Mesenchymal stromal cells engineered to express erythropoietin induce anti-erythropoietin antibodies and anemia in allorecipients.
Ontology highlight
ABSTRACT:
SUBMITTER: Campeau PM
PROVIDER: S-EPMC2835073 | biostudies-other | 2009 Feb
REPOSITORIES: biostudies-other
Similar Datasets
Project description:Effective vaccines inducing lifelong protection against many important infections such as respiratory syncytial virus (RSV), HIV, influenza virus, and Epstein-Barr virus (EBV) are not yet available despite decades of research. As an alternative to a protective vaccine, we developed a genetic engineering strategy in which CRISPR-Cas9 was used to replace endogenously encoded antibodies with antibodies targeting RSV, HIV, influenza virus, or EBV in primary human B cells. The engineered antibodies were expressed efficiently in primary B cells under the control of endogenous regulatory elements, which maintained normal antibody expression and secretion. Using engineered mouse B cells, we demonstrated that a single transfer of B cells engineered to express an antibody against RSV resulted in potent and durable protection against RSV infection in RAG1-deficient mice. This approach offers the opportunity to achieve sterilizing immunity against pathogens for which traditional vaccination has failed to induce or maintain protective antibody responses.
| S-EPMC6913193 | biostudies-literature
Project description:Mesenchymal stem/stromal cells (MSCs) regulate immunity through myeloid-derived suppressor cells (MDSCs), which are a heterogeneous population of immature myeloid cells with phenotypic and functional diversity. Herein, we identified a distinct subset of MDSCs induced by MSCs in the BM under inflammatory conditions. MSCs directed the differentiation of Ly6Glo BM cells from CD11bhiLy6Chi cells to CD11bmidLy6Cmid cells both in cell contact-independent and -dependent manners upon GM-CSF stimulation in vitro and in mice with experimental autoimmune uveoretinitis (EAU). RNA-Seq indicated that MSC-induced CD11bmidLy6CmidLy6Glo cells had a distinct transcriptome profile from CD11bhiLy6ChiLy6Glo cells. Phenotypic, molecular, and functional analyses showed that CD11bmidLy6CmidLy6Glo cells differed from CD11bhiLy6ChiLy6Glo cells by low expression of MHC class II and costimulatory molecules and proinflammatory cytokines, high production of immunoregulatory molecules, lack of change in response to LPS, and inhibition of T cell proliferation and activation. Consequently, adoptive transfer of MSC-induced CD11bmidLy6CmidLy6Glo cells significantly attenuated the development of EAU in mice. Further mechanistic study revealed that suppression of prostaglandin E2 (PGE2) and HGF secretion in MSCs by siRNA transfection partially reversed the effects of MSCs on MDSC differentiation. Altogether, data demonstrate that MSCs drive the differentiation of BM cells toward CD11bmidLy6CmidLy6Glo MDSCs, in part through HGF and COX-2/PGE2, leading to resolution of ocular autoimmune inflammation.
| S-EPMC7406289 | biostudies-literature
Project description:Background and purposePerinatal stroke is a common cause of life-long neurobehavioral compromise. Mesenchymal stromal cells (MSCs) and EPO (erythropoietin) have each demonstrated short-term benefit with delayed administration after stroke, and combination therapy may provide the most benefit. The purpose of this study is to determine the long-term histological and functional efficacy of enhanced, intranasal stem cell therapy (MSC preexposed to EPO) compared with standard MSC or multidose systemic EPO.MethodsTransient middle cerebral artery occlusion or sham surgery was performed in postnatal day (P) 10 Sprague-Dawley rats, who were treated with single-dose intranasal MSC, MSC preexposed to EPO (MSC/EPO), multidose systemic EPO (EPO3; 1000 u/kg per dose×3 every 72 hours), or cell-conditioned media on P13 (day 3 [P13-P19] for EPO), or on P17 (day 7 [P17-P23] for EPO). At 2 months of age, animals underwent novel object recognition, cylinder rearing, and open field testing to assess recognition memory, sensorimotor function, and anxiety in adulthood.ResultsMSC, MSC/EPO, and EPO3 improved brain volume when administered at 3 or 7 days after middle cerebral artery occlusion. MSC/EPO also enhanced long-term recognition memory with either day 3 or day 7 treatment, but EPO3 had the most long-term benefit, improving recognition memory and exploratory behavior and reducing anxiety.ConclusionsThese data suggest that single-dose MSC/EPO and multidose systemic EPO improve long-term neurobehavioral outcomes even when administration is delayed, although EPO was the most effective treatment overall. It is possible that EPO represents a final common pathway for improved long-term repair, although the specific mechanisms remain to be determined.
