from healthy and IPF patients and cell proliferation was assessed using MTS assay. The yield and characteristics of EVs derived from bone marrow MSCs were unaffected by 3D culture. The particles showed expression of CD81/CD63/CD9/CD105 and average diameter of

Immunomodulatory benefits of mesenchymal stem cells treated with Caffeine in adjuvant-induced arthritis

PurposeWe intend to assess the effect of the conditioned medium of Caffeine pulsed MSCS in the amelioration of rheumatoid arthritis (RA)-afflicted rats. MethodsMSCs were incubated with 0, 0.1, 0.5 or 1 mM Caffeine for 2 weeks. RA was induced by the injection of complete Freund's adjuvant (CFA) into the base of the tail of Wistar rats. According to in vitro studies, RA rats were intraperitoneally treated with MSCs, Caffeine (0.5 mM) pulsed MSCs or vehicle on day 14 when all rats had shown signs of RA. ResultsOur results suggest that the least effective dose concentration of Caffeine that can induce potent anti-inflammatory property in the MSC population is 0.5 mM. Without any significant impact on the vitality or MScs' marker, Caffeine at this concentration could induce lower levels of IFN-γ, IL-6, and IL-1β and a higher level of IDO, TGF-β, and IL-10 compared to other groups. Therefore, MSCs pulsed with Caffeine at 0.5 mM concentration was selected for in vitro studies. Caffeine pulsed MSCs could reduce the severity of the disease and improve weight-gaining more profoundly than treatment with MSCs alone. Furthermore, Caffeine pulsed MSCs caused a significant reduction in the serum levels C-reactive protein, Nitric oxide, Myeloperoxidase, TNF-α and conversely led a significant increase in the levels of IL-10 more prominent than the similar findings brought about by MSCs alone. ConclusionIn general, caffeine-treated MSCs may be a promising strategy for cell-based therapy of RA.

Effects exerted by mesenchymal stem cells on monocytes obtained from patients with rheumatoid arthritis and progressive systemic sclerosis

In the context of autoimmune inflammatory diseases, the therapeutic benefits of mesenchymal stem cells (MSCs) could be found in their potential to exert immunosuppressive effects and to regulate the immune response. In pursuit of having a more complete look a the regulatory mechanisms performed by AT-MSC, we examined the influence of adipose stem cells (AT-MSC) on blood monocytes from patients with rheumatoid arthritis (RA). Comparison of the effect exerted by the soluble factors produced by AT-MSC vs. cell culture control media, on peripheral blood mononuclear cells (PBMC), showed a significant decrease in the percentage of HLA-DR expressing monocytes, 55.3% (IQR 30-65%) vs. 72% (IQR 62-81%), p = 0.001, as well as a significant decrease in mean fluorescence intensity MFI of HLA-DR was observed, 265 MFI (IQR 102-896 MFI) vs. 473 MFI IQR 160-2201 MFI), p = 0.001. The percentage of CD14 expressing monocytes and CD14 MFI, was increased in PBMC cultured with AT-MSC conditioned media as opposed to control media: 11.7% (IQR 7.6-16.5%) vs. 6.6% (IQR 4.6-11.8%), p = 0.013 and the surface expression density of CD14, 2702 (IQR 1548-3418) vs. 1540 (IQR 1146-2140), p = 0.05. sVEGF-A levels in PBMC cultures from PA patients cultured with conditioned media from AT-MSC were significantly higher than PBMC cultured with control media suppressing secretion of sVEGF-A, 5012 (IQR 2516-5054 pg/ml) vs. 561 pg/ml (IQR 288-699 pg/ml), p = 0.001.

Current understanding of the therapeutic benefits of mesenchymal stem cells in acute respiratory distress syndrome.

