scholarly journals BDNF-Overexpressing Engineered Mesenchymal Stem Cells Enhances Their Therapeutic Efficacy against Severe Neonatal Hypoxic Ischemic Brain Injury

2021 ◽  
Vol 22 (21) ◽  
pp. 11395
Author(s):  
So Yoon Ahn ◽  
Dong Kyung Sung ◽  
Yun Sil Chang ◽  
Se In Sung ◽  
Young Eun Kim ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Death ◽  
Mesenchymal Stem Cells ◽  
Brain Injury ◽  
Therapeutic Efficacy ◽  
Inflammatory Responses ◽  
Apoptotic Cell ◽  
Glucose Deprivation

We investigated whether irradiated brain-derived neurotropic factor (BDNF)-overexpressing engineered human mesenchymal stem cells (BDNF-eMSCs) improve paracrine efficiency and, thus, the beneficial potency of naïve MSCs against severe hypoxic ischemic (HI) brain injury in newborn rats. Irradiated BDNF-eMSCs hyper-secreted BDNF > 10 fold and were >5 fold more effective than naïve MSCs in attenuating the oxygen-glucose deprivation-induced increase in cytotoxicity, oxidative stress, and cell death in vitro. Only the irradiated BDNF-eMSCs, but not naïve MSCs, showed significant attenuating effects on severe neonatal HI-induced short-term brain injury scores, long-term progress of brain infarct, increased apoptotic cell death, astrogliosis and inflammatory responses, and impaired negative geotaxis and rotarod tests in vivo. Our data, showing better paracrine potency and the resultant better therapeutic efficacy of the irradiated BDNF-eMSCs, compared to naïve MSCs, suggest that MSCs transfected with the BDNF gene might represent a better, new therapeutic strategy against severe neonatal HI brain injury.

Abstract TP270: Adipose Derived Mesenchymal Stem Cells Reduce Autophagic Flux After Ischemic Stroke in Mice via Extracellular Vesicle Transfer of MiR-25-3p

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Yaoyun Kuang ◽  
Xuan Zheng ◽  
Lin Zhang ◽  
Irina Graf ◽  
Mathias Bähr ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Death ◽  
Mesenchymal Stem Cells ◽  
Glucose Deprivation ◽  
Neurological Recovery ◽  
Signaling Cascades ◽  
Autophagic Flux ◽  
Primary Neurons

Transplantation of mesenchymal stem cells (MSCs) yields neuroprotection and enhanced neurological recovery in pre-clinical stroke models, which is mediated by the secretion of extracellular vesicles (EVs). The latter are a heterogenous group of vesicles containing microvesicles, exosomes, and apoptotic bodies. The neuroprotective cargo of EVs, however, has not yet been identified. To investigate such a cargo and its underlying mechanism, we designed a series of in vitro and in vivo experiments. Primary neurons were exposed to oxygen-glucose-deprivation (OGD) and co-cultured with either adipose-derived MSCs (ADMSCs) or treated with ADMSC-secreted EVs. As expected, both ADMSCs and ADMSC-secreted EVs significantly reduced neuronal death after 12 h of OGD and 24 h of reoxygenation, showing no difference between the two treatment groups. Screening for various signaling cascades being involved in the interaction between ADMSCs and neurons revealed a decreased autophagic flux as well as a declined p53-Bnip3 activity. However, these signaling cascades were significantly blocked when ADMSCs were pretreated with the inhibitor of exosomal secretion GW4869. In light of miR-25-3p being the most highly expressed miRNA in ADMSC-EVs interacting with the p53 pathway, further in vitro work focused on this pathway. Treatment with a miR-25-3p oligonucleotide mimic reduced cell death, whereas the anti-oligonucleotide increased autophagic flux and cell death by modulating p53-Bnip3 signaling in primary neurons exposed to OGD. Likewise, native ADMSC-EVs but not EVs obtained from ADMSCs pretreated with the anti-miR-25-3p oligonucleotide (ADMSC-EVs anti-miR-25-3p ) confirmed the aforementioned in vitro observations in C57BL6 mice exposed to cerebral ischemia. Infarct size was reduced and neurological recovery was increased in mice treated with native ADMSC-EVs when compared to ADMSC-EVs anti-miR-25-3p . As such, ADMSCs induce neuroprotection - at least in part - by improved autophagic flux through secreted EVs containing miR-25-3p. Hence, our work for the first time uncovers a key factor in naturally secreted ADMSC-EVs for the regulation of autophagy and induction of neuroprotection in a pre-clinical stroke model.

scholarly journals Adipose-Derived Mesenchymal Stem Cells Migrate and Rescue RPE in the Setting of Oxidative Stress

