Mesenchymal Stem Cell-based Therapy Research Articles

Mesenchymal Stem Cell-Based Therapy of Inflammatory Lung Diseases: Current Understanding and Future Perspectives.

During acute or chronic lung injury, inappropriate immune response and/or aberrant repair process causes irreversible damage in lung tissue and most usually results in the development of fibrosis followed by decline in lung function. Inhaled corticosteroids and other anti-inflammatory drugs are very effective in patients with inflammatory lung disorders, but their long-term use is associated with severe side effects. Accordingly, new therapeutic agents that will attenuate ongoing inflammation and, at the same time, promote regeneration of injured alveolar epithelial cells are urgently needed. Mesenchymal stem cells (MSCs) are able to modulate proliferation, activation, and effector function of all immune cells that play an important role in the pathogenesis of acute and chronic inflammatory lung diseases. In addition to the suppression of lung-infiltrated immune cells, MSCs have potential to differentiate into alveolar epithelial cells in vitro and, accordingly, represent new players in cell-based therapy of inflammatory lung disorders. In this review article, we described molecular mechanisms involved in MSC-based therapy of acute and chronic pulmonary diseases and emphasized current knowledge and future perspectives related to the therapeutic application of MSCs in patients suffering from acute respiratory distress syndrome, pneumonia, asthma, chronic obstructive pulmonary diseases, and idiopathic pulmonary fibrosis.

Immunoregulatory properties of I.A. mesenchymal stem cells are maintained in a xenogenic animal model

Purpose: Osteoarthritis is a chronic joint disease afflicting a significant portion of the world’s population with no currently available cure. Clinical trials using mesenchymal stem cell-based therapies have a positive effect on pain and quality of life in osteoarthritis but the mechanism of action remains unclear. This study aimed to identify the lymphocyte response to a xenogeneic human umbilical cord-derived MSC-based cell therapy in the face of osteoarthritis progression. Methods: A unilateral medial meniscal release model was employed in 14 sheep to create OA where n=7 sheep received I.A. cell therapy (OACT) in the operated knee and n=7 received saline as controls (OA). Another unoperated group (n=7) received cell therapy (CT Control). Three months later IA cell therapy consisting of 1.0× 107 Human SHC-MSCs* (Small Mesenchymal Stem Cells primed with Hypoxia and Calcium ions) was administered into the medial knee joint space. Synovial fluid was aspirated periodically for 13 weeks for flow cytometry analysis. At termination of the study, the stifle joints underwent macroscopic and histologic assessments using the OARSI histology scoring system for subchondral bone, cartilage and synovial membrane. Flow cytometry data was analyzed with a linear mixed effects model while pathology scores were analyzed by the Mann-Whitney U test and Wilcoxon signed rank test, with the Bonferroni correction for multiple comparisons. Results: There were no adverse reactions to the I.A. therapy. Cell therapy administration induced an influx of CD4+ leukocytes (Fig 1). Of these there was a significant increase in the proportion of CD4+CD25+ and CD4+CD25hi leukocytes; the CD4+CD25hi being subset that may be composed of regulatory T cells. There was no significant effect of the cell therapy treatment on the proportion of synovial fluid CD8+ cells or B cells (BAQ44A+), and B cells occurred in small numbers. Conclusions: Xenogeneic cell therapy did not trigger a classical host versus graft reaction leading to tissue injury. Cell therapy induced chemotaxis of CD4+ cells to the joint space but this was not associated with pathological change in tissues. Despite expression of activation markers (CD25+) these cells may regulate the immune response since CD4+cells can be sources of anti-inflammatory cytokines such as IL-4 and IL-10, as well as inhibiting the release of pro-inflammatory cytokines such as IL-1β or TNF-α. These findings support the notion that phenomena unrelated to long-term survival and engraftment of injected cells may have clear immunoregulatory effects.

A Rat Model of Radiation Vasculitis for the Study of Mesenchymal Stem Cell-Based Therapy.

