Tesis sobre el tema "Cellules souches autologues"
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Li, Yan. "Thérapie cellulaire cardiaque avec cellules souches mésenchymateuses médullaires autologues : étude expérimentale de la bio-disponibilité et la bio-distribution du greffon cellulaire". Nancy 1, 2006. http://www.theses.fr/2006NAN11318.
Myocardial infarction (MI) results in an apparent loss of contractile cardiomyocytes, a diminution of cardiac vessels (angiogenesis) which are responsible for the progressive alteration in the cardiac architecture and function. Recently, the reconstruction of the damaged cardiac tissue by using autologous stem cells (cardiac cell therapy) based partly on their ability to give rise to new cardiomyocytes and/or to promote angiogenesis has been proposed as a new therapeutic approach of the cardiac cell therapy. This thesis describes difIerent steps of pre-clinical investigation in order to assess the capability of bone marrow, derived mesenchymal stem cells (BMSCs) to repair infarct and necrotic myocardium. After initial phases of validation of various techniques of BMSCs' selection (cell harvesting, culture and phenotype characterization) and the development of a rat model of myocardial infarction by permanent coronary ligation, the main focus of this project was to develop new investigational methodologies allowing to track non-invasively implanted therapeutic cells. Therefore, the number of engrafted cells, their relative distribution within infarct versus normal myocardial tissue might be precisely determined and sequentially followed up. Outcomes from the bio-availability and the bio-distribution of grafted cells might have a critical importance when analyzing the effects of cardiac cell therapy and contribute to improve the cell therapeutic indication
Lerouxel, Emmanuelle Giumelli Bernard Malard Olivier. "Phosphates de calcium et cellules autologues base d'une ingénierie tissulaire pour la reconstruction osseuse en territoire irradié /". [S.l.] : [s.n.], 2007. http://castore.univ-nantes.fr/castore/GetOAIRef?idDoc=57226.
Lerouxel, Emmanuelle. "Phosphates de calcium et cellules autologues : base d'une ingénierie tissulaire pour la reconstruction osseuse en territoire irradié". Nantes, 2007. https://archive.bu.univ-nantes.fr/pollux/show/show?id=bc057180-d0dc-4d31-8f81-a716260ff382.
Treatment of most forms of squamous cell carcinoma requires surgical procedures and high dose irradiation, which often produce major esthetic and functional injuries in the maxillofacial area. Radiotherapy produces irreversible side-effects on bone, involving damages to its reparation properties and complications such as infections, healing delays and osteoradionecrosis (ORN). Synthetic biphasic Calcium Phosphates (CaP) have been used extensively as bone substitutes in maxillofacial and dental applications as alternatives to autologous bone without irradiation. The aim of this rat study was to determine the influence on osseous repair of autologous cells grafts, bone marrow (BM) or mesenchymal stem cells (MSC), added to CaP ceramics, used as granules or injectable form, in previously irradiated bone. The development of an animal model of localized ORN has been previously developed. Ceramics were biotolerated, yet with low osteoconductive properties in irradiated bone. The BM grafts led to a significant increase in bone in growth in the irradiated areas. BM or adipose tissue derived MSC were not able to enhance bone ingrowth in irradiated osseous defects. These results could be explained by BM resources in cells and in growth factors indispensable for osseous repair. These results allow to highlight the interest of bone substitution by association of CaP ceramics and BM grafts in irradiated bone. Further studies will have to assess the role of grafted cells in osteogenesis and neoangiogenesis. This study allows also to foresee ORN treatment with tissue engineered materials
Perez, Castiglioni Monica Patricia. "Le statut juridique des cellules souches : de la greffe d’organes à la thérapie cellulaire". Electronic Thesis or Diss., Paris 8, 2021. http://www.theses.fr/2021PA080048.
Stem cells as cellular products for therapeutic purposes (PCT) or as advanced therapy drugs (ITNs) within the framework of regenerative medicine have revolutionized the medicine of the 21st century. Faced with recent discoveries of new stem cells created by researchers (parthenotes, cloned stem cells, iPS cells), other possibilities for regenerative therapy are emerging over time.The law, which has always accompanied the scientific and technical development of cell therapy since the 17th century, must be more present than ever to protect human beings who lend themselves to new treatments or to experimentation. The historical development of this therapeutic revolution allows us to show the importance of legal and ethical reflection for scientific progress.Old questions, such as the status of the prenatal being and the authorization for cryopreservation of autologous tissues or cells, are re-emerging in the face of the presence of supernumerary human embryonic stem cells and the success of regenerative therapy. Teratogenic treatments and episodes of child abuse during pregnancy have destroyed or damaged thousands of unborn children. Recognition of prenatal life is offered in certain circumstances to protect the embryo and fetus before birth
Sadelli, Kevin. "Potentiel thérapeutique des transplantations autologues et syngéniques de cellules souches olfactives ecto-mésenchymateuses (CSO-EMS) dans deux modèles d'atteintes du système nerveux central (SNC)". Thesis, Aix-Marseille, 2017. http://www.theses.fr/2017AIXM0669.
