MK2206 and U0126 synergistically inhibit proliferation of deep endometriotic stromal cells and autophagy inhibition enhances the therapeutic effects of the combination therapy in vitro

2016 ◽  
Author(s):  
Sachiko Matsuzaki
Keyword(s):  
Combination Therapy ◽  
Stromal Cells ◽  
Therapeutic Effects ◽  
Autophagy Inhibition

scholarly journals Suppression of Autophagy Sensitizes Osteosarcoma to mTOR Inhibition

2020 ◽  
Author(s):  
Ke Zeng ◽  
Lei Jin ◽  
Xiao Yang ◽  
Zhengjie Yang ◽  
Guoxin Zhu
Keyword(s):  
Combination Therapy ◽  
Colony Formation ◽  
Resistance Mechanism ◽  
Osteosarcoma Cell ◽  
Osteosarcoma Cells ◽  
Mtor Inhibition ◽  
Major Health Problem ◽  
Induced Apoptosis ◽  
Autophagy Inhibition

Abstract Aim Osteosarcoma is some major health problem. We intended to investigate the role of Rapamycin and autophagy inhibition in the treatment of osteosarcoma. Method We conducted a series of in vitro studies using two osteosarcoma cell lines. Using genetic and pharmaceutical interventions we studied whether combined autophagy inhibition could sensitize osteosarcoma sales to a Rapamycin treatment. Proliferation, innovation, migration, and colony formation assays were performed. Results Osteosarcoma cells had low basal autophagy levels. Inhibition of mTOR only demonstrated moderate effects but induced increased autophagy levels, indicating possible resistance mechanism. Inhibition of both autophagy and mTOR axis synergistically inhibited proliferation, migration, invasion, and colony formation of osteosarcoma cells. The combination therapy induced apoptosis, which could be restored in part by NEC1. Conclusion Increased autophagy level was responsible for compromised effect of mTOR inhibition in osteosarcoma. Combination therapy using rapamycin and chloroquine held promise to the development of novel mortality.

scholarly journals BMP Antagonists Secreted by Mesenchymal Stromal Cells Improve Colonic Organoid Formation: Application for the Treatment of Radiation-induced Injury

2020 ◽  
Vol 29 ◽  
pp. 096368972092968
Author(s):  
Lara Moussa ◽  
Alexia Lapière ◽  
Claire Squiban ◽  
Christelle Demarquay ◽  
Fabien Milliat ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Radiation Effects ◽  
Fluorescent Protein ◽  
Therapeutic Benefit ◽  
Therapeutic Effects ◽  
Gastrointestinal Complications

Radiation therapy is crucial in the therapeutic arsenal to cure cancers; however, non-neoplastic tissues around an abdominopelvic tumor can be damaged by ionizing radiation. In particular, the radio-induced death of highly proliferative stem/progenitor cells of the colonic mucosa could induce severe ulcers. The importance of sequelae for patients with gastrointestinal complications after radiotherapy and the absence of satisfactory management has opened the field to the testing of innovative treatments. The aim of this study was to use adult epithelial cells from the colon, to reduce colonic injuries in an animal model reproducing radiation damage observed in patients. We demonstrated that transplanted in vitro-amplified epithelial cells from colonic organoids (ECO) of C57/Bl6 mice expressing green fluorescent protein implant, proliferate, and differentiate in irradiated mucosa and reduce ulcer size. To improve the therapeutic benefit of ECO-based treatment with clinical translatability, we performed co-injection of ECO with mesenchymal stromal cells (MSCs), cells involved in niche function and widely used in clinical trials. We observed in vivo an improvement of the therapeutic benefit and in vitro analysis highlighted that co-culture of MSCs with ECO increases the number, proliferation, and size of colonic organoids. We also demonstrated, using gene expression analysis and siRNA inhibition, the involvement of bone morphogenetic protein antagonists in MSC-induced organoid formation. This study provides evidence of the potential of ECO to limit late radiation effects on the colon and opens perspectives on combined strategies to improve their amplification abilities and therapeutic effects.

