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Zeitschriftenartikel zum Thema "Cellule stromale lymphoïde"
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Shakhpazyan, Nikolay, Liudmila Mikhaleva, Arkady Bedzhanyan, Zarina Gioeva, Nikolay Sadykhov, Alexander Mikhalev, Dmitri Atiakshin, Igor Buchwalow, Markus Tiemann und Alexander Orekhov. „Cellular and Molecular Mechanisms of the Tumor Stroma in Colorectal Cancer: Insights into Disease Progression and Therapeutic Targets“. Biomedicines 11, Nr. 9 (23.08.2023): 2361. http://dx.doi.org/10.3390/biomedicines11092361.
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Colorectal cancer (CRC) is a major health burden worldwide and is the third most common type of cancer. The early detection and diagnosis of CRC is critical to improve patient outcomes. This review explores the intricate interplay between the tumor microenvironment, stromal interactions, and the progression and metastasis of colorectal cancer. The review begins by assessing the gut microbiome’s influence on CRC development, emphasizing its association with gut-associated lymphoid tissue (GALT). The role of the Wnt signaling pathway in CRC tumor stroma is scrutinized, elucidating its impact on disease progression. Tumor budding, its effect on tumor stroma, and the implications for patient prognosis are investigated. The review also identifies conserved oncogenic signatures (COS) within CRC stroma and explores their potential as therapeutic targets. Lastly, the seed and soil hypothesis is employed to contextualize metastasis, accentuating the significance of both tumor cells and the surrounding stroma in metastatic propensity. This review highlights the intricate interdependence between CRC cells and their microenvironment, providing valuable insights into prospective therapeutic approaches targeting tumor–stroma interactions.
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Matsumoto, Mitsuru, Kikue Iwamasa, Paul D. Rennert, Takuji Yamada, Rika Suzuki, Akemi Matsushima, Masaru Okabe, Shigeru Fujita und Minesuke Yokoyama. „Involvement of Distinct Cellular Compartments in the Abnormal Lymphoid Organogenesis in Lymphotoxin-α-Deficient Mice and Alymphoplasia (aly) Mice Defined by the Chimeric Analysis“. Journal of Immunology 163, Nr. 3 (01.08.1999): 1584–91. http://dx.doi.org/10.4049/jimmunol.163.3.1584.
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Abstract Both lymphotoxin-α (LTα)-deficient mice and alymphoplasia (aly) mice, a natural mutant strain, manifest a quite similar phenotype: lack of lymph nodes (LN) and Peyer’s patches (PP), with disturbed spleen architecture. The mechanisms underlying the defective lymphoid organogenesis in these mice were investigated by generating aggregation chimeras; ex vivo fused morulae were implanted into pseudo-pregnant host females and allowed to develop to term. Chimeric mice between LTα-deficient mice and wild-type mice restored LN and PP almost completely, suggesting that LTα expressed by circulating bone marrow-derived cells is essential for lymphoid organogenesis as well as for organization of spleen architecture. By contrast, chimeric mice between aly mice and wild-type mice showed only limited restoration of LN and PP. This suggests that the putative aly gene product does not act as a circulating ligand for lymphoid organogenesis, like LTα. Rather, abnormal development of lymphoid organs in aly mice seems most likely due to the defective development of the incipient stromal cells of the LN and PP. Supporting this hypothesis, up-regulation of VCAM-1 on aly mouse embryonic fibroblasts by signals through LTβR, which is exclusively expressed by nonlymphoid cells, was disturbed. These studies demonstrate that LTα and the putative aly gene product together control lymphoid organogenesis with a close mechanistic relationship in their biochemical pathways through governing the distinct cellular compartments, the former acting as a circulating ligand and the latter as a LTβR-signaling molecule expressed by the stroma of the lymphoid organs.
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Nitta, Takeshi. „Understanding the Thymic Microenvironment: the Cellular and Molecular Basis of T Cell Development“. Central Asian Journal of Medical Sciences 2, Nr. 2 (25.11.2016): 111–26. http://dx.doi.org/10.24079/cajms.2016.02.002.