Radiation vasculitis is one of the most common detrimental effects of radiotherapy for malignant tumors. This is developed at the vasculature of adjacent organs. Animal experiments have showed that transplantation of mesenchymal stem cells (MSCs) restores vascular function after irradiation. But the population of MSCs being engrafted into irradiated vessels is too low in the conventional models to make assessment of therapeutic effect difficult. This is presumably because circulating MSCs are dispersed in adjacent tissues being irradiated simultaneously. Based on the assumption, a rat model, namely, RT (radiation) plus TX (transplantation), was established to promote MSC homing by sequestering irradiated vessels. In this model, a 1.5 cm long segment of rat abdominal aorta was irradiated by 160kV X-ray at a single dose of 35Gy before being procured and grafted to the healthy counterpart. F344 inbred rats served as both donors and recipients to exclude the possibility of immune rejection. A lead shield was used to confine X-ray delivery to a 3 cm×3 cm square-shaped field covering central abdominal region. The abdominal viscera especially small bowel and colon were protected from irradiation by being pushed off the central abdominal cavity. Typical radiation-induced vasculopathy was present on the 90th day after irradiation. The recruitment of intravenously injected MSCs to irradiated aorta was significantly improved by using the RT-plus-TX model as compared to the model with irradiation only. Generally, the RT-plus-Tx model promotes MSC recruitment to irradiated aorta by separating irradiated vascular segment from adjacent tissue. Thus, the model is preferred in the study of MSC-based therapy for radiation vasculitis when the evaluation of MSC homing is demanding.

Characteristics of Intestinal Microecology during Mesenchymal Stem Cell-Based Therapy for Mouse Acute Liver Injury.

Background The mechanisms of mesenchymal stem cell (MSC) transplantation to protect against acute liver injury have been well studied within the liver. However, the associated changes in the intestinal microbiota during this process are poorly understood. Methods In this study, compact bone-derived MSCs were injected into mice after carbon tetrachloride (CCl4) administration. Potential curative effect of MSC was evaluated by survival rate and biochemical and pathological results. Overall structural changes of microbial communities and alterations in the intestinal microbiota were assessed by sequenced 16S rRNA amplicon libraries from the contents of the cecum and colon. Results MSCs significantly reduced the serum levels of aspartate transaminase and alanine transaminase and improved the histopathology and survival rate. Lower expression and discontinuous staining of zonula occludens, as well as disrupted tight junctions, were observed in CCl4-treated mice at 48 h compared with MSC-transplanted mice. Moreover, MSC transplantation to the liver leads to intestinal microbiota changes that were reflected in the decreased abundance of Bacteroidetes S24-7 and Bacteroidaceae and increased abundance of Firmicutes Clostridiales, Ruminococcaceae, and Lactobacillus at the initial time point compared with that in CCl4-treated mice. In addition, phylogenetic investigation of communities by the reconstruction of unobserved states (PICRUSt) based on the Greengenes database revealed functional biomarkers of MSC-transplanted mice involved in cell motility, signal transduction, membrane transport, transcription, and metabolism of lipids, cofactors, vitamins, terpenoids, and polyketides, as well as xenobiotics. Conclusion The initial alterations in the Firmicutes/Bacteroidetes ratio, which resulted from MSC infusion to the liver, maintain intestinal mucosal biology and homeostasis that may be beneficial to liver repair.

Mesenchymal stem cell-based therapy for autoimmune diseases: emerging roles of extracellular vesicles

In autoimmune disease body's own immune system knows healthy cells as undesired and foreign cells. Over 80 types of autoimmune diseases have been recognized. Currently, at clinical practice, treatment strategies for autoimmune disorders are based on relieving symptoms and preventing difficulties. In other words, there is no effective and useful therapy up to now. It has been well-known that mesenchymal stem cells (MSCs) possess immunomodulatory effects. This strongly suggests that MSCs might be as a novel modality for treatment of autoimmune diseases. Supporting this notion a few preclinical and clinical studies indicate that MSCs ameliorate autoimmune disorders. Interestingly, it has been found that the beneficial effects of MSCs in autoimmune disorders are not relying only on direct cell-to-cell communication but on their capability to produce a broad range of paracrine factors including growth factors, cytokines and extracellular vehicles (EVs). EVs are multi-signal messengers that play a serious role in intercellular signaling through carrying cargo such as mRNA, miRNA, and proteins. Numerous studies have shown that MSC-derived EVs are able to mimic the effects of the cell of origin on immune cells. In this review, we discuss the current studies dealing with MSC-based therapies in autoimmune diseases and provide a vision and highlight in order to introduce MSC-derived EVs as an alternative and emerging modality for autoimmune disorders.