The main goal of my thesis was to evaluate whether autografts of ecto-mesenchymal olfactory stem cell (EM-OSCs) restored learning and memory abilities in a rats model of amnesia following global cerebral ischemia (GCI). The latter can occur following cardiac arrest (CA) and lead to deleterious neurological consequences such as cognitive and / or sensorimotor injuries.Finally, the final step in my project was to evaluate the effect of EM-OSCs autografts on restoration of cognitive functions in ischemic rats. First of all, I had to develop a protocol to monitor the fate of EM-OSCs following autografts, without altering their endogenous properties. Then, I demonstrated that these GFP+ EM-OSCs autografts: i) restored learning and memory abilities, ii) stimulated neurogenesis, and iii) improved PLT in ischemic rats. All the data gathered during my thesis give credibility to the use of EM-OSCs in the framework of therapies against the CNS damages
Rakic, Rodolphe. "Nouvelles stratégies thérapeutiques des affections articulaires du cheval : évaluation du potentiel thérapeutique des chondrocytes autologues et des cellules souches de cordon ombilical (sang et gelée de Wharton) : vers l'industrialisation de cellules médicaments". Thesis, Normandie, 2017. http://www.theses.fr/2017NORMC406/document.
Articular cartilage disorders, such as focal defects and osteoarthritis, are the main causes of decreased performance or early retirement of sport- and racehorses. Thus, cartilage disorders represent a major veterinary issue in the equine industry, due to significant financial losses. Poor intrinsic cartilage repair properties and the absence of long- term therapy for cartilage defects lead to the development and use of new generation therapies such as autologous chondrocytes implantation. In this context, our study aimed to compare different cell types for the in vitro cartilage generation, in order to implant the biological substitute to treat cartilage defects in the horse. A therapeutic strategy initially developed in human medicine, the autologous chondrocytes transplantation, always represents a "gold standard" in cartilage tissue engineering. In the present study, after developing a new generation of cartilaginous substitute of high biological quality, composed of equine articular chondrocytes, technical and biological limits inherent to the cell type persist. Thus, we have used alternative cell types such as neonatal mesenchymal stem/stromal cells (MSCs) from umbilical cord, such as umbilical cord blood MSC (UCB-MSCs) and umbilical cord matrix or Wharton jelly MSCs (UCM- MSCs). These MSCs sources could represent a therapeutic advantage due to their non-invasive isolation, their high cell proliferation and their ability to differentiate into chondrocytes. Nevertheless, it is essential to define the best therapeutic candidate between these two MSCs sources, to obtain an optimal quality for the neocartilaginous substitute. Our data highlighted important differences in the chondrogenesis process of these two neonatal MSCs sources, allowing us to consider UCB-MSCs as the best therapeutic candidate for equine cartilage tissue engineering. This work allows a better understanding of the chondrocyte and MSCs biology. Moreover, this work leads the way to setting-up future clinical trials in the horse, in order to treat articular defects of this large animal model
Lorme, Bertrand de. "Etude de la qualité du greffon et de la récupération hématologique après chimio-intensification avec support de cellules souches périphériques autologues dans les tumeurs solides et les lymphopathies". Montpellier 1, 1998. http://www.theses.fr/1998MON11154.
Marsol, Marie-Christine. "Traitement de la maladie de Kahler par autogreffe de cellules souches périphériques chez 14 patients". Bordeaux 2, 1990. http://www.theses.fr/1990BOR25082.
Rice, Alison Mary. "Caractérisation fonctionnelle des cellules souches sanguines mobilisées par chimiothérapie". Bordeaux 2, 1993. http://www.theses.fr/1993BOR28240.
GRAVIS, GWENAELLE. "Chimiotherapie a haute dose avec reinjection de cellules souches hematopoietiques dans les adenocarcinomes mammaires". Aix-Marseille 2, 1994. http://www.theses.fr/1994AIX20855.
Maureira, Juan Pablo. "Traitement de l'infarctus du myocarde chronique : contribution des cellules souches mésenchymateuses de moelle osseuse autologue". Thesis, Université de Lorraine, 2012. http://www.theses.fr/2012LORR0411/document.