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Aya Barzelay ◽  
Shira Weisthal Algor ◽  
Anat Niztan ◽  
Sebastian Katz ◽  
Moshe Benhamou ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stem Cells ◽  
Cell Death ◽  
Mesenchymal Stem Cells ◽  
Conditioned Medium ◽  
Early Passage ◽  
Systemic Injection ◽  
Rpe Cells

Oxidative stress leads to the degeneration of retinal pigment epithelial (RPE) and photoreceptor cells. We evaluated the potential of adipose-derived mesenchymal stem cells (ASCs) as a therapeutic tool by studying the migration capacity of ASCs in vitro and their protective effect against RPE cell death under oxidative stress in vitro and in vivo. ASCs exhibited enhanced migration when exposed to conditioned medium of oxidative stressed RPE cells obtained by hydrogen peroxide. Migration-related axis SDF-1/CXCR4 was studied, and upregulation of SDF-1 in stressed RPE and of CXCR4 in ASCs was detected. Moreover, ASCs’ conditioned medium prevented H2O2-induced cell death of RPE cells. Early passage ASCs had high expression level of HGF, low VEGF levels, and unmodulated IL-1β levels, compared to late passage ASCs. Thus, early passage ASCs show the potential to migrate towards damaged RPE cells and protect them in a paracrine manner from cell death induced by oxidative stress. In vivo, mice received systemic injection of NaIO3, and 72 h later, ASCs were transplanted in the subretinal space. Seven days after ASC transplantation, the eyes were enucleated fixed and frozen for immunohistochemical analysis. Under such conditions, ASC-treated mice showed preservation of nuclear layers in the outer nuclear layer and stronger staining of RPE and photoreceptor layer, compared to PBS-treated mice. Taken together, our results indicate that ASCs are able to home in on damaged RPE cells and protect against damage to the RPE and PR layers caused by oxidative stress. These data imply the potential that ASCs have in regenerating RPE under oxidative stress, providing the basis for a therapeutic approach to retinal degeneration diseases related to oxidative stress that could help save the eyesight of millions of people worldwide.

scholarly journals The TRIM protein Mitsugumin 53 enhances survival and therapeutic efficacy of stem cells in murine traumatic brain injury

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Fangxia Guan ◽  
Tuanjie Huang ◽  
Xinxin Wang ◽  
Qu Xing ◽  
Kristyn Gumpper ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Stem Cells ◽  
Brain Injury ◽  
Therapeutic Efficacy ◽  
Brain Dysfunction ◽  
Vital Role ◽  
Neurological Deficits ◽  
Human Umbilical Cord

Abstract Background Traumatic brain injury (TBI) is a common neurotrauma leading to brain dysfunction and death. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) hold promise in the treatment of TBI. However, their efficacy is modest due to low survival and differentiation under the harsh microenvironment of the injured brain. MG53, a member of TRIM family protein, plays a vital role in cell and tissue damage repair. The present study aims to test whether MG53 preserves hUC-MSCs against oxidative stress and enhances stem cell survival and efficacy in TBI treatment. Methods In this study, we performed a series of in vitro and in vivo experiments in hUC-MSCs and mice to define the function of MG53 enhancing survival, neurogenesis, and therapeutic efficacy of stem cells in murine traumatic brain injury. Results We found that recombinant human MG53 (rhMG53) protein protected hUC-MSCs against H2O2-induced oxidative damage and stimulated hUC-MSC proliferation and migration. In a mouse model of contusion-induced TBI, intravenous administration of MG53 protein preserved the survival of transplanted hUC-MSCs, mitigated brain edema, reduced neurological deficits, and relieved anxiety and depressive-like behaviors. Co-treatment of MG53 and hUC-MSCs enhanced neurogenesis by reducing apoptosis and improving PI3K/Akt-GSK3β signaling. Conclusion MG53 enhances the efficacy of hUC-MSCs in the recovery of TBI, indicating that such adjunctive therapy may provide a novel strategy to lessen damage and optimize recovery for brain injury.

scholarly journals Mesenchymal Stem Cells Attenuate Radiation-Induced Brain Injury by Inhibiting Microglia Pyroptosis

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Huan Liao ◽  
Hongxuan Wang ◽  
Xiaoming Rong ◽  
Enqin Li ◽  
Ren-He Xu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Brain Injury ◽  
Inflammasome Activation ◽  
Rt Pcr ◽  
Caspase 1 ◽  
Radiation Induced ◽  
The Impact