Autologous mesenchymal stem cell-based cellular therapy impacts peripheral blood immunocompetent cells’ content in patients with symptomatic epilepsy

Autologous mesenchymal stem cell-based cellular therapy impacts peripheral blood immunocompetent cells’ content in patients with symptomatic epilepsy

Pre-Clinical Assessment of Mesenchymal Stem Cell-Based Therapies in Spinocerebellar Ataxia Type 3

Motor uncoordination is one of the symptoms of spinocerebellar ataxia type 3/ Machado-Joseph disease (MJD), for which there is no effective treatment. In recent years, stem-cell related therapies begun to be explored for the treatment of neurodegenerative diseases. Beyond their potential for cell replacement therapies, stem cells also act as immunomodulators and neuroprotectors. Despite the evidence of beneficial outcomes in this context, the short duration of the pre and clinical trials and the fact that most patients regressed to the disease stage prior to treatment, highlights the urgency to assess therapeutic efficacy in a chronic fashion. The purpose of this study was to compare the therapeutic efficacy of hMSC transplantation versus administration of their secretome in different disease-relevant regions of the CNS, using a mouse model of MJD. We observed a more marked and sustained therapeutic benefit with hMSC transplantation into the cerebellum when compared to substantia nigra/ striatum or the spinal cord, or to administration of MSC secretome. Funding Statement: This work has been funded the National Ataxia Foundation (NAF), by FEDER, through the Competitiveness Factors Operational Programme (COMPETE), project NORTE-01-0145-FEDER-000013, supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, and by National funds through the Foundation for Science and Technology (FCT) under the scope of the project UID/Multi/50026/2019 and fellowships to A.N-C., B. M-P., J. S. C., F. G. T., N. S., R. L., and S. D-S. (SFRH/BPD/118779/2016, SFRH/BD/120124/2016, SFRH/BD/140624/2018, SFRH/BPD/118408/2016, CEECIND/04794/2017, PD/BDE/127836/2016 and PTDC/NEUNMC/3648/2014). Declaration of Interests: The authors have no conflict of interests to report. Ethics Approval Statement: All procedures were conducted in accordance with European regulations (European Union Directive 86/609/EEC). Animal facilities and the people directly involved in animal experiments (A.N.C, B.M.P, J.S.C., S.D.S, S.M., F.G.T, F.L., R.L., N.A.S) as well as the principal investigators (A.J.S. and P.M.) were certified by the Portuguese regulatory entity Direcao Geral de Alimentacao e Veterinaria. All the protocols performed were approved by the Animal Ethics Committee of the Life and Health Sciences Research Institute, University of Minho (Braga, Portugal) and by the national regulatory agency, Direcao Geral de Alimentacao e Veterinaria (DGAV 020317).

Histone deacetylase inhibitor panobinostat potentiates the anti-cancer effects of mesenchymal stem cell-based sTRAIL gene therapy against malignant glioma

Human adipose tissue-derived mesenchymal stem cells expressing the secreted form of the tumor necrosis factor-related apoptosis-inducing ligand (hAT-MSC.sTRAIL) have demonstrated therapeutic activity against various tumors in preclinical studies. However, the limited expression of TRAIL death receptors remains a challenge. We evaluated the therapeutic efficacy of panobinostat in enhancing the sensitivity of hAT-MSC.sTRAIL-mediated apoptosis in malignant glioma. Panobinostat effectively inhibited all malignant glioma cells (IC50, 0.03–0.23 μM), enhancing the expression of DRs, but not in hAT-MSCs. Combined treatment with hAT-MSC.sTRAIL and panobinostat significantly suppressed cell viability and enhanced apoptosis. In a diffuse intrinsic pontine glioma (DIPG) mouse model, the combined treatment induced decreases in tumor volume and prolonged survival. Our study demonstrates that panobinostat enhances the expression of TRAIL DRs and potentiates the anti-cancer effects of hAT-MSC.sTRAIL.