scholarly journals Increased In Vitro Intercellular Barrier Function of Lung Epithelial Cells Using Adipose-Derived Mesenchymal Stem/Stromal Cells

Pharmaceutics ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1264
Author(s):  
Mitsutoshi Ishii ◽  
Tomoshi Tsuchiya ◽  
Ryoichiro Doi ◽  
Yoichi Morofuji ◽  
Takashi Fujimoto ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Stromal Cells ◽  
Barrier Function ◽  
Lung Epithelial Cells ◽  
Gene Profiling ◽  
Cell Junctions ◽  
Cell Junction ◽  
Therapeutic Effects ◽  
Lung Epithelial

With the emergence of coronavirus disease-2019, researchers have gained interest in the therapeutic efficacy of mesenchymal stem/stromal cells (MSCs) in acute respiratory distress syndrome; however, the mechanisms of the therapeutic effects of MSCs are unclear. We have previously reported that adipose-derived MSCs (AD-MSCs) strengthen the barrier function of the pulmonary vessels in scaffold-based bioengineered rat lungs. In this study, we evaluated whether AD-MSCs could enhance the intercellular barrier function of lung epithelial cells in vitro using a transwell coculture system. Transepithelial electrical resistance (TEER) measurements revealed that the peak TEER value was significantly higher in the AD-MSC coculture group than in the AD-MSC non-coculture group. Similarly, the permeability coefficient was significantly decreased in the AD-MSC coculture group compared to that in the AD-MSC non-coculture group. Immunostaining of insert membranes showed that zonula occuldens-1 expression was significantly high at cell junctions in the AD-MSC coculture group. Moreover, cell junction-related gene profiling showed that the expression of some claudin genes, including claudin-4, was upregulated in the AD-MSC coculture group. Taken together, these results showed that AD-MSCs enhanced the barrier function between lung epithelial cells, suggesting that both direct adhesion and indirect paracrine effects strengthened the barrier function of lung alveolar epithelium in vitro.

scholarly journals Ex vivo Ikkβ ablation rescues the immunopotency of mesenchymal stromal cells from diabetics with advanced atherosclerosis

2020 ◽  
Author(s):  
Ozge Kizilay Mancini ◽  
David N Huynh ◽  
Liliane Menard ◽  
Dominique Shum-Tim ◽  
Huy Ong ◽  
...  
Keyword(s):  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Inflammatory Responses ◽  
Ex Vivo ◽  
Therapeutic Effects ◽  
Atherosclerotic Cardiovascular Disease ◽  
Myocardial Repair ◽  
Iκb Kinase

Abstract Aims Diabetes is a conventional risk factor for atherosclerotic cardiovascular disease and myocardial infarction (MI) is the most common cause of death among these patients. Mesenchymal stromal cells (MSCs) in patients with type 2 diabetes mellitus (T2DM) and atherosclerosis have impaired ability to suppress activated T-cells (i.e. reduced immunopotency). This is mediated by an inflammatory shift in MSC-secreted soluble factors (i.e. pro-inflammatory secretome) and can contribute to the reduced therapeutic effects of autologous T2DM and atherosclerosis-MSC post-MI. The signalling pathways driving the altered secretome of atherosclerosis- and T2DM-MSC are unknown. Specifically, the effect of IκB kinase β (IKKβ) modulation, a key regulator of inflammatory responses, on the immunopotency of MSCs from T2DM patients with advanced atherosclerosis has not been studied. Methods and results MSCs were isolated from adipose tissue obtained from patients with (i) atherosclerosis and T2DM (atherosclerosis+T2DM MSCs, n = 17) and (ii) atherosclerosis without T2DM (atherosclerosis MSCs, n = 17). MSCs from atherosclerosis+T2DM individuals displayed an inflammatory senescent phenotype and constitutively expressed active forms of effectors of the canonical IKKβ nuclear factor-κB transcription factors inflammatory pathway. Importantly, this constitutive pro-inflammatory IKKβ signature resulted in an altered secretome and impaired in vitro immunopotency and in vivo healing capacity in an acute MI model. Notably, treatment with a selective IKKβ inhibitor or IKKβ knockdown (KD) (clustered regularly interspaced short palindromic repeats/Cas9-mediated IKKβ KD) in atherosclerosis+T2DM MSCs reduced the production of pro-inflammatory secretome, increased survival, and rescued their immunopotency both in vitro and in vivo. Conclusions Constitutively active IKKβ reduces the immunopotency of atherosclerosis+T2DM MSC by changing their secretome composition. Modulation of IKKβ in atherosclerosis+T2DM MSCs enhances their myocardial repair ability.