Cellular therapy and tissue engineering are new strategies to be tested in the treatment of ischemic cardiopathy. In chronic infarction (MI) specifically, the possibility of rehabilitating a cicatricial zone using bone marrow mesenchymal stem cells (BMSC) as well as the feasibility of remodeling parietal ventricular architecture are especially discussed. The first part reviews the main concepts which have led to these new promising avenues of treatment. In the second part we present our work concerning (1) direct myocardial cellular injection via the epicardium in rats and in humans suffering from MI, and (2) direct epicardial surgical application of a tissular patch consisting of BMSC in a type I collagen network. The results show that direct cellular injection is responsible for an immediate non-specific inflammatory reaction. Nevertheless, the work also supports the notions that (1) BMSCs stimulate local angiogenesis on the basis of residual metabolic activity, and (2) the BMSC patch stimulates inverse ventricular remodeling in infarcted rats. The final part is devoted to a wider discussion of these results which are as yet too limited to hope to heal severe myocardial failure. However, despite the fact that these experiments do not confirm the cardiogenic potential of BMSCs, they do strongly hint at the possibility of using this methodology to invert the natural course of MI
Cartron, Guillaume. "Etude quantitative et fonctionnelle du compartiment des progéniteurs primitifs après autogreffe de cellules souches hématopoïétiques chez l'homme". Tours, 2003. http://www.theses.fr/2003TOUR3311.
Intensive therapy with autologous stem cells transplantation (ASCT) is now widely used in hematology. We have assessed primitive progenitor cell compartment after ASCT using peripheral stem cells and shown a deep and durable decrease of clonogenic progenitor counts in vivo. In vitro studies have demonstrated a constant decrease of LTC-IC frequencies and CD34+/CD38_ counts associated with functional abnormalities (defect in proliferative and érythroïd differentiation of LTC-IC). We have shown also a proliferative defect of CD34+ cells in response to early-acting cytokines and a decrease of both CD34 antigen expression and ability of c-Kit to bind to SCF into CD34+ cell population. After ASCT, there are both quantitative and qualtitative defects of primitive progenitor cell compartment which could led to a impaired self-renewal of this compartment and jeopardize long-lasting marrow reconstitution
Thepenier, Cédric. "Optimisation d'un procédé de culture d'épiderme autologue : influence d'un feeder humanisé et d'une faible tension d'oxygène". Paris 7, 2014. http://www.theses.fr/2014PA077083.
To enhance the production conditions for cultured epidermal autografts (CEA) for large burns, we sought to study the in vitro effect of a low oxygen level on epidermal growth. We tested this parameter on CEA grown on murin feeder cells (Green's method) as well as human feeder cells. We first could evidence that the optimal feeder density depended on the oxygen level. A feeder density made optimal at 20% 02 could prove inhibitory on keratinocyte growth at 3% 02. At their respective best feeder densities, low oxygen level (3%) led to an average 4,2 fold increase in keratinocyte yield for a same arrest day as compared with 20% culture. This effect proved to be stable on several successive passagings, showing the increase in proliferation did not take place at the expense of tell self renewal. Keratinocytes grown at a low oxygen level kept their ability to form a stratifying epidermis on an in vivo NOD/SCID mouse excisional model. In parallel, the increase in proliferation was also observed when keratinocytes were cultured on human feeder cells, bone marrow mesenchymal stroma' cells and dermal fibroblasts. This effect of a low oxygen tension on keratinocytes appears to be partly direct, as the growth rate of HaCat feederless keratinocytes was enhanced at 3% vs 20% 02. It is also partly an indirect effect, as conditioned medium from murin feeder cells cultured in hypoxia has a more pronounced positive effect on keratinocyte growth than its normoxic counterpart. These preliminary resuits could lead to the modification on the culture protocol currently in use for the majority of CEA grafts for large burns. The expected benefits for the patients, beyond slightly shortening culture time, would include salvaging abortive cultures and bringing less differentiated keratinocytes, a parameter linked with a decrease in fibrotic evolution on murin models
Steichen, Clara. "Eléments d'évaluation pour l'utilisation d'hépatocytes dérivés de cellules souches pluripotentes induites (iPSC) en thérapie cellulaire". Paris 7, 2014. http://www.theses.fr/2014PA077045.