| S-EPMC7770074 | biostudies-literature
Project description:Podocytes are specialized cells with a limited capacity for cell division that do not regenerate in response to injury and loss. Insults that compromise the integrity of podocytes promote proteinuria and progressive renal disease. The aim of this study was to evaluate the potential renoprotective and regenerative effects of mesenchymal stromal cells (mSC) in a severe form of the podocyte injury model induced by intraperitoneal administration of puromycin, aggravated by unilateral nephrectomy. Bone derived mSC were isolated and characterized according to flow cytometry analyses and to their capacity to differentiate into mesenchymal lineages. Wistar rats were divided into three groups: Control, PAN, and PAN+ mSC, consisting of PAN rats treated with 2 × 105 mSC. PAN rats developed heavy proteinuria, hypertension, glomerulosclerosis and significant effacement of the foot process. After 60 days, PAN rats treated with mSC presented a significant amelioration of all these abnormalities. In addition, mSC treatment recovered WT1 expression, improved nephrin, podocin, synaptopodin, podocalyxin, and VEGF expression, and downregulated proinflammatory Th1 cytokines in the kidney with a shift towards regulatory Th2 cytokines. In conclusion, mSC administration induced protection of podocytes in this experimental PAN model, providing new perspectives for the treatment of renal diseases associated with podocyte damage.
| S-EPMC6925195 | biostudies-literature
Project description:Transient cell therapy is an emerging drug class that requires new approaches for pharmacological monitoring during use. Human mesenchymal stem cells (MSCs) are a clinically-tested transient cell therapeutic that naturally secrete anti-inflammatory factors to attenuate immune-mediated diseases. MSCs were used as a proof-of-concept with the hypothesis that measuring the release of secreted factors after cell transplantation, rather than the biodistribution of the cells alone, would be an alternative monitoring tool to understand the exposure of a subject to MSCs. By comparing cellular engraftment and the associated serum concentration of secreted factors released from the graft, we observed clear differences between the pharmacokinetics of MSCs and their secreted factors. Exploration of the effects of natural or engineered secreted proteins, active cellular secretion pathways, and clearance mechanisms revealed novel aspects that affect the systemic exposure of the host to secreted factors from a cellular therapeutic. We assert that a combined consideration of cell delivery strategies and molecular pharmacokinetics can provide a more predictive model for outcomes of MSC transplantation and potentially other transient cell therapeutics.
| S-EPMC3931832 | biostudies-literature
Project description:Mesenchymal stromal cells (MSCs) are multipotent cells obtained from many tissues including bone marrow, adipose tissue, umbilical cord, amniotic fluid, and placenta. MSCs are the leading cell source for stem cell therapy due to their regenerative and immunomodulatory properties, their low risk of tumorigenesis and lack of ethical constraints. However, clinical applications of MSCs remain limited. MSC therapeutic development continues to pose challenges in terms of preparation, purity, consistency, efficiency, reproducibility, processing time and scalability. Additionally, there are issues with their poor engraftment and survival in sites of disease or damage that limit their capacity to directly replace damaged cells. A key recent development in MSC research, however, is the now widely accepted view that MSCs primarily exert therapeutic effects via paracrine factor secretion. One of the major paracrine effectors are extracellular vesicles (EVs). EVs represent a potential cell-free alternative to stem cell therapy but are also rapidly emerging as a novel therapeutic platform in their own right, particularly in the form of engineered EVs (EEVs) tailored to target a broad range of clinical indications. However, the development of EVs and EEVs for therapeutic application still faces a number of hurdles, including the establishment of a consistent, scalable cell source, and the development of robust GMP-compliant upstream and downstream manufacturing processes. In this review we will highlight the clinical challenges of MSC therapeutic development and discuss how EVs and EEVs can overcome the challenges faced in the clinical application of MSCs.