Hydrogel from Acellular Porcine Adipose Tissue Accelerates Wound Healing by Inducing Intradermal Adipocyte Regeneration

As an important component of the skin, intradermal adipocytes are closely associated with skin homeostasis and wound healing. Although studies have focused on the role of fibroblasts, keratinocytes, and inflammatory cells in wound healing, the role of adipocytes has not been fully investigated. Here, we verified whether the induction of adipocyte regeneration in a wound bed can effectively promote wound healing, finding that the hydrogel from acellular porcine adipose tissue in combination with adipose-derived stem cells can induce in situ adipogenesis in the wound microenvironment. The newly regenerated adipocytes enhanced fibroblast migration, accelerated wound closing, and enhanced wound epithelialization. More importantly, newly formed intact skin structure was observed after treating the wound with adipose-derived stem cell-loaded hydrogel from acellular porcine adipose tissue. These results show that hydrogel from acellular porcine adipose tissue might substantially improve re-epithelialization, angiogenesis, and skin-appendage regeneration, making it a promising therapeutic biomaterial for skin wound healing.

Systemic Injection of Substance P Promotes Murine Calvarial Repair Through Mobilizing Endogenous Mesenchymal Stem Cells

Craniofacial defect is a critical problem in dental clinic, which has a tremendous impact on patients’ quality of life. Mesenchymal stem cell-based therapy has emerged as a promising approach for tissue defect repair. However, reduced survival after mesenchymal stem cells (MSCs) transplantation remains as a major problem in this area, which hampers the outcome of regeneration. Recently, the mechanism to mobilize endogenous MSCs for tissue regeneration has received increasing attentions, as it does not require exogenous cell transplantation. The primary goal of this study was to confirm the role of intravenous substance P in mobilizing endogenous CD45−CD11b−CD29+ MSCs in critical-sized bone defect animals and to investigate the effects of substance P on calvarial bone repair. Flow cytometry analyses revealed that intravenous substance P promoted the mobilization of endogenous CD45−CD11b−CD29+ MSCs after bone defect. In addition, Micro-CT showed that intravenous substance P improved the outcomes of calvarial bone repair. Furthermore, we discovered that systemic injection of substance P attenuated inflammation and enhanced the survival of the local-transplanted GFP+ MSCs. Our findings suggested that substance P together with its mobilized CD45−CD11b−CD29+ MSCs helped improve calvarial defect repair through regulating inflammatory conditions and promoting the survival of local-transplanted cells.

Chronic Niche Inflammation in Endometriosis-Associated Infertility: Current Understanding and Future Therapeutic Strategies.

Endometriosis is an estrogen-dependent inflammatory disease that affects up to 10% of women of reproductive age and accounts for up to 50% of female infertility cases. It has been highly associated with poorer outcomes of assisted reproductive technology (ART), including decreased oocyte retrieval, lower implantation, and pregnancy rates. A better understanding of the pathogenesis of endometriosis-associated infertility is crucial for improving infertility treatment outcomes. Current theories regarding how endometriosis reduces fertility include anatomical distortion, ovulatory dysfunction, and niche inflammation-associated peritoneal or implantation defects. This review will survey the latest evidence on the role of inflammatory niche in the peritoneal cavity, ovaries, and uterus of endometriosis patients. Nonhormone treatment strategies that target these inflammation processes are also included. Furthermore, mesenchymal stem cell-based therapies are highlighted for potential endometriosis treatment because of their immunomodulatory effects and tropism toward inflamed lesion foci. Potential applications of stem cell therapy in treatment of endometriosis-associated infertility in particular for safety and efficacy are discussed.