Among the various potential applications of induced pluripotent stem cells (iPSCs), this Ph. D project focused on the use of iPSC-derived hepatocytes in cell therapy. Human iPSCs have been generated by repeated transfections of messenger RNAs. The genomic integrity of these cells was analyzed, in comparison with iPSCs generated in parallel by a viral method. The SNP profile of mRNA-iPSC is not significantly different from the parental fibroblasts one, in contrary to what we observed with viral-iPSCs. The number of deletions or duplications (CNVs) is not dependent on the reprogramming method. This genomic analysis also highlighted an atypical mRNA-iPSC line displaying a complex, stable and balanced genomic rearrangement including a large region of de novo uniparental disomy, and a defect in teratoma formation capacity. The second part of this work describes the generation of hiPSCs from hemophilia B patients biopsy. To correct the genetic defect, we used artificial nucleases to drive the insertion of a therapeutic cassette coding the FIX gene. The differentiation of these corrected iPSCs into hepatocytes will allow us to validate this correction approach in vitro first and in vivo in a hemophilia B mouse model. The last part of this PHD work focused on differentiating simian iPSCs into hepatocytes to perform an autologous transplantation into the liver of the donor monkey, alter a portal vein embolization. We would like to establish the proof of principle of an autologous iPSC-based therapy in a non-human primate preclinical model
Abed, Soumeya. "Développement et évaluation du potentiel hématopoïétique de cellules souches induites à la pluripotence chez le primate humain et non humain". Paris 7, 2014. http://www.theses.fr/2014PA077112.
Induced pluripotent stem cells (iPSC) technology is a cellular model full of challenge for fundamental research and important for cellular and gene therapy applications. Before clinical application, capacity and safety of iPSC-hematopoietic derivates must be scrupulously tested in animal model close enough to humans. VVe generated Cynomolgus iPSC and carried out a kinetic analysis of hematopoietic ceil development during EB and co-culture differentiation in order to explore their capacity to engraft efficientely after autologus transplantation. We demonstrated improved hematopoietic differentiation, as evidenced by significant levels of CD34+CD45+ progenitors and CFU activity. However, achieving hematopoietic engraftment in immunodeficient mice using Cy-iPS-derived hematopoietic cells remain challenging. In the second study, we combined the iPS cells properties and the therapeutic potency of gene transfert for beta-thalassemia/HBE treatment. We have generated iPSC from the beta thalassemia/HBE patient's somatic cells and corrected them with a lentiviral vector (LV) carrying beta-globin therapeutic gene. We demonstrate their production of hematopoietic cells, in vitro, showing high expression of the transferred globin gene, differentiation into multiple blood cell types in immunocompromises mice, and endogenous globin switching in vivo. LV integration occured in regions of low and high genotoxicity and common integration sites (CIS) were identified across thal-iPSC and cells retrieved from isogenic and non isogenic gene therapy patients; suggesting that CIS observed in absence of tumorigenesis result from nonrandom LV integration rather than oncogenic in vivo selection
Benboubker, Lotfi. "Cellules souches hématopoi͏̈étiques du sang périphérique : caractérisation fonctionnelle et facteurs intervenant dans la capacité de mobilisation". Tours, 2002. http://www.theses.fr/2002TOUR3308.
Vinsonneau, Ulric. "Traitement du myélome par double intensification avec autogreffe de cellules souches périphériques CD34+ : à propos de 19 cas, étude non randomisée". Bordeaux 2, 1999. http://www.theses.fr/1999BOR2M040.
Moby-Stutzmann, Vanessa Menu Patrick. "Multicouche de polyélectrolytes et CSM deux acteurs complémentaires nécessaires à l'endothélialisation autologue de prothèses vasculaires synthétiques en PTFEe /". S. l. : Nancy 1, 2008. http://www.scd.uhp-nancy.fr/docnum/SCD_T_2008_0121_MOBY-STUTZMANN.pdf.
Aligier, Nathalie. "Chimiothérapie intensive avec greffe de cellules souches hématopoi͏̈etiques dans les tumeurs épithéliales malignes de l'ovaire : à propos de 11 cas". Montpellier 1, 1997. http://www.theses.fr/1997MON11102.
Siegenthaler, Michèle. "Chimiothérapie supra-intensive et transplantation autologue de cellules souches hématopoïétiques dans les cancers du sein de mauvais pronostic : l'expérience genevoise /". Genève : [s.n.], 2004. http://www.unige.ch/cyberdocuments/theses2004/SiegenthalerMA/these.pdf.
Delagrèverie, Héloïse. "Impact de stratégies thérapeutiques sur le réservoir viral cellulaire dans l'infection par le VIH-1". Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCC312.