| S-EPMC8366519 | biostudies-literature
Project description:Cell-based gene therapy holds a great promise for the treatment of human malignancy. Among different cells, mesenchymal stem cells (MSCs) are emerging as valuable anti-cancer agents that have the potential to be used to treat a number of different cancer types. They have inherent migratory properties, which allow them to serve as vehicles for delivering effective therapy to isolated tumors and metastases. MSCs have been engineered to express anti-proliferative, pro-apoptotic, and anti-angiogenic agents that specifically target different cancers. Another field of interest is to modify MSCs with the cytokines that activate pro-tumorigenic immunity or to use them as carriers for the traditional chemical compounds that possess the properties of anti-cancer drugs. Although there is still controversy about the exact function of MSCs in the tumor settings, the encouraging results from the preclinical studies of MSC-based gene therapy for a large number of tumors support the initiation of clinical trials.
| S-EPMC5035934 | biostudies-literature
Project description:Therapeutic mesenchymal stromal cells (MSCs) are attractive in part due to their immunomodulatory properties, achieved by their paracrine secretion of factors including prostaglandin E2 (PGE2). Despite promising pre-clinical data, demonstrating clinical efficacy has proven difficult. The current studies were designed to develop approaches to pre-induce desired functions from naïve MSCs and examine MSC donor variability, two factors contributing to this disconnect. MSCs from six human donors were pre-activated with interleukin 1 beta (IL-1?) at a concentration and duration identified as optimal or interferon gamma (IFN-?) as a comparator. Their secretion of PGE2 after pre-activation and secondary exposure to pro-inflammatory molecules was measured. Modulation of tumor necrosis factor alpha (TNF-?) secretion from M1 pro-inflammatory macrophages by co-cultured pre-activated MSCs was also measured. Our results indicated that pre-activation of MSCs with IL-1? resulted in upregulated PGE2 secretion post exposure. Pre-activation with IL-1? or IFN-? resulted in higher sensitivity to induction by secondary stimuli compared to no pre-activation. While IL-1? pre-activation led to enhanced MSC-mediated attenuation of macrophage TNF-? secretion, IFN-? pre-activation resulted in enhanced TNF-? secretion. Donor variability was noted in PGE2 secretion and upregulation and the level of improved or impaired macrophage modulation.
| S-EPMC5932627 | biostudies-literature
Project description:Extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) possess pro-regenerative potential in different animal models with renal injury. EVs contain different molecules, including proteins, lipids and nucleic acids. Among the shuttled molecules, miRNAs have a relevant role in the pro-regenerative effects of EVs and are a promising target for therapeutic interventions. The aim of this study was to increase the content of specific miRNAs in EVs that are known to be involved in the pro-regenerative effect of EVs, and to assess the capacity of modified EVs to contribute to renal regeneration in in vivo models with acute kidney injuries. To this purpose, MSCs were transiently transfected with specific miRNA mimics by electroporation. Molecular analyses showed that, after transfection, MSCs and derived EVs were efficiently enriched in the selected miRNAs. In vitro and in vivo experiments indicated that EVs engineered with miRNAs maintained their pro-regenerative effects. Of relevance, engineered EVs were more effective than EVs derived from naïve MSCs when used at suboptimal doses. This suggests the potential use of a low amount of EVs (82.5 × 106) to obtain the renal regenerative effect.
| S-EPMC6567878 | biostudies-literature
Project description:Mesenchymal stromal cells (MSCs) represent a promising tool for therapy in regenerative medicine, transplantation, and autoimmune disease due to their trophic and immunomodulatory activities. However, we are still far from understanding the mechanisms of action of MSCs in these processes. Transforming growth factor (TGF)-?1 is a pleiotropic cytokine involved in MSC migration, differentiation, and immunomodulation. Recently, glycoprotein A repetitions predominant (GARP) was shown to bind latency-associated peptide (LAP)/TGF-?1 to the cell surface of activated Foxp3(+) regulatory T cells (Tregs) and megakaryocytes/platelets. In this manuscript, we show that human and mouse MSCs express GARP which presents LAP/TGF-?1 on their cell surface. Silencing GARP expression in MSCs increased their secretion and activation of TGF-?1 and reduced their proliferative capacity in a TGF-?1-independent manner. Importantly, we showed that GARP expression on MSCs contributed to their ability to inhibit T-cell responses in vitro. In summary, we have found that GARP is an essential molecule for MSC biology, regulating their immunomodulatory and proliferative activities. We envision GARP as a new target for improving the therapeutic efficacy of MSCs and also as a novel MSC marker.
| S-EPMC4309416 | biostudies-literature