scholarly journals Efficient Intracytoplasmic Labeling of Human Umbilical Cord Blood Mesenchymal Stromal Cells with Ferumoxides

2007 ◽  
Vol 16 (8) ◽  
pp. 849-857 ◽  
Author(s):  
Jae Kwon Lee ◽  
Man Kyoung Lee ◽  
Hye Jin Jin ◽  
Dal-Soo Kim ◽  
Yoon Sun Yang ◽  
...  
Keyword(s):  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Superparamagnetic Iron Oxide ◽  
Cell Labeling ◽  
Human Umbilical Cord Blood ◽  
Human Umbilical Cord ◽  
Therapeutic Effects ◽  
Noninvasive Technique

Mesenchymal stromal cells (MSCs) are multipotent cells found in several adult tissues; they have the capacity to differentiate into mesodermal, ectodermal, and endodermal tissues in vitro. There have been several reports that MSCs have therapeutic effects in a variety of diseases. Therefore, using a cell labeling technique, monitoring their temporal and spatial migration in vivo, would be useful in the clinical setting. Magnetic resonance imaging (MRI)—tracking of superparamagnetic iron oxide (SPIO)-labeled cells—is a noninvasive technique for determining the location and migration of transplanted cells. In the present study, we evaluated the influence and toxicity of SPIO (ferumoxides) labeling on multiple differentiated MSCs. To evaluate the influence and toxicity of ferumoxides labeling on differentiation of MSCs, a variety of concentrations of ferumoxides were used for labeling MSCs. We found that the cytoplasm of adherent cells was effectively labeled at low concentrations of ferumoxides. Compared with unlabeled controls, the ferumoxides-labeled MSCs exhibited a similar proliferation rate and apoptotic progression. The labeled MSCs differentiated into osteoblasts and adipocytes in an identical fashion as the unlabeled cells. However, chondrogenesis and neurogenesis were inhibited at high concentrations of ferumoxides. Our results suggest the effective concentration for ferumoxides use in tracking MSCs.

Abstract T P94: Differential Response to Treatment of Stroke in Rats With T1dm With Bone Marrow Stromal Cells Derived From Normal or T1DM Rats

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Chengcheng Cui ◽  
Michael Chopp ◽  
Xinchun Ye ◽  
Alex Zacharek ◽  
Ruizhuo Ning ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cerebral Artery ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Marrow Stromal Cells ◽  
Border Zone ◽  
Response To Treatment ◽  
Vascular Density ◽  
Therapeutic Effects