In HIV-1 infection, the persistence of latent viral forms in infected cells precludes the cure. New cure strategies aim at reducing or inactivating this viral reservoir. We studied the impact of intensive chemotherapy and hematopoietic stem cell transplantation on the viral reservoir in 13 retrospective patients. Blood cell-associated viral DNA (CA-DNA) was quantified longitudinally by real-time PCR. Viral diversity and phylogeny were studied by deep sequencing the viral C2V3 region. Despite intensive chemotherapy, the viral reservoir was reconstituted within a few weeks following transplantation and its diversity was unaltered. The reconstitution was driven by the early homeostatic proliferation of infected memory T cells. In HIV gene therapy trials, it may therefore be relevant to administer modified T cells in addition to stem cells to achieve a better engraftment of resistant cells. We also studied the effect of antiretroviral initiation with either raltegravir (2 doses) or efavirenz on the reduction in CA-DNA and inflammation markers in 153 patients co-infected with tuberculosis, from the ANRS REFLATE-TB trial. CA-DNA decreased on treatment by -0.9 log10 copies/106CD4+ over 48 weeks. Plasma CRP, D-dimer, IL-6 and sCD14 levels were initially high. All decreased but had not reached normal values by 48 weeks. There were no differences according to treatment; raltegravir and efavirenz were equally effective. Finally, we studied anti-HIV-1-gp41 humoral responses in 683 patients with long-term suppressed viral replication. Persistent antibody levels correlated with both the duration of viral suppression and the size of the CA-DNA reservoir. Antibody levels were higher in participants with residual replication. Measuring anti-gp41 responses may be useful as a surrogate marker of the viral reservoir and of effective viral suppression
Lobry, Tatiana. "Cystinosis : new findings involving inflammation in the kidney pathogenesis and preclinical studies for autologous hematopoietic stem cell gene therapy". Thesis, Brest, 2019. http://www.theses.fr/2019BRES0011.
Cystinosis is an inherited lysosomal storage disorder caused by mutations in the gene CTNS encoding the cystine transporter cystinosin, and is characterized by accumulation of cystine in the tissues leading to multiorgan degeneration.The kidney is the first organ impacted by cystinosis but the pathogenesis is still not fully understood. The study of new partners of cystinosin revealed an interaction with galectin-3, a member of the galectin’s family. The investigation of this interaction unraveled a new role for cystinosin in chronic inflammation associated with kidney pathology in cystinosis. Indeed, the cystinosis mouse model, Ctns-/ mice, had increased expression of Gal3 and abundant pro-inflammatory infiltrates in their kidney, as well as increased expression of Monocyte Chemoattractant Protein-1 (MCP1), a proinflammatory cytokine, in their serum.In contrast, few infiltrates and normal MCP1 levels were observed in the Ctns-/- Gal3-/- mice, which also demonstrated better kidney structure and function.This study may lead to the discovery of new drug targets for cystinosis treatment.Previous studies showed that wild-type Hematopoietic Stem Cells (HSCs) transplantation had the potential to rescue cystinosis in Ctns-/- mice.However, due to the risks associated with allogeneic transplant, an autologous transplantation of HSCs genetically modified ex vivo to express a functional CTNS gene has been developed in the laboratory. In this work, we summarized the pharmacology and toxicology studies and manufacturing development that will be included in an Investigational New Drug application to be submitted to the FDA to start a phase I/II clinical trial for cystinosis
Magalon, Jérémy. "Développement d'un médicament de thérapie innovante utilisant la fraction vasculaire stromale du tissu adipeux autologue dans la sclérodermie systémique : de la caractérisation biologique à l'identification de biomarqueurs potentiels d'efficacité". Thesis, Aix-Marseille, 2018. http://www.theses.fr/2018AIXM0048.
The aim of this work is to characterize the antifibrotic and angiogenic effects of FVS and to evaluate the impact of the scleroderma context on these angiogenic properties. On the other hand, to identify a strategy of biological monitoring of this therapy applicable to the sclerodermic context.The first step was to determine whether locally injected FVS can limit fibrosis in vivo. The injection of SVF performed early or late is accompanied by a significant reduction in the area of fibrosis in favor of muscle surfaces in a porcine model of urinary incontinence. The second component was to investigate whether the autologous context of systemic scleroderma affects the angiogenic properties of SVF. This study showed a slight alteration of angiogenic capacity on in vivo Matrigel Plug assays associated with a transcriptomic signature of SVF of scleroderma patients. The third component was to identify a biological monitoring strategy that could be used to objectively evaluate the impact of new therapies on vasculopathy associated with systemic sclerosis. The elevation of EPCs and Fractalkine independently predict the severity score of the disease and the severity of pulmonary fibrosis.This work has made it possible to progress in the development of an innovative cell therapy to limit the ischemic vasculopathy and the fibrosis causing hand handicap in scleroderma patients and to monitor its effectiveness in the future
Luce, Eléanor. "Hépatocytes différenciés à partir de cellules souches pluripotentes induites : modèle pour la thérapie cellulaire et génique autologue de l'hémophilie B et modèle préclinique chez le primate". Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLS520/document.