The acute respiratory distress syndrome (ARDS) is a multifaceted lung disorder in which no specific therapeutic intervention is able to effectively improve clinical outcomes. Despite an improved understanding of molecular mechanisms and advances in supportive care strategies, ARDS remains associated with high mortality, and survivors usually face long-term morbidity. In recent years, preclinical studies have provided mounting evidence of the potential of mesenchymal stem cell (MSC)-based therapies in lung diseases and critical illnesses. In several models of ARDS, MSCs have been demonstrated to induce anti-inflammatory and anti-apoptotic effects, improve epithelial and endothelial cell recovery, and enhance microbial and alveolar fluid clearance, thus resulting in improved lung and distal organ function and survival. Early-stage clinical trials have also demonstrated the safety of MSC administration in patients with ARDS, but further, large-scale investigations are required to assess the safety and efficacy profile of these therapies. In this review, we summarize the main mechanisms whereby MSCs have been shown to exert therapeutic effects in experimental ARDS. We also highlight questions that need to be further elucidated and barriers that must be overcome in order to efficiently translate MSC research into clinical practice.

Can photobiomodulation associated with implantation of mesenchymal adipose-derived stem cells attenuate the expression of MMPs and decrease degradation of type II collagen in an experimental model of osteoarthritis?

This study aimed to determine whether photobiomodulation therapy (PBMT) could improve the bioavailability and chondroprotective benefits of mesenchymal stem cells injected into the knees of rats used as an experimental model of osteoarthritis (OA) as well as reduce the expression of matrix metalloproteinases (MMPs) and degradation of type II collagen (COL2-1) in the cartilage. Adipose-derived stem/stromal cells (ADSCs) were collected from three male Fischer 344 rats and characterized by flow cytometry. Fifty female Fischer 344 rats were distributed into five groups of 10 animals each. These groups were as follows: control, OA, OA PBMT, OA ADSC, and OA ADSC PBMT. OA was induced in the animals using a 4% papain solution. Animals from the OA ADSC and OA ADSC PBMT groups received an intra-articular injection of 10 × 106 ADSCs and were treated with PBMT by irradiation (wavelength: 808nm, power: 50mW, energy: 42J, energy density: 71.2J/cm2, spot size: 0.028). Euthanasia was performed 7days after the first treatment. The use of PBMT alone and the injection of ADSCs resulted in downregulation of pro-inflammatory cytokines and MPs in cartilage compared to the OA group. PBMT and ADSCs caused upregulation of tissue inhibitors of MPs 1 and 2 and mRNA and protein expression of COL2-1 in cartilage compared to the OA group. The intra-articular injection of ADSCs and PBMT prevented joint degeneration resulting from COL2-1 degradation and modulated inflammation by downregulating cytokines and MMPs in the OA group.

Potential benefits of mesenchymal stem cells and electroacupuncture on the trophic factors associated with neurogenesis in mice with ischemic stroke

The beneficial effects of mesenchymal stem cells (MSCs) and electroacupuncture (EA) on neurogenesis and related trophic factors remain unclear. Bone marrow MSCs (mBMSC) were transplanted into the striatum of mice with middle cerebral artery occlusion (MCAO), and EA stimulation was applied at two acupoints, Baihui and Dazhui. EA treatment significantly improved motor function, and a synergistic effect of combined mBMSC and EA treatment was observed. Combined mBMSC and EA treatment reduced prominent atrophic changes in the striatum and led to proliferation of neural progenitor cells in the subventricular zone (SVZ) and the surrounding areas of the striatum (SVZ + striatum) of MCAO mice. The mBMSC and EA treatment markedly enhanced mature brain-derived neurotrophic factor (mBDNF) expression in the SVZ + striatum and hippocampus of mice with MCAO, and combined treatment enhanced neurotrophin-4 (NT4) expression. The number of mBDNF- and NT4-positive neurons in the SVZ + striatum and hippocampus increased following EA treatment. Combined treatment led to an increase in the expression levels of phosphorylated cAMP response element binding protein in the neuroblasts of the striatum. Our results indicate that combined MSC and EA treatment may lead to a better therapeutic effect via co-regulation of neurotrophic factors in the brain, by regulating neurogenesis more than single therapy.

