Mesenchymal Stem Cell-based Therapy Research Articles

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.

Lipocalin 2 enhances mesenchymal stem cell-based cell therapy in acute kidney injury rat model.

Acute kidney injury (AKI) is one of the most common health-threatening diseases in the world. There is still no effective medical treatment for AKI. Recently, Mesenchymal stem cell (MSC)-based therapy has been proposed for treatment of AKI. However, the microenvironment of damaged kidney tissue is not favorable for survival of MSCs which would be used for therapeutic intervention. In this study, we genetically manipulated MSCs to up-regulate lipocalin-2 (Lcn2) and investigated whether the engineered MSCs (MSC-Lcn2) could improve cisplatin-induced AKI in a rat model. Our results revealed that up-regulation of Lcn2 in MSCs efficiently enhanced renal function. MSC Lcn2 up-regulates expression of HGF, IGF, FGF and VEGF growth factors. In addition, they reduced molecular biomarkers of kidney injury such as KIM-1 and Cystatin C, while increased the markers of proximal tubular epithelium such as AQP-1 and CK18 following cisplatin-induced AKI. Overall, here we over-expressed Lcn2, a well-known cytoprotective factor against acute ischemic renal injury, in MSCs. This not only potentiated beneficial roles of MSCs for cell therapy purposes but also suggested a new modality for treatment of AKI.

Mesenchymal Stem Cell-Based Therapies against Podocyte Damage in Diabetic Nephropathy.

Injury to podocytes is an early event in diabetic nephropathy leading to proteinuria with possible progression to end-stage renal failure. The podocytes are unique and highly specialized cells that cover the outer layer of kidney ultra-filtration barrier and play an important role in glomerular function. In the past few decades, adult stem cells, such as mesenchymal stem cells (MSCs) with a regenerative and differentiative capacity have been extensively used in cell-based therapies. In addition to their capability for regeneration and differentiation, MSCs contributes to their milieu by paracrine action of a series of growth factors via antiapoptotic, mitogenic and other cytokine actions that actively participate in treatment of podocyte damage through prevention of podocyte effacement, detachment and apoptosis. It is hoped that novel stem cell-based therapies will be developed in the future to prevent podocyte injury, thereby reducing the burden of kidney disease.

Human menstrual blood-derived mesenchymal stem cells as a cellular vehicle for malignant glioma gene therapy.

Despite many advances in conventional treatment strategies, there is no effective treatment modality for malignant gliomas. Gene therapy may offer a promising option for gliomas and several gene therapy approaches have shown anti-tumor efficiency in previous studies. Mesenchymal stem cell-based gene therapies, in which stem cells are genetically engineered to express therapeutic molecules, have shown tremendous potential because of their innate homing ability. In this study, human menstrual blood-derived MSCs (MenSC), a novel type of multipotential MSCs displays tropism for human malignant glioma when used as a gene delivery vehicle for therapeutics. Secretable trimeric TRAIL (stTRAIL) contains the receptor-binding domain of TRAIL, a death ligand that induces apoptosis in tumor cells. To overexpress stTRAIL, MenSCs were infected with efficient adenoviral serotype 35 vectors that had no influence on its broad multipotency and low immunophenotype. The modified MenSCs served as an excellent local drug delivery system for tumor site-specific targeted delivery and demonstrated therapeutic efficacy in an animal xenografts tumor model of U-87 MG cells. The MenSC-stTRAIL cells induced antitumor effects in vitro by significantly increasing apoptosis (P < 0.05). It also significantly reduced tumor burden in vivo (P < 0.05). The results showed that the proliferation of tumor cells was significantly reduced (P < 0.05). The MenSC, as a cellular delivery vehicle has a wide potential therapeutic role, which includes the treatment of tumors.

307 - Mesenchymal stem cell-based therapies alleviate high-fat diet-induced obesity

307 - Mesenchymal stem cell-based therapies alleviate high-fat diet-induced obesity

Mesenchymal Stem Cell Injections for the Treatment of Perianal Crohn’s Disease: What We Have Accomplished and What We Still Need to Do

Perianal Crohn's disease [CD] is found in a quarter of patients with CD and remains notoriously difficult to treat. Several medical and surgical therapies are available. However, none is particularly effective nor reliably provides sustained remission. In addition, surgical intervention is complicated by poor healing and the potential for incontinence. Mesenchymal stem cell-based therapies provide a promising treatment alternative for perianal CD, with demonstrated safety, improved efficacy, and a decreased side effect profile. Several phase I, II, and now III randomised controlled trials have now reported safety and efficacy in treating perianal CD. The aim of this review is to discusses the outcomes of conventional treatment approaches, outcomes of mesenchymal stem cell therapies, considerations specific to stem cell-based therapies, and future directions for research.