This PhD project aims to model and to bring a proof of concept for autologous cell/gene therapy of inherited liver diseases by transplanting hepatocytes differentiated from patient-specific induced pluripotent stem cells (iPSCs), after correction of the genetic defect. Hemophilia B (HB) is an inherited disease caused by a mutation in the F9 gene encoding clotting factor IX (FIX), synthesized in the liver by hepatocytes. Fibroblasts of a patient with the "royal mutation" were reprogrammed in iPSCs then differentiated into hepatocytes. The study of the F9 mRNA by high-throughput sequencing confirmed the presence of an abnormal splice site leading to a truncated protein explaining hemophilia. Other iPSCs were obtained and characterized from the cells of a second HB patient expressing an inactive FIX. By targeting in these iPSCs the insertion of a therapeutic cassette encoding FIX into a safe harbor site using artificial endonucleases (CRISPR/Cas9), we differentiated the corrected and non-corrected iPSC into hepatocytes. Quantitative analyzes confirmed a higher expression of F9 mRNA and FIX protein in the corrected clones. In contrast, we did not detect transgenic FIX activity due to a lack of post-translational modifications necessary for FIX activity. We then developed a protocol of differentiation in spheroids quantitatively more efficient to produce FIX. Detection of FIX activity will validate our in vitro approach before validation in vivo by transplanting the corrected hepatocytes in a F9KO mouse model. Finally, the last part of this work consisted in the development of a differentiation protocol of nonhuman primate iPSCs into hepatocytes for autologous transplantation into the liver of the donor animal in order to validate the feasibility and the safety of such an approach in the large animal
Weber, Leslie. "New therapeutic strategies for the treatment of β-hemoglobinopathies". Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCC272.
Highly efficient curative therapeutic strategies are in great demand for patients affected by β-hemoglobinopathies, namely sickle cell disease (SCD) and β-thalassemia. Indeed, the poor access to compatible donors restrains the application of the only approved definitive therapy, the allogeneic hematopoietic stem cell (HSC) transplantation. In the first part of this thesis, we aimed at optimizing an established therapeutic alternative consisting in the autologous transplantation of lentivirus (LV)-corrected hematopoietic HSCs. The development of β-globin expressing LVs and the improvement of HSC transduction conditions have led to a clear clinical benefit for SCD and β-thalassemia patients treated with this approach in the frame of recent clinical trials. Despite these significant progresses, there is room for further improvement. Indeed, the correction of severe transfusion-dependent B-thalassemia and SCD patients requires high levels of transgene expression. The goal of this project was to select a high-titer LV able to transduce efficiently HSCs and to drive high levels of transgene expression in HSC-derived RBCs. To this purpose, we compared different combinations of regulatory elements, in order to define the minimal regulatory cassette needed for achieving high levels of globin expression in the frame of LVs. We constructed 2 mini-LCRs containing either HS2 and HS3 (total size 2.6 kb) or HS2, HS3 and HS4 (total size 3.7 kb) derived from the 16-kb Locus Control Region. These cassettes were inserted in the β-AS3 and β-AS3 HS4 LVs, respectively, driving the expression of an anti-sickling βAS3-globin transgene. First, we aimed at comparatively evaluate the transduction efficiency of β-AS3 and β-AS3 HS4 in SCD hematopoietic stem progenitor cells (HSPCs) and long term-repopulating HSCs. The second aim of the study was to assess β-AS3 and β-AS3 HS4 derived transgene expression in RBCs produced from SCD HSPCs, and to evaluate the efficacy of the best-performing LV in rescuing the SCD phenotype. The second part of this thesis aimed to develop a novel genome editing-based strategy to restore fetal γ-globin genes expression. This therapeutic approach stems from the observation that the clinical course of β-thalassemia and SCD is improved in the presence of elevated HbF levels. By using the innovative CRISPR/Cas9 technology, we aimed at disrupting repressors binding sites in the γ-globin promoters to reactivate HbF expression in SCD HSPCs-derived RBCs. Reactivating fetal γ-globin genes at their endogenous genomic locus can circumvent the difficulties associated with the relatively low LV-derived transgene expression per vector copy, likely because the low LV vector capacity allows the usage only of short DNA stretches from the LCR, arranged in a non-physiological manner. In addition, this strategy offers a potentially safer targeted approach compared to the LV-based gene addition. In SCD, this therapeutic approach can favor the anti-sickling γ-globin expression, at the expense of the mutated βS-globin, given the competition between the fetal and the adult genes for the interaction with the LCR. In a comparative approach, we intended to evaluate novel and known therapeutic targets in the γ-globin promoters. To this purpose, several gRNAs have been designed to target 3 regions of the γ-globin promoters, where variants associated with elevated HbF levels and/or binding sites for HbF repressors have been described. We aimed to screen these gRNAs in an adult erythroid cell line (HUDEP-2) and SCD HSPCs-derived RBCs in terms of HbF reactivation and correction of the patient phenotype, to select the best therapeutic target for an efficient and safe therapeutic approach for β-hemoglobinopathies
Girard, Anne-Claire. "Thérapies à partir du tissu adipeux : de la chirurgie esthétique et reconstructrice à la thérapie cellulaire. Application à la régénération des tendons chez les chevaux". Thesis, La Réunion, 2012. http://www.theses.fr/2012LARE0034/document.