Critical Role of Tumor Necrosis Factor Signaling in Mesenchymal Stem Cell-Based Therapy for Autoimmune and Inflammatory Diseases.

Mesenchymal stem cells (MSCs) have been broadly used as a therapy for autoimmune disease in both animal models and clinical trials. MSCs inhibit T effector cells and many other immune cells, while activating regulatory T cells, thus reducing the production of pro-inflammatory cytokines, including tumor necrosis factor (TNF), and repressing inflammation. TNF can modify the MSC effects via two TNF receptors, i.e., TNFR1 in general mediates pro-inflammatory effects and TNFR2 mediates anti-inflammatory effects. In the central nervous system, TNF signaling plays a dual role, which enhances inflammation via TNFR1 on immune cells while providing cytoprotection via TNFR2 on neural cells. In addition, the soluble form of TNFR1 and membrane-bound TNF also participate in the regulation to fine-tune the functions of target cells. Other factors that impact TNF signaling and MSC functions include the gender of the host, disease course, cytokine concentrations, and the length of treatment time. This review will introduce the fascinating progress in this aspect of research and discuss remaining questions and future perspectives.

Mesenchymal Stem Cell-Based Therapy for Cardiovascular Disease: Progress and Challenges.

Administration of mesenchymal stem cells (MSCs) to diseased hearts improves cardiac function and reduces scar size. These effects occur via the stimulation of endogenous repair mechanisms, including regulation of immune responses, tissue perfusion, inhibition of fibrosis, and proliferation of resident cardiac cells, although rare events of transdifferentiation into cardiomyocytes and vascular components are also described in animal models. While these improvements demonstrate the potential of stem cell therapy, the goal of full cardiac recovery has yet to be realized in either preclinical or clinical studies. To reach this goal, novel cell-based therapeutic approaches are needed. Ongoing studies include cell combinations, incorporation of MSCs into biomaterials, or pre-conditioning or genetic manipulation of MSCs to boost their release of paracrine factors, such as exosomes, growth factors, microRNAs, etc. All of these approaches can augment therapeutic efficacy. Further study of the optimal route of administration, the correct dose, the best cell population(s), and timing for treatment are parameters that still need to be addressed in order to achieve the goal of complete cardiac regeneration. Despite significant progress, many challenges remain.

Cell therapy-processing economics: small-scale microfactories as a stepping stone toward large-scale macrofactories.

Manufacturing methods for cell-based therapies differ markedly from those established for noncellular pharmaceuticals and biologics. Attempts to 'shoehorn' these into existing frameworks have yielded poor outcomes. Some excellent clinical results have been realized, yet emergence of a 'blockbuster' cell-based therapy has so far proved elusive. The pressure to provide these innovative therapies, even at a smaller scale, remains. In this process, economics research paper, we utilize cell expansion research data combined with operational cost modeling in a case study to demonstrate the alternative ways in which a novel mesenchymal stem cell-based therapy could be provided at small scale. This research outlines the feasibility of cell microfactories but highlighted that there is a strong pressure to automate processes and split the quality control cost-burden over larger production batches. The study explores one potential paradigm of cell-based therapy provisioning as a potential exemplar on which to base manufacturing strategy.

Ex vivo allotransplantation engineering: Delivery of mesenchymal stem cells prolongs rejection-free allograft survival.

Current pharmacologic regimens in transplantation prevent allograft rejection through systemic recipient immunosuppression but are associated with severe morbidity and mortality. The ultimate goal of transplantation is the prevention of allograft rejection while maintaining recipient immunocompetence. We hypothesized that allografts could be engineered ex vivo (after allotransplant procurement but before transplantation) by using mesenchymal stem cell-based therapy to generate localized immunomodulation without affecting systemic recipient immunocompetence. To this end, we evaluated the therapeutic efficacy of bone marrow-derived mesenchymal stem cells in vitro and activated them toward an immunomodulatory fate by priming in inflammatory or hypoxic microenvironments. Using an established rat hindlimb model for allotransplantation, we were able to significantly prolong rejection-free allograft survival with a single perioperative ex vivo infusion of bone marrow-derived mesenchymal stem cells through the allograft vasculature, in the absence of long-term pharmacologic immunosuppression. Critically, transplanted rats rejected a second, nonengineered skin graft from the same donor species to the contralateral limb at a later date, demonstrating that recipient systemic immunocompetence remained intact. This study represents a novel approach in transplant immunology and highlights the significant therapeutic opportunity of the ex vivo period in transplant engineering.