Radiation-induced brain injury (RI) commonly occurs in patients who received head and neck radiotherapy. However, the mechanism of RI remains unclear. We aimed to evaluate whether pyroptosis was involved in RI and the impact of mesenchymal stem cells (MSCs) on it. BALB/c male mice (6–8 weeks) were cranially irradiated (15 Gy), and MSCs were transplanted into the bilateral cortex 2 days later; then mice were sacrificed 1 month later. Meanwhile, irradiated BV-2 microglia cells (10 Gy) were cocultured with MSCs for 24 hours. We observed that irradiated mice brains presented NLRP3 and caspase-1 activation. RT-PCR then indicated that it mainly occurred in microglia cells but not in neurons. Further, irradiated BV-2 cells showed pyroptosis and increased production of IL-18 and IL-1β. RT-PCR also demonstrated an increased expression of several inflammasome genes in irradiated BV-2 cells, including NLRP3 and AIM2. Particularly, NLRP3 was activated. Knockdown of NLRP3 resulted in decreased LDH release. Noteworthily, in vivo, MSCs transplantation alleviated radiation-induced NLRP3 and caspase-1 activation. Moreover, in vitro, MSCs could decrease caspase-1 dependent pyroptosis, NLRP3 inflammasome activation, and ROS production induced by radiation. Thus, our findings proved that microglia pyroptosis occurred in RI. MSCs may act as a potent therapeutic tool in attenuating pyroptosis.

scholarly journals Bone Marrow-Derived NCS-01 Cells Advance a Novel Cell-Based Therapy for Stroke

2020 ◽  
Vol 21 (8) ◽  
pp. 2845 ◽  
Author(s):  
John Brown ◽  
You Jeong Park ◽  
Jea-Young Lee ◽  
Thomas N. Chase ◽  
Minako Koga ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Clinical Trials ◽  
Mesenchymal Stem Cells ◽  
Infarct Volume ◽  
Glucose Deprivation ◽  
Preclinical Research ◽  
Cell Based Therapy

Human mesenchymal stem cells have been explored for their application in cell-based therapies targeting stroke. Identifying cell lines that stand as safe, accessible, and effective for transplantation, while optimizing dosage, timing, and method of delivery remain critical translational steps towards clinical trials. Preclinical studies using bone marrow-derived NCS-01 cells show the cells’ ability to confer functional recovery in ischemic stroke. Coculturing primary rat cortical cells or human neural progenitor cells with NCS-01 cells protects against oxygen-glucose deprivation. In the rodent middle cerebral artery occlusion model, intracarotid artery administration of NCS-01 cells demonstrate greater efficacy than other mesenchymal stem cells (MSCs) at improving motor and neurological function, as well as reducing infarct volume and peri-infarct cell loss. NCS-01 cells secrete therapeutic factors, including basic fibroblast growth factor and interleukin-6, while also demonstrating a potentially novel mechanism of extending filopodia towards the site of injury. In this review, we discuss recent preclinical advancements using in vitro and in vivo ischemia models that support the transplantation of NCS-01 in human stroke trials. These results, coupled with the recommendations put forth by the consortium of Stem cell Therapeutics as an Emerging Paradigm for Stroke (STEPS), highlight a framework for conducting preclinical research with the ultimate goal of initiating clinical trials.

scholarly journals Adipose-Derived Mesenchymal Stem Cells-Derived Exosomes Carry MicroRNA-671 to Alleviate Myocardial Infarction Through Inactivating the TGFBR2/Smad2 Axis

Inflammation ◽  
2021 ◽  
Author(s):  
Xue Wang ◽  
Yuhai Zhu ◽  
Chengcheng Wu ◽  
Wennan Liu ◽  
Yujie He ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Glucose Deprivation ◽  
Bioinformatic Analysis ◽  
In Cells

Abstract Mesenchymal stem cells (MSCs) and their derived extracellular vesicles have been reported as promising tools for the management of heart disease. The aim of this study was to explore the function of adipose-derived MSCs (adMSCs)-derived exosomes (Exo) in the progression of myocardial infarction (MI) and the molecules involved. Mouse cardiomyocytes were treated with oxygen-glucose deprivation (OGD) to mimic an MI condition in vitro. The adMSCs-derived Exo were identified and administrated into the OGD-treated cardiomyocytes, and then the viability and apoptosis of cells, and the secretion of fibrosis- and inflammation-related cytokines in cells were determined. Differentially expressed microRNAs (miRNAs) in cells after Exo treatment were screened using a microarray analysis. The downstream molecules regulated by miR-671 were explored through bioinformatic analysis. Involvements of miR-671 and transforming growth factor beta receptor 2 (TGFBR2) in the exosome-mediated events were confirmed by rescue experiments. A murine model with MI was induced and treated with Exo for functional experiments in vivo. Compared to phosphate-buffered saline treatment, the Exo treatment significantly enhanced viability while reduced apoptosis of cardiomyocytes, and in reduced myocardial fibrosis and inflammation both in vitro and in vivo. miR-671 was significantly upregulated in cells after Exo treatment. Downregulation of miR-671 blocked the protective functions of Exo. miR-671 targeted TGFBR2 and suppressed phosphorylation of Smad2. Artificial downregulation of TGFBR2 enhanced viability of the OGD-treated cardiomyocytes. This study suggested that adMSC-derived exosomal miR-671 directly targets TGFBR2 and reduces Smad2 phosphorylation to alleviate MI-like symptoms both in vivo and in vitro.