Despite the dark side of obesity in the pathogenesis of metabolic diseases, adipose tissue has been shown to be a good therapeutic tool. First, autologous fat grafting, also named lipofilling, has been used for over a century and represents a safe technique for soft tissue filling. However, although the technique has seen marked improvements over time, surgeons are still facing graft resorption that often requires overcorrection of the treated area or other interventions so that the aesthetic result is in line with expectations of the patient. Thus, MICROFILL® process has been developed in order to increase the rate of engraftment by promoting cell survival within the graft. The latter is enhanced by: - sampling and reinjection of small fat lobules in order to reduce ischemia and poor nutrition of the cells- elimination of deleterious elements (anesthetics, inflammatory cytokines) by a non-traumatic protocol involving soft centrifugations and washings. Furthermore, in recent years, adipose tissue has been found to have a greater therapeutic power by hosting mesenchymal stem cells with great potential. These adipose stem cells (ASCs) are present in large quantities and can be easily obtained from a simple liposuction. However, liposuction procedure often involves the use of a local anesthetic and a vasoconstrictor that can harm cells. Our studies have shown that lidocaine, an anesthetic commonly used, exerts cytotoxic effects on adipose stem cells, inhibiting cell proliferation (cell cycle arrest in G0-G1 phase) and inducing necrosis. Nonetheless, appropriate handling of adipose tissue, quite similarly to MICROFILL® protocol, reduces cell death. The deleterious effects of lidocaine appear to be related to the occurrence of cytoplasmic vacuolization whose nature is so far unclear. In addition, lidocaine also induces a process of autophagy, including molecular mechanisms of induction also unknown and whose physiological purpose could be cell survival despite the stress. The findings of these studies lead to some recommendations to follow regarding the use of lidocaine for the extemporaneous reinjection of ASCs in a patient. Also, in order to treat equine tendinopathy, these studies have been used to optimize adipose tissue harvest by liposuction on horses and the protocol of extraction of ASCs.Finally, this thesis has allowed developing a kit for veterinary use to treat equine tendinopathy. This new method of cell therapy has been tested in horses and has shown very promising results for tendon regeneration, knowing that treated horses could rapidly return to work
Labiad, Yasmine. "Contribution de l’approche transcriptomique dans la physiopathologie et le traitement des hémopathies malignes". Thesis, Aix-Marseille, 2016. http://www.theses.fr/2016AIXM4068.
The aim of this research is to demonstrate transcriptomic approach contribution in the physiopathology and treatment of hematological malignancies. In particular, how microarrays technology is used to study several oncohematology difficulties; which remain deaths-related infection, as well as the failure to obtain remission and death related relapse. In the first part, our focus was to study natural killer cells (Nks) in patients affected with acute myeloid leukemia (AML). We compared transcriptomic AML-NKs signature with healthy donors-NKs signature and suggested that ETS-1 transcription factor is a good candidate able to regulate the natural cytotoxicity receptors (NCRs), whose coding genes, are located on two different chromosomes even if their expression remain strongly coordinated.Our second part, aimed to predict sepsis using a transcriptomic approach in the case of autologous stem cell transplantation (auto-HSCT). Using the same model, in the third part, we highlighted the melphalan high-dose chemotherapy effect on peripheral blood mononuclear cells and identified a potential good biomarker of early relapse in patients affected by myeloma in the case of auto-HSCT.Our final focus was to analyze gene expression profile of HIV-related large diffuse B-cell lymphoma type in order to verify the existence of subgroups described in immune-competent patients
Bertoni, Lélia. "Évaluation du potentiel thérapeutique des cellules souches mésenchymateuses dans un modèle d'arthropathie expérimentale induite chez le cheval Characterization and use of Equine Bone Marrow Mesenchymal Stem Cells in Equine Cartilage Engineering. Study of their Hyaline Cartilage Forming Potential when Cultured under Hypoxia within a Biomaterial in the Presence of BMP-2 and TGF-ß1 Intra-Articular Injection of 2 Different Dosages of Autologous and Allogeneic Bone Marrow- and Umbilical Cord-Derived Mesenchymal Stem Cells Triggers a Variable Inflammatory Response of the Fetlock Joint on 12 Sound Experimental Horses An experimentally induced osteoarthritis model in horses performed on both metacarpophalangeal and metatarsophalangeal joints: Technical, clinical, imaging, biochemical, macroscopic and microscopic characterization Evaluation of allogeneic bone-marrow-derived and umbilical cord blood-derived mesenchymal stem cells to prevent the development of osteoarthritis in an equine model Chondrogenic Differentiation of Defined Equine Mesenchymal Stem Cells Derived from Umbilical Cord Blood for Use in Cartilage Repair Therapy". Thesis, Normandie, 2020. http://www.theses.fr/2020NORMC417.