Mesenchymal Stem Cell-Based Therapy Improves Lower Limb Movement After Spinal Cord Ischemia in Rats

Spinal cord ischemia is a devastating complication after thoracic and thoracoabdominal aortic operations. In this study, we aimed to investigate the effects of mesenchymal stem cells (MSCs), which have regenerative capability and exert paracrine actions on damaged tissues, injected into rat models of spinal cord ischemia-reperfusion injury. Forty-five Sprague-Dawley rats were divided into sham, phosphate-buffered saline (PBS), and MSC groups. Spinal cord ischemia was induced in the latter two groups by balloon occlusion of the thoracic aorta. MSCs and PBS were then immediately injected into the left carotid artery of the MSC and PBS groups, respectively. Hindlimb motor function was evaluated at 6 and 24 hours. The spinal cord was removed at 24 hours after ischemia-reperfusion injury, and histologic and immunohistochemical analyses and real-time polymerase chain reaction assessments were performed. Rats in the MSC and PBS groups showed flaccid paraparesis/paraplegia postoperatively. Hindlimb function was significantly better at 6 and 24 hours after ischemia-reperfusion injury in the MSC group than in the PBS group (p < 0.05). The number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive neuron cells in the spinal cord and the ratio of Bax to Bcl2 were significantly larger (p < 0.05) in the PBS group than in the MSC group. The injected MSCs were observed in the spinal cord 24 hours after ischemia-reperfusion injury. The MSC therapy by transarterial injection immediately after spinal cord ischemia-reperfusion injury may improve lower limb function by preventing apoptosis of neuron cells in the spinal cord.

Mesenchymal Stem Cell-based Therapy

Mesenchymal Stem Cell-based Therapy

Graphene oxide cellular patches for mesenchymal stem cell-based cancer therapy

Graphene oxide (GO) is a versatile platform for drug delivery, but poor accumulation at the tumor site limits the translation of this technology. Mesenchymal stem cells (MSC) on the other hand is tumor trophic but is limited to delivering only protein-based drugs. Our solution is to combine the individual attributes of GO and MSC by loading GO on the surface of MSC to create a unique drug delivery platform wherein, GO can be used to load a range of therapeutics and MSC can carry the drug effectively to the site of the tumor. Here, we demonstrated that GO can be loaded with two types of chemo drugs, doxorubicin and mitoxantrone, with similar efficiency (>30%). The drug-GO complex was loaded on MSC without affecting the MSC viability significantly. On exposure to GO-mitoxantrone, 87% of MSC survived while only 28% of the cancer cells (LN18) survived, demonstrating the selective killing of the cancer cells but not MSC. Furthermore, drug-GO loading did not affect the tumor trophic property of MSC, and co-culture of the drug-GO loaded MSC with LN18 showed a dose-dependent killing of LN18. Together, these results show the feasibility of using drug-GO loaded MSC as an effective carrier for cancer therapy.

Molecular and Cellular Mechanisms Involved in Mesenchymal Stem Cell-Based Therapy of Inflammatory Bowel Diseases.

Mesenchymal stem cells (MSCs) are promising resource for the therapy of inflammatory bowel diseases (IBDs) on the grounds of their differentiation capabilities and immuno-modulatory characteristics. Results of clinical studies indicate that local application of MSCs is a secure and beneficial approach for the treatment of perianal fistulas while systemic application of MSCs leads to the attenuation or aggravation of IBDs. Herein, we emphasized molecular mechanisms and approaches that should improve efficacy of MSC-based therapy of IBDs.

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.