MRI reveals therapeutical efficacy of stem cells: An experimental study on the SOD1(G93A) animal model.

The first part of the experiment identifies and validates MRI biomarkers distinctive of the disease progression in the transgenic superoxide dismutase gene (SOD1(G93A)) animal model. The second part assesses the efficacy of a mesenchymal stem cell-based therapy through the MRI biomarkers previously defined. The first part identifies MRI differences between SOD1(G93A) and healthy mice. The second part of the experiment follows the disease evolution of stem cell-treated and non-stem-cell treated SOD1(G93A) mice. The analysis focused on voxel-based morphometry and T2 mapping on the brain tissues, and T2-weighted imaging and diffusion tensor imaging (DTI) on the hind limbs. Comparing diseased mice to healthy control revealed gray matter alterations in the brainstem area, accompanied by increased T2 relaxation time. Differences in muscle volume, muscle signal intensity, fractional anisotropy, axial diffusivity, and radial diffusivity were measured in the hind limbs. In the comparison between stem cell-treated mice and nontreated ones, differences in muscle volume, muscle signal intensity, and DTI-derived maps were found. MRI-derived biomarkers can be used to identify differences between stem cell-treated and nontreated SOD1(G93A) mice. Magn Reson Med 79:459-469, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

IL-1β impedes the chondrogenic differentiation of synovial fluid mesenchymal stem cells in the human temporomandibular joint.

Mesenchymal stem cell-based therapy has great therapeutic potential for temporomandibular joint (TMJ) cartilage repair. However, the behavior of mesenchymal stem cells in the inflammatory milieu following their delivery remains poorly understood. Synovial fluid-derived mesenchymal stem cells (SFMSCs) are a promising resource for TMJ cartilage repair, as they are easily obtained from patients with TMJ disorders (TMD). In this study, we obtained SFMSCs from patients with TMD and expanded them in vitro; we then stimulated the cells with interleukin (IL)-8, IL-1β, IL-6, IL-10, tumor necrosis factor (TNF)-α and IL-12p. The cells expressed CD90, CD44, CD105 and CD73, and were negative for CD45, CD34, CD11b, CD19 and HLA-DR. They could be induced to differentiate into osteogenic, chondrogenic, adipogenic and neurogenic lineages in vitro. Only the levels of IL-6 and IL-8 were upregulated significantly following stimulation with IL-8, IL-1β, IL-6, IL-10, TNF-α and IL-12p. Furthermore, IL-6 and IL-8 expression was driven mainly by IL-1β-dependent nuclear factor-κB (NF-κB) pathway activation, and was independent of IL-8, IL-6, IL-10, TNF-α and IL-12p. IL-6 and IL-8 expression was inhibited completely by treatment with the NF-κB inhibitor, BAY11-7082. SRY-box 9 (SOX9) was downregulated and matrix metalloproteinase (MMP)13 was upregulated upon chondrogenic differentiation induced in the cells also exposed to IL-1β. Sulfated glycosaminoglycan production was also reduced upon chondrogenic differentiation in the presence of IL-6, but not IL-8. Thus, IL-1β in the inflammatory milieu is crucial in regulating SFMSCs. In doing so, IL-1β impedes the chondrogenic differentiation of SFMSCs. The upregulation of IL-6 and NF-κB pathway activation also contribute to this biological behavior. The findings of our study indicate the potential adverse effects of IL-1β on the chondrogenic differentiation of SFMSCs, and may thus provide new insight into the pathogenesis of TMD.

Emerging role of exosomes in liver physiology and pathology.

Exosomes can mediate intercellular communication by conveying various bioactive molecules. Plentiful evidence suggests that exosomes are involved in many liver diseases including hepatitis C virus infection, hepatitis B virus infection, hepatocellular carcinoma, liver fibrosis, cirrhosis, non-alcoholic fatty liver disease, and alcoholic liver disease. Moreover, exosomes are present in nearly all human body fluids. Therefore, exosomal miRNA or proteins have the potential to be novel biomarkers of liver diseases. In the treatment of liver diseases, exosomes could participate in adaptive immune response and mesenchymal stem cell-based therapy. Exosomes can also be used as vehicles for genetic materials and drug delivery.