Objective: Treatment of stroke with bone-marrow-stromal cells (BMSCs) derived from normal rats (Nor-BMSCs) at 24h after stroke onset improves functional recovery in non-DM rats, but not in type-one DM (T1DM) rats. In the present study, we tested the differential therapeutic effects and mechanisms of action of the treatment of T1DM stroke with BMSCs derived from DM rats (DM-BMSCs) or Nor-BMSCs. Methods: T1DM rats were subjected to 2h of middle cerebral artery occlusion (MCAo) and were treated with DM-BMSCs, Nor-BMSCs or vehicle control (n=8/group) initiated at 24h after MCAo. A battery of functional tests, and vascular and white matter (WM) changes and in vitro cell culture experiments were performed. Results: Compared with Nor-BMSCs, treatment of stroke in T1DM rats with DM-BMSCs significantly improved functional outcome. DM-BMSCs increased vascular remodeling identified by cerebral vascular density and cerebral artery density, increased Bielschowsky silver (axon marker) and Luxol fast blue (myelin marker) expression in the ischemic border zone (IBZ) compared to T1DM-MCAo rats (p<0.05). However, DM-BMSC treatment also increased artherosclerosis-like changes identified by an increased internal carotid wall thickness, artery intimae thickness, and decreased cerebral artery diameter (p<0.05) compared to T1DM-MCAo control. DM-BMSCs treatment significantly increased PDGF, but decreased RhoA and ROCK expression in the IBZ. In vitro, DM-BMSCs have higher miR133b (1.9 fold) expression compared to Nor-BMSCs. DM-BMSC conditioned medium increased brain endothelial cell, smooth muscle cell and oligodendrocyte progenitor cell survival, as well as increased subventricular zone explant cell migration and primary cortical neuron axon outgrowth compared to Nor-BMSC conditioned or control medium. Conclusion: Treatment of stroke in T1-DM rats with DM-BMSCs have dual effects on stroke, i.e. significantly increases neurovascular remodeling, improves neurological recovery, and induces artherosclerosis-like vascular changes. The miR133b/RhoA/ROCK pathway may play a role in the DM-BMSC induced neurorestorative effects.

scholarly journals Extracellular Vesicles from Mesenchymal Stromal Cells for the Treatment of Inflammation-Related Conditions

2021 ◽  
Vol 22 (6) ◽  
pp. 3023
Author(s):  
Sean T. Ryan ◽  
Elham Hosseini-Beheshti ◽  
Dinara Afrose ◽  
Xianting Ding ◽  
Binbin Xia ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Animal Studies ◽  
Therapeutic Potential ◽  
Early Stage ◽  
Small Animal ◽  
Therapeutic Effects ◽  
Anti Inflammatory

Over the past two decades, mesenchymal stromal cells (MSCs) have demonstrated great potential in the treatment of inflammation-related conditions. Numerous early stage clinical trials have suggested that this treatment strategy has potential to lead to significant improvements in clinical outcomes. While promising, there remain substantial regulatory hurdles, safety concerns, and logistical issues that need to be addressed before cell-based treatments can have widespread clinical impact. These drawbacks, along with research aimed at elucidating the mechanisms by which MSCs exert their therapeutic effects, have inspired the development of extracellular vesicles (EVs) as anti-inflammatory therapeutic agents. The use of MSC-derived EVs for treating inflammation-related conditions has shown therapeutic potential in both in vitro and small animal studies. This review will explore the current research landscape pertaining to the use of MSC-derived EVs as anti-inflammatory and pro-regenerative agents in a range of inflammation-related conditions: osteoarthritis, rheumatoid arthritis, Alzheimer’s disease, cardiovascular disease, and preeclampsia. Along with this, the mechanisms by which MSC-derived EVs exert their beneficial effects on the damaged or degenerative tissues will be reviewed, giving insight into their therapeutic potential. Challenges and future perspectives on the use of MSC-derived EVs for the treatment of inflammation-related conditions will be discussed.

scholarly journals Nestin+ Mesenchymal Precursors Generate Distinct Spleen Stromal Cell Subsets and Have Immunomodulatory Function

2021 ◽  
Author(s):  
Jing Huang ◽  
Minrong Li ◽  
Ronghai Deng ◽  
Weiqiang Li ◽  
Meihua Jiang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stromal Cells ◽  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Cell Phenotype ◽  
Therapeutic Effects ◽  
Inflammatory Bowel ◽  
Inflammatory Milieu