Nicotine Augments the Beneficial Effects of Mesenchymal Stem Cell-based Therapy in Rat Model of Multiple Sclerosis

ABSTRACTExperimental autoimmune encephalomyelitis (EAE) in rats through immunization with guinea pig spinal cord homogenate (GPSCH) produces a chronic disease with a relapsing pattern such as multiple sclerosis (MS) in humans. In previous studies, the immunomodulatory benefits of mesenchymal stem cells (MSCs) and nicotine have already been determined. Thus, this research was conducted to assess the additional benefits of the combination therapy of MSCs and nicotine in a rat model of MS. EAE was induced by GPSCH and complete Freund’s adjuvant (CFA) in female Wistar rats. The therapies were initiated at day 12 post-immunization (p.i.), when the rats developed a neurological disability score. The symptoms were recorded daily until day 33, when the rats were sacrificed. Finally, the splenocytes were evaluated by Enzyme-linked immunosorbent assay (ELISA) for cytokine production. The therapeutic treatment in the EAE rats with a combination of MSCs and nicotine exhibited a more desirable outcome, causing the regression of the average mean clinical score and neuropathological features to be more favorable than the treatment with either therapy alone. The combination therapy led to a significant reduction in the cumulative disease disability from day 21. For the EAE rats treated with nicotine and MSCs, this period was started from day 22 and 28 p.i., respectively. Besides the increase in the levels of IL-10, the combined therapy significantly reduced the splenocytes production of pro-inflammatory IL-17 as well as TNF-α more profoundly than either of the medications alone. In conclusion, the combination of MSCs and nicotine can be suggested as a promising strategy for further MS therapeutics improvement.

Interleukin-10 secreted by mesenchymal stem cells attenuates acute liver failure through inhibiting pyroptosis.

Recently, the benefit of mesenchymal stem cells (MSCs) as a cell-based therapy for acute liver failure (ALF) has gained much attention, although the mechanism of action of MSCs in the treatment of ALF remains elusive. Pyroptosis is a novel form of programmed cell death with an intense inflammatory response. The aim of the present study was to explore the soluble cytokines secreted by MSCs and their therapeutic effects through inhibiting pyroptosis in ALF. Mesenchymal stem cells obtained from C57BL/6 mice were isolated and cultured according to an established protocol. The MSCs were transplanted into mice with D-galactosamine (D-Gal)-induced ALF. Liver function, survival rate, histology, and inflammatory factors were determined. Exogenous recombinant rat interleukin (IL)-10, ShIL-RNA, and MCC950 (NLRP3 inhibitor) were given to the mice to explore the therapeutic mechanism of MSCs. Statistical analyses were carried out with spss version 19.0, and all data were analyzed by independent-samples t-test. Injection of IL-10 or MSC transplantation ameliorated D-Gal-induced increase in alanine aminotransferase, aspartate aminotransferase, total bilirubin, NH3, and inflammatory cytokines. Blockage of IL-10 confirmed the therapeutic significance of this cytokine. Pyroptosis was inhibited after IL-10 infusion and inhibition of NLRP3 by MCC950 reversed liver dysfunction.

Surfactant effects on the viability and function of human mesenchymal stem cells: in vitro and in vivo assessment

BackgroundSurfactant therapy has become the standard of care for preterm infants with respiratory distress syndrome. Preclinical studies have reported the therapeutic benefits of mesenchymal stem cells (MSCs) in experimental bronchopulmonary dysplasia. This study investigated the effects of a surfactant on the in vitro viability and in vivo function of human MSCs.MethodsThe viability, phenotype, and mitochondrial membrane potential (MMP) of MSCs were assessed through flow cytometry. The in vivo function was assessed after intratracheal injection of human MSCs (1 × 105 cells) diluted in 30 μl of normal saline (NS), 10 μl of a surfactant diluted in 20 μl of NS, and 10 μl of a surfactant and MSCs (1 × 105 cells) diluted in 20 μl of NS in newborn rats on postnatal day 5. The pups were reared in room air (RA) or an oxygen-enriched atmosphere (85% O2) from postnatal days 1 to 14; eight study groups were examined: RA + NS, RA + MSCs, RA + surfactant, RA + surfactant + MSCs, O2 + NS, O2 + MSCs, O2 + surfactant, and O2 + surfactant + MSCs. The lungs were excised for histological and cytokine analysis on postnatal day 14.ResultsCompared with the controls, surfactant-treated MSCs showed significantly reduced viability and MMP after exposure to 1:1 and 1:2 of surfactant:MSCs for 15 and 60 minutes. All human MSC samples exhibited similar percentages of CD markers, regardless of surfactant exposure. The rats reared in hyperoxia and treated with NS exhibited a significantly higher mean linear intercept (MLI) than did those reared in RA and treated with NS, MSCs, surfactant, or surfactant + MSCs. Treatment with MSCs, surfactant, or surfactant + MSCs significantly reduced the hyperoxia-induced increase in MLI. The O2 + surfactant + MSCs group exhibited a significantly higher MLI than did the O2 + MSCs group. Furthermore, treatment with MSCs and MSCs + surfactant significantly reduced the hyperoxia-induced increase in apoptotic cells.ConclusionsCombination therapy involving a surfactant and MSCs does not exert additive effects on lung development in hyperoxia-induced lung injury.