Efficacy of umbilical cord-derived mesenchymal stem cell-based therapy for osteonecrosis of the femoral head: A three-year follow-up study.

This is a retrospective analysis of the clinical effects of transplant of mesenchymal stem cells (MSCs) derived from human umbilical cord-derived MSCs (hUC-MSCs) for the treatment of osteonecrosis of the femoral head (ONFH). The biological characteristics of hUC-MSCs were assessed using flow cytometry. Nine eligible patients were enrolled in the study as they adhered to the Association Research Circulation Osseous (ARCO) classification of stage II–IIIa, and hUC-MSCs were grafted by intra-arterial infusion. Organize effective perfusion was assessed using the oxygen delivery index (ODI). The results showed that the ODI was increased at three days post-operation. The MRI results revealed that at 12 and 24 months after treatment, the necrotic volume of the femoral heads was significantly reduced. No obvious abnormalities were observed. Taken together, these data indicate that intra-arterially infused hUC-MSCs migrate into the necrotic field of femoral heads and differentiate into osteoblasts, thus improving the necrosis of femoral heads. This finding suggested that intra-arterial infusion of hUC-MSCs MSCs is a feasible and relatively safe method for the treatment of femoral head necrosis.

Osteoporosis: the current status of mesenchymal stem cell-based therapy.

Osteoporosis, or bone loss, is a progressive, systemic skeletal disease that affects millions of people worldwide. Osteoporosis is generally age related, and it is underdiagnosed because it remains asymptomatic for several years until the development of fractures that confine daily life activities, particularly in elderly people. Most patients with osteoporotic fractures become bedridden and are in a life-threatening state. The consequences of fracture can be devastating, leading to substantial morbidity and mortality of the patients. The normal physiologic process of bone remodeling involves a balance between bone resorption and bone formation during early adulthood. In osteoporosis, this process becomes imbalanced, resulting in gradual losses of bone mass and density due to enhanced bone resorption and/or inadequate bone formation. Several growth factors underlying age-related osteoporosis and their signaling pathways have been identified, such as osteoprotegerin (OPG)/receptor activator of nuclear factor B (RANK)/RANK ligand (RANKL), bone morphogenetic protein (BMP), wingless-type MMTV integration site family (Wnt) proteins and signaling through parathyroid hormone receptors. In addition, the pathogenesis of osteoporosis has been connected to genetics. The current treatment of osteoporosis predominantly consists of antiresorptive and anabolic agents; however, the serious adverse effects of using these drugs are of concern. Cell-based replacement therapy via the use of mesenchymal stem cells (MSCs) may become one of the strategies for osteoporosis treatment in the future.

Therapeutic effects of umbilical cord blood derived mesenchymal stem cell-conditioned medium on pulmonary arterial hypertension in rats

IntroductionHuman umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) may have multiple therapeutic applications cell based therapy with one being for treatment of pulmonary artery hypertension. As low survival rates and potential tumorigenicity of implanted cells could undermine the mesenchymal stem cell-based therapy, we chose to investigate the use of conditioned medium (CM) from a culture of MSC cells. Material and methodsCM was prepared by culturing hUCB-MSCs in three-dimensional spheroids. In a rat model of PAH induced by monocrotaline, we infused CM or the control unconditioned culture media via tail-vein of 6-week-old Sprague-Dawley rats. ResultsCompared with the control unconditioned media, CM infusion reduced the ventricular pressure, the right ventricle/(left ventricle+interventricular septum) ratio, and maintained respiratory function in the treated animals. Also the number of IL-1α, CCL5 and TIMP-1-positive cells increased in lung samples and the number of TUNEL-positive cells decreased significantly in the CM treated animals. DiscussionFrom our in vivo data in the rat model, the observed decreases in the TUNEL staining point to a potential therapeutic benefit of the CM in ameliorating PAH-mediated lung tissue damage. Increased IL-1α, CCL5 and TIMP-1 levels may play important roles in this regard.

Mesenchymal stem cell-based gene therapy for erectile dysfunction.

Despite the overwhelming success of PDE5 inhibitor (PDE5I), the demand for novel pharmacotherapeutic and surgical options for ED continues to rise owing to the increased proportion of elderly individuals in the population, in addition to the growing percentage of ED patients who do not respond to PDE5I. Surgical treatment of ED is associated with many complications, thus warranting the need for nonsurgical therapies. Moreover, none of the above-mentioned treatments essentially corrects, cures or prevents ED. Although gene therapy is a promising option, many challenges and obstacles such as local inflammatory response and random transgene expression, in addition to other safety issues, limit its use at the clinical level. The use of stem cell therapy alone also has many shortcomings. To overcome these inadequacies, many scientists and clinicians are investigating new gene and stem cell therapies.