Abstract Background Mesenchymal stromal cells (MSCs) are known to be widespread in many tissues and possess a broad spectrum of immunoregulatory properties. They have been used in the treatment of a variety of inflammatory diseases; however, the therapeutic effects are still inconsistent owing to their heterogeneity. Spleen stromal cells have evolved to regulate the immune response at many levels as they are bathed in a complex inflammatory milieu during infection. Therefore, it is unknown whether they have stronger immunomodulatory effects than their counterparts derived from other tissues. Methods Here, using a transgenic mouse model expressing GFP driven by the Nestin (Nes) promoter, Nes-GFP+ cells from bone marrow and spleen were collected. Artificial lymphoid reconstruction in vivo was performed. Cell phenotype, inhibition of T cell inflammatory cytokines, and in vivo therapeutic effects were assessed. Results We observed Nes-GFP+ cells colocalized with splenic stromal cells and further demonstrated that these Nes-GFP+ cells had the ability to establish ectopic lymphoid-like structures in vivo. Moreover, we showed that the Nes-GFP+ cells possessed the characteristics of MSCs. Spleen-derived Nes-GFP+ cells exhibited greater immunomodulatory ability in vitro, and more remarkable therapeutic efficacy in inflammatory diseases, especially inflammatory bowel disease (IBD) than bone marrow-derived Nes-GFP+ cells. Conclusions Overall, our data showed that Nes-GFP+ cells contributed to subsets of spleen stromal populations and possessed the biological characteristics of MSCs with a stronger immunoregulatory function and therapeutic potential than bone marrow-derived Nes-GFP+ cells.

scholarly journals IL-1β-primed mesenchymal stromal cells exert enhanced therapeutic effects to alleviate Chronic Prostatitis/Chronic Pelvic Pain Syndrome through systemic immunity

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hanchao Liu ◽  
Xinning Zhu ◽  
Xiaohui Cao ◽  
Ani Chi ◽  
Jian Dai ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Chronic Prostatitis ◽  
Chronic Pelvic Pain ◽  
Chronic Pelvic Pain Syndrome ◽  
Pain Syndrome ◽  
Prostate Tissue ◽  
Pelvic Pain Syndrome ◽  
Therapeutic Effects ◽  
Systemic Immunity

Abstract Background Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) seriously affects patient health. Despite the elusiveness of innate therapeutic effects, mesenchymal stromal cells (MSCs) hold great promise for inflammation-related diseases. Recent evidence indicates that disease-specific inflammatory cytokines could enhance the therapeutic effects of MSCs. Methods By establishing a CP/CPPS mouse model and pretreating MSCs with the cytokine interleukin-1β (IL-1β), we studied the IL-1β-primed MSC immunoregulatory ability and targeted migration ability in vitro and in CP/CPPS mice. Results IL-1β levels significantly increased in the prostate tissue and serum of experimental autoimmune prostatitis (EAP) mice. Pretreatment with IL-1β enhanced the immunomodulatory potential and targeted migration of MSCs in vitro. Furthermore, intravenous infusion of IL-1β-primed MSCs dampened inflammation in prostate tissues and alleviated hyperalgesia in EAP mice. The infused MSCs inhibited monocyte infiltration and promoted regulatory T lymphocyte formation in prostate tissue, thus remodeling the local environment. Surprisingly, IL-1β-primed MSCs exhibited improved accumulation in the spleen but not in prostate tissue. Accordingly, infused MSCs reshaped systemic immunity by reducing the proportion of Ly6ChighCD11b+ monocytes and boosting the proportion of CD4+Foxp3+ regulatory T lymphocytes in the spleen and lung. Inflammatory chemokine (C–C motif) ligand 2 (CCL2) decreased through the downregulation of the NF-κB and JNK/MAPK pathways by inflammatory resolution via MSCs infusion to alleviate pain. Conclusion In summary, IL-1β-primed MSCs restored systemic immunologic homeostasis to alleviate CP/CPPS by modulating systemic immunity. These findings provide a novel strategy to boost the therapeutic effects of MSC-based therapy for CP/CPPS and reveal the essential role of systematic immunity in the treatment of CP/CPPS with MSC infusion.

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