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Objectives: The thymus is a primary lymphoid organ that provides specialized microenvironment for T cell development. A variety of thymic stromal cells form the thymic tissue architecture and critically regulate the development and repertoire selection of T cells. Methods: We reviewed historical and recent studies on thymic stromal cells, especially focusing on the well-characterized functions of thymic epithelial cells (TECs) and the significance of as yet less characterized non-TEC thymic stromal cells and hematopoietic antigen-presenting cells in the regulation of T cell development. Results: Cortical TECs (cTECs) induce positive selection of diverse and functional T cells, while medullary TECs (mTECs) establish T cell tolerance via the negative selection of auto-reactive T cells and their conversion into regulatory T cells. These modes of T cell tolerance induction are also mediated by hematopoietic antigen-presenting cells such as dendritic cells and thymic B cells. Thymic mesenchymal cells, a prominent component of non-TEC thymic stromal cells, support the development and maintenance of TECs and thereby T cell production. Conclusion: Understanding the cellular and molecular basis for thymic stromal subsets will provide invaluable information toward in vivo reconstitution of the thymic microenvironment for future therapeutic applications.
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Shadlinskaya, S. V. „Cellular composition and microanatomy of lymphoid formations of the vestibule of the vagina in postnatal ontogenesis“. Sechenov Medical Journal 10, Nr. 1 (30.03.2019): 57–62. http://dx.doi.org/10.47093/22187332.2019.1.57-62.
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Aim - presents data on the number of cells of the lymphoid series and the cellular composition of the lymphoid tissue in the mucosa of the vaginal vestibule at different age periods of ontogenesis. Materials and methods. The study material was preparations of the vaginal vestibule taken from 45 women of different ages (from newborns to 75 years). By age periods, the material was subdivided according to the standard scheme of age periodization. Cross sections of the organ wall were stained with hematoxylin - eosin and according to Van Gieson. In a number of cases, the silvering of Grimelius was performed. Obtained during the study of digital data were subjected to statistical processing. Results. Analysis of the results showed that lymphoid formations are located mainly near the glands. Glandular - lymphoid relationships are less impressed in newborns, to the maximum extent from early childhood to the 1st period of adulthood, in the elderly and senile age of cells. There are fewer lymphoid rows near the initial divisions and in the stroma of the glands. The lymphoid apparatus of the vaginal vestibule is represented by all the morphogenetic forms of the lymphoid tissue. The qualitative composition of lymphoid tissue is of the same type in all its morphogenetic forms, regardless of age. It has been established that there are close microsynthopic connections between immune structures and small glands of the vestibule. The intensity of these relationships has ontogenetic features. They are relatively weak in new - borns, are maximal in early childhood and weaken after the 1st period of adulthood. Conclusion. The study allowed us to identify previously unknown patterns of morphogenesis of lymphoid structures of the vaginal vestibule.
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Cakala-Jakimowicz, Marta, Paulina Kolodziej-Wojnar und Monika Puzianowska-Kuznicka. „Aging-Related Cellular, Structural and Functional Changes in the Lymph Nodes: A Significant Component of Immunosenescence? An Overview“. Cells 10, Nr. 11 (12.11.2021): 3148. http://dx.doi.org/10.3390/cells10113148.
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Aging affects all tissues and organs. Aging of the immune system results in the severe disruption of its functions, leading to an increased susceptibility to infections, an increase in autoimmune disorders and cancer incidence, and a decreased response to vaccines. Lymph nodes are precisely organized structures of the peripheral lymphoid organs and are the key sites coordinating innate and long-term adaptive immune responses to external antigens and vaccines. They are also involved in immune tolerance. The aging of lymph nodes results in decreased cell transport to and within the nodes, a disturbance in the structure and organization of nodal zones, incorrect location of individual immune cell types and impaired intercellular interactions, as well as changes in the production of adequate amounts of chemokines and cytokines necessary for immune cell proliferation, survival and function, impaired naïve T- and B-cell homeostasis, and a diminished long-term humoral response. Understanding the causes of these stromal and lymphoid microenvironment changes in the lymph nodes that cause the aging-related dysfunction of the immune system can help to improve long-term immune responses and the effectiveness of vaccines in the elderly.