Mesenchymal stem cell-based therapy in kidney transplantation

Kidney transplantation is the best treatment for end-stage renal disease, but its implementation is limited by organ shortage and immune rejection. Side effects of current immunosuppressive drugs, such as nephrotoxicity, opportunistic infection, and tumorigenic potential, influence long-term graft outcomes. In recent years, continued research and subsequent discoveries concerning the properties and potential utilization of mesenchymal stem cells (MSCs) have aroused considerable interest and expectations. Biological characteristics of MSCs, including multi-lineage differentiation, homing potential, paracrine effect and immunomodulation, have opened new horizons for applications in kidney transplantation. However, many studies have shown that the biological activity of MSCs depends on internal inflammatory conditions, and the safety and efficacy of the clinical application of MSCs remain controversial. This review summarizes the findings of a large number of studies and aims to provide an objective viewpoint based on a comprehensive analysis of the presently established benefits and obstacles of implementing MSC-based therapy in kidney transplantation, and to promote its clinical translation.

Transplantation of Mesenchymal Stem Cells Enhances Angiogenesis after Ischemic Limb Injury in Mice

Mesenchymal stem cell-based therapy has emerged as a promising approach for the treatment of peripheral arterial disease. This study was designed to examine the potential effects of human placenta-derived mesenchymal stem cells (PMSCs) on treatment of mouse hindlimb ischemia. PMSCs were isolated from human placenta tissue and characterized by flow cytometry. An in vivo surgical ligation-induced mouse limb ischemia model was generated with fluorescent dye (CM-DiI) labelled PMSCs delivered via intramuscular injection. Our data show that PMSCs treatment significantly enhanced microvessel density, improved blood perfusion and diminished pathologies in ischemic mouse hindlimbs as compared to those in the control group. Further immunostaining studies suggested that injected PMSCs can incorporate into the vasculature and differentiate into endothelial and smooth muscle cells to enhance angiogenesis in ischemic hind limbs. This may in part explain the beneficial effects of PMSCs treatment. Taken together, we found that PMSCs treatment might be an effective treatment modality for treatment of ischemia-induced injury to mouse hind limbs by enhancement of angiogenesis.

Resveratrol augments therapeutic efficiency of mouse bone marrow mesenchymal stem cell-based therapy in experimental autoimmune encephalomyelitis

Experimental autoimmune encephalitis (EAE) is an inflammatory demyelinating disease, which served as a useful model providing considerable insights into the pathogenesis of multiple sclerosis (MS). Mouse bone marrow mesenchymal stem cells (mBM-MSC) were shown to have neuroprotection capabilities in EAE. Resveratrol is a small polyphenolic compound and possess therapeutic activity in various immune-mediated diseases. The sensitivity of mBM-MSCs to resveratrol was determined by an established cell-viability assay. Resveratrol-treated mBM-MSCs were also characterized with flow cytometry using MSC-specific surface markers and analyzed for their multiple differentiation capacities. EAE was induced in C57BL/6 mice by immunization with MOG35-55. Interferon gamma (IFN-γ)/tumor necrosis factor alpha (TNF-α) and interleukin-4 (IL-4)/interleukin-10 (IL-10), the hallmark cytokines that direct T helper type 1 (Th1) and Th2 development, were detected with enzyme-linked immunosorbent assay (ELISA). In vivo efficacy experiments showed that mBM-MSCs or resveratrol alone led to a significant reduction in clinical scores, and combined treatment resulted in even more prominent reduction. The combined treatment with mBM-MSCs and resveratrol enhanced the immunomodulatory effects, showing suppressed proinflammatory cytokines (IFN-γ, TNF-α) and increased anti-inflammatory cytokines (IL-4, IL-10). The combination of mBM-MSCs and resveratrol provides a novel potential experimental protocol for alleviating EAE symptoms.

Umbilical Cord as Prospective Source for Mesenchymal Stem Cell-Based Therapy.

The paper presents current evidence on the properties of human umbilical cord-derived mesenchymal stem cells, including origin, proliferative potential, plasticity, stability of karyotype and phenotype, transcriptome, secretome, and immunomodulatory activity. A review of preclinical studies and clinical trials using this cell type is performed. Prospects for the use of mesenchymal stem cells, derived from the umbilical cord, in cell transplantation are associated with the need for specialized biobanking and transplant standardization criteria.