Osteoarthritis is a common cause of pain and economic loss in both humans and horses. There is currently no curative treatment for osteoarthritis, because of the lack of spontaneous regenerative capacity of the articular cartilage. Mesenchymal stem cells (MSC) based regenerative medicine comes across as a promising strategy given their pro-regenerative and anti-inflammatory potential. The first objective of this study was to evaluate the safety of umbilical cord blood (UCB) and bone marrow (BM) derived MSC in healthy joints. The blind controlled study conducted on 12 experimental horses showed that the injection of BM-MSC caused significantly more signs of inflammatory reaction than the injection of UCB-MSC, and that the injection of MSC, regardless of their origin, caused a discrete to moderate inflammatory reaction, greater than that of the placebo, with great individual variability in sensitivity to the same cell line. The second objective was to evaluate the efficacy of BM-MSC and UCB-MSC in a model of induced osteoarthritis. The blind controlled study conducted on 8 experimental horses showed a significant reduction in the progression of osteoarthritis associated signs with imaging techniques after injection of allogeneic BM-MSC compared to placebo. These promising results, to be considered in light of the limitations of the studies, indicate a beneficial effect of allogeneic BM-MSC in the management of osteoarthritis in horses. They underline the need for further research to confirm these results, and to optimize the effects of MSC through their combination with a vector or through an acellular approach with administration of the nanovesicles they secrete that ared considered to be responsible for their therapeutic effects
Eilers, Smith Olivia. "Dérivation de cellules souches pluripotentes induites autologues à partir du clonage somatique équin". Thèse, 2013. http://hdl.handle.net/1866/11564.
For veterinarians, regenerative medicine in horses has focused mainly in the use of stem cells for arthritis, tendon and ligament repair, indicating a need for treating musculoskeletal injuries. The recent developments in cell reprogramming have paved the way for alternative cell sources for stem cell therapies. Autologous pluripotent stem cell lines can be derived from adult cells either by direct reprogramming through induced expression of pluripotency genes (iPS) or indirectly by reprogramming through somatic cell nuclear transfer (SCNT) followed by the derivation of embryonic stem cells (ESC). However, outcome efficiencies of SCNT and iPS protocols are invariably low, indicating that alone neither of these reprogramming routes is sufficient for deriving genetically and epigenetically stable pluripotent stem cells. We hereby report on the production of autologous equine iPS cells by combining SCNT and iPS reprogramming protocols. Adult skin fibroblasts were used for SCNT, and the resulting cloned embryos were either used to obtain cloned fetal fibroblast cells (ntFF), or used for ESC culture (ntES). Cells were then transfected with reprogramming factors to derive autologous iPS cells. Both ntFF-iPS and ntES-iPS cells are capable of extensive proliferation and express important pluripotency factors. However, ntES reprogramming efficiency is significantly higher than ntFF cells, with ntES-iPS colonies forming three times faster. Additionally, ntES-iPS cells showed improved pluripotency marker expression when compared with ntES cells. The results presented in this memoir indicate that stable equine iPS cell lines may be readily obtained from secondary reprogramming of cloned ntFF and ntES cells, opening novel avenues for developing autologous pluripotent stem cell therapies.
Alary, Anouck. "La conservation autologue de sang de cordon ombilical : une ouverture sur une forme émergente de «citoyenneté biologique»". Thèse, 2015. http://hdl.handle.net/1866/16231.
The recent transformation of cord blood to a precious source of stem cells has given rise to a global commercial industry of conservation, which is now competing with a large network of public cord blood banks. This dissertation explores the socio-cultural context surrounding the emergence of that industry and aims at elucidating the ethical and political concerns that it generates. It begins by examining how public cord blood banks define themselves (and are defined by ethical commitees) as purveyors of values such as altruism and national solidarity -that is, values which were traditionally linked to the « redistributive » model of human blood and organs exchanges that emerged after World War II. It next argues that private banks are bringing about a radical transformation of the relationship between mothers and their biological “products”. This dissertation suggests that this innovative model of exchange is an expression of contemporary reconfigurations of the very notion of community, which is now characterized by what we call new forms of “biosociality”. Our hypothesis is that these new socialities can be understood as the consequence of a collective hope to improve familial biological conditions, which is itself the product of the growing financiarization of life sciences. By way of a foray into the « promissive » discourse employed by private banks for their promotional material, the dissertation attemps to identify how these potentialities attributed to cord blood define new maternal subjectivities characterized by specific moral duties and obligations.