Abstract 308: CTRP9 Regulates the Fate of Implanted Mesenchymal Stem Cells and Mobilizes Their Protective Effects Against Ischemic Heart Injury via Multiple Novel Signaling Pathways

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Wenjun Yan ◽  
Wayne Lau ◽  
Theodore Christopher ◽  
Bernard Lopez ◽  
Erhe Gao ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Death ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Cell Survival ◽  
Therapeutic Efficacy ◽  
Apoptotic Cell ◽  
Biological Effects ◽  
Ischemic Heart ◽  
And Migration

Cell therapy remains the most promising approach against ischemic heart failure. However, the poor survival of engrafted stem cells in the ischemic environment limits their therapeutic efficacy for cardiac repair post-MI. CTRP9 is a novel pro-survival cardiokine with significantly downregulated expression after MI. Here, we tested a hypothesis that CTRP9 might be a cardiokine required for a healthy microenvironment promoting stem cell survival and cardioprotection. Mice were subjected to MI and treated with adipose-derived mesenchymal stem cells (ADSCs, intramyocardial transplantation), CTRP9, or their combination. Administration of ADSCs alone failed to exert significant cardioprotection. However, administration of ADSCs in addition to CTRP9 further enhanced the cardioprotective effect of CTRP9 (P<0.05 vs. CTRP9 alone), suggesting a synergistic effect. CTRP9 significantly increased ADSCs survival and migration after implantation. Conversely, the number of engrafted ADSCs was significantly reduced in the CTRP9KO heart. CTRP9 promoted ADSCs proliferation and migration in vitro, and protected ADSCs against hydrogen peroxide-induced cellular death. Discovery-drive approaches followed by cause-effect analysis identified that CTRP9 enhances ADSCs proliferation/migration by ERK1/2-MMP-9 signaling. CTRP9 promotes anti-apoptotic/cell survival via ERK-Nrf2/anti-oxidative protein expression. Mass spectrometry, immunocytochemistry, and immunoprecipitation identified N-cadherin as the novel CTRP9 binding partner on ADSC. N-cadherin knockdown completely abolished the above noted CTRP9 biological effects. Finally, CTRP9 promotes Sod-3 expression and secretion from ADSCs, protecting cardiomyocytes against oxidative stress-induced cell death. We provide the first evidence that CTRP9 promotes ADSCs proliferation/survival, stimulates ADSCs migration, and attenuates cardiomyocyte cell death by previously unrecognized signaling mechanisms (N-cadherin-ERK/MMP-9 and N-cadherin-ERK/Nrf2-SOD). These results suggest that CTRP9 is a cardiokine critical in maintaining a healthy microenvironment facilitating stem cell engraftment in infarcted myocardial tissue, thereby enhancing stem cell therapeutic efficacy.

scholarly journals Novel Diketopiperazine Enhances Motor and Cognitive Recovery after Traumatic Brain Injury in Rats and Shows Neuroprotection In Vitro and In Vivo

2003 ◽  
Vol 23 (3) ◽  
pp. 342-354 ◽  
Author(s):  
Alan I. Faden ◽  
Susan M. Knoblach ◽  
Ibolja Cernak ◽  
Lei Fan ◽  
Robert Vink ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Cell Death ◽  
Brain Injury ◽  
Apoptotic Cell ◽  
Thyroid Stimulating Hormone ◽  
Neuroprotective Activity ◽  
Magnesium Concentration ◽  
Binding Studies