Cell therapy and vocal fold scarring

Vocal fold microstructure is complex and can be affected by laryngeal microsurgery, inducing scarring that prevents mechanical uncoupling of epithelium and muscle, leading to vibration disorder and disabling dysphonia. Treatment options presently are few, and often without efficacy for vibration, having only an impact on volume to reduce glottal closure defect. The present review of the literature had two aims: (i) to report the current state of the literature on cell therapy in vocal fold scarring; and (ii) to analyze the therapeutic interest of the adipose-derived stromal vascular fraction in the existing therapeutic armamentarium. A PubMed® search conducted in September 2016 retrieved English or French-language original articles on the use of stem cells to treat vocal fold scarring. Twenty-seven articles published between 2003 and 2016 met the study selection criteria. Mesenchymal stem cells were most widely used, mainly derived from bone marrow or adipose tissue. Four studies were performed in vitro on fibroblasts, and 18 in vivo on animals. End-points comprised: (i) scar analysis (macro- and micro-scopic morphology, viscoelastic properties, extracellular matrix, fibroblasts); and (ii) assessment of stem cell survival and differentiation. The studies testified to the benefit of mesenchymal stem cells, and especially those of adipose derivation. The stromal vascular fraction exhibits properties that might improve results by facilitating production logistics.

Therapeutic benefit of mesenchymal stem cells in pregnant rats with angiotensin receptor agonistic autoantibody-induced hypertension: Implications for immunomodulation and cytoprotection

ABSTRACTImmunomodulation by mesenchymal stem cells (MSCs) is potentially important for maintaining peripheral tolerance. Preeclampsia may be due to maternal immune rejection of the genetically foreign fetus. This study aimed to investigate the biological function of human umbilical cord–derived mesenchymal stem cells (HU-MSCs) for the treatment of angiotensin receptor agonistic autoantibody (AT1-AA)-induced hypertension during pregnancy. HU-MSCs were isolated, cultured, and labeled in vitro. AT1-AA and HU-MSCs were administered to pregnant rats. Green fluorescent protein (GFP)–positive HU-MSCs infused in vivo were identified by immunofluorescence. Systolic blood pressure (SBP) was evaluated. The effects of HU-MSCs on fetal weight, kidney burden, and spiral artery remodeling, as well as on the expression of tumor necrosis factor α (TNF-α), interleukin 10 (IL-10), and heme oxygenase 1 (HO-1), were investigated. The SBP levels in the HU-MSC-treated pregnant hypertension rats decreased by gestational day 19. The reduction in fetal weight was largely ameliorated after HU-MSC treatment. Lesion burden in the kidney was attenuated and spiral artery remodeling was improved in HU-MSC-treated pregnant hypertension rats. However, green fluorescent protein (GFP)–labeled cells were sparingly observed in the kidney and placenta. Intravenous infusion of HU-MSCs into AT1-AA-induced rats significantly downregulated serum TNF-α levels and upregulated IL-10 levels, concomitant with increased placenta and mesometrial triangle (MT) HO-1 expression. Taken together, intravenous infusion of HU-MSCs ameliorates AT1-AA-induced pregnancy hypertension, intrauterine growth retardation, kidney impairment, and spiral artery remodeling impairment. Moreover, the potential benefits of HU-MSCs may be attributable to both an interference with the pathogenic immune response and a paracrine cytoprotective action.