The authors developed a novel diketopiperazine that shows neuroprotective activity in a variety of in vitro models, as well as in a clinically relevant experimental model of traumatic brain injury (TBI) in rats. Treatment with 1-ARA-35b (35b), a cyclized dipeptide derived from a modified thyrotropin-releasing hormone (TRH) analog, significantly reduced cell death associated with necrosis (maitotoxin), apoptosis (staurosporine), or mechanical injury in neuronal–glial cocultures. Rats subjected to lateral fluid percussion–induced TBI and then treated with 1 mg/kg intravenous 35b thirty minutes after trauma showed significantly improved motor recovery and spatial learning compared with vehicle-treated controls. Treatment also significantly reduced lesion volumes as shown by magnetic resonance imaging, and decreased the number of TUNEL-positive neurons observed in ipsilateral hippocampus. Unlike TRH or traditional TRH analogs, 35b treatment did not change mean arterial pressure, body temperature, or thyroid-stimulating hormone release, and did not have analeptic activity. Moreover, in contrast to TRH or typical TRH analogs, 35b administration after TBI did not alter free-magnesium concentration or cellular bioenergetic state. Receptor-binding studies showed that 35b did not act with high affinity at 50 classical receptors, channels, or transporters. Thus, 35b shows none of the typical physiologic actions associated with TRH, but possesses neuroprotective actions in vivo and in vitro, and appears to attenuate both necrotic and apoptotic cell death.

Autologous transplantation of mesenchymal stem cells into the portal vein of the miniature pig; a preliminary experiment for NOTES approach

2019 ◽  
Vol 98 (9) ◽  
pp. 350-355
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Cell Therapy ◽  
Portal Vein ◽  
Liver Parenchyma ◽  
Miniature Pig ◽  
Hepatic Diseases ◽  
Study Results

Introduction: There is evidence that mesenchymal stem cells (MSCs) could trans-differentiate into the liver cells in vitro and in vivo and thus may be used as an unfailing source for stem cell therapy of liver disease. Combination of MSCs (with or without their differentiation in vitro) and minimally invasive procedures as laparoscopy or Natural Orifice Transluminal Endoscopic Surgery (NOTES) represents a chance for many patients waiting for liver transplantation in vain. Methods: Over 30 millions of autologous MSCs at passage 3 were transplanted via the portal vein in an eight months old miniature pig. The deposition of transplanted cells in liver parenchyma was evaluated histologically and the trans-differential potential of CM-DiI labeled cells was assessed by expression of pig albumin using immunofluorescence. Results: Three weeks after transplantation we detected the labeled cells (solitary, small clusters) in all 10 samples (2 samples from each lobe) but no diffuse distribution in the samples. The localization of CM-DiI+ cells was predominantly observed around the portal triads. We also detected the localization of albumin signal in CM-DiI labeled cells. Conclusion: The study results showed that the autologous MSCs (without additional hepatic differentiation in vitro) transplantation through the portal vein led to successful infiltration of intact miniature pig liver parenchyma with detectable in vivo trans-differentiation. NOTES as well as other newly developed surgical approaches in combination with cell therapy seem to be very promising for the treatment of hepatic diseases in near future.

Differentiation of mesenchymal stem cells from humans and animals into insulin-producing cells: An overview in vitro induction forms

2020 ◽  
Vol 16 ◽  
Author(s):  
Bruna O. S. Câmara ◽  
Bruno M. Bertassoli ◽  
Natália M. Ocarino ◽  
Rogéria Serakides
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Culture Medium ◽  
Adipogenic Differentiation ◽  
Medium Composition ◽  
Cell Therapies ◽  
Insulin Producing Cells ◽  
Msc Differentiation

The use of stem cells in cell therapies has shown promising results in the treatment of several diseases, including diabetes mellitus, in both humans and animals. Mesenchymal stem cells (MSCs) can be isolated from various locations, including bone marrow, adipose tissues, synovia, muscles, dental pulp, umbilical cords, and the placenta. In vitro, by manipulating the composition of the culture medium or transfection, MSCs can differentiate into several cell lineages, including insulin-producing cells (IPCs). Unlike osteogenic, chondrogenic, and adipogenic differentiation, for which the culture medium and time are similar between studies, studies involving the induction of MSC differentiation in IPCs differ greatly. This divergence is usually evident in relation to the differentiation technique used, the composition of the culture medium, the cultivation time, which can vary from a few hours to several months, and the number of steps to complete differentiation. However, although there is no “gold standard” differentiation medium composition, most prominent studies mention the use of nicotinamide, exedin-4, ß-mercaptoethanol, fibroblast growth factor b (FGFb), and glucose in the culture medium to promote the differentiation of MSCs into IPCs. Therefore, the purpose of this review is to investigate the stages of MSC differentiation into IPCs both in vivo and in vitro, as well as address differentiation techniques and molecular actions and mechanisms by which some substances, such as nicotinamide, exedin-4, ßmercaptoethanol, FGFb, and glucose, participate in the differentiation process.

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