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Jansen, Caroline S., BaoHan Vo, Ewelina Sobierajska, Rachel Greenwald, Patrick Mullane, Nataliya Prokhnevska, Maria Cardenas et al. „Abstract B030: Form and function in intratumoral immune organization: Understanding the cellular composition of TCF1+ CD8+ T cell niches in human cancer“. Cancer Research 83, Nr. 16_Supplement (15.08.2023): B030. http://dx.doi.org/10.1158/1538-7445.kidney23-b030.
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Abstract Tumor infiltrating T cells are a positive prognosticator in many tumor types, and our prior work demonstrated that in renal cell carcinoma, patients with higher CD8 T cell infiltration have improved survival (Jansen Nature 2019). We described that this T cell response is supported by TCF1+ stem-like CD8 T cells, which reside within dense regions of closely clustered antigen presenting cells within the tumor. Interestingly, aggregations of immune cells have also been described in other settings and termed ‘tertiary lymphoid structures’ (TLS), raising an important question of whether the described immune niches are similar to these TLS or if they represent a distinct type of peripheral immune organization. In the work presented here, we use quantitative immunofluorescence image analysis to examine the cellular composition and organization of intratumoral immune niches, TLS, and secondary lymphoid tissue. The novel data presented here describes how immune niches are distinct from TLS and are more similar to the organization of T cell zones in secondary lymphoid tissue. Immune niches are T cell dominant structures, with T cell and antigen presenting cell compartments similar to T cell zones, whereas these niches profoundly lack the B cell presence seen in TLS and B cell zones of secondary lymphoid tissue. Immune niches are comparatively small in size (50-200um), while TLS are much larger (often >1mm), and, importantly, immune niches are found inside the tumor border, while TLS are located peripherally in tumor tissue. Notably, we find that immune niches have a marked presence of aSMA+ stromal cells, which are similar to those found in T cell zones but absent in B cell zones and TLS. When probed by flow cytometry and RNAseq, we find that aSMA+ stroma in immune niches are myofibroblast-like, similar those known to maintain the structure of secondary lymphoid tissues, and are distinct from those found in healthy kidney tissue. These data suggest these aSMA+ cells may play an important role in the organization of immune niches in tumor tissue. As we have shown that a robust T cell response is beneficial for patient outcomes, it is crucial to understand the mechanisms which support that response. Recently, our group defined that CD8 T cell activation in cancer is comprised of two phases, with an initial priming phase in the lymph node and a second phase of effector program acquisition in the tumor tissue (Prokhnevska Immunity 2023). We suggest that these immune niches represent an important hub for this development of T cell function, which is required for the robust, effective anti-tumor T cell response that supports improved patient outcomes and is the basis for the response to immunotherapy. Advancing our understanding of intratumoral immune organization will allow for enhanced biomarker discovery, improvement in existing therapies, and innovation in developing novel therapeutic strategies that will convert immunologically “cold” tumors to be immunologically “hot” and enhance anti-tumor immunity. Citation Format: Caroline S. Jansen, BaoHan Vo, Ewelina Sobierajska, Rachel Greenwald, Patrick Mullane, Nataliya Prokhnevska, Maria Cardenas, Mehmet Asim Bilen, Adeboye O. Osunkoya, Viraj A. Master, Haydn T. Kissick. Form and function in intratumoral immune organization: Understanding the cellular composition of TCF1+ CD8+ T cell niches in human cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr B030.
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Voermans, Carlijn, und Mette D. Hazenberg. „Cellular therapies for graft-versus-host disease: a tale of tissue repair and tolerance“. Blood 136, Nr. 4 (23.07.2020): 410–17. http://dx.doi.org/10.1182/blood.2019000951.
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Abstract The success of allogeneic hematopoietic cell transplantation depends heavily on the delicate balance between the activity of the donor immune system against malignant and nonmalignant cells of the recipient. Abrogation of alloreactivity will lead to disease relapse, whereas untamed allo-immune responses will lead to lethal graft-versus-host disease (GVHD). A number of cell types have been identified that can be used to suppress alloreactive immune cells and prevent lethal GVHD in mice. Of those, mesenchymal stromal cells and, to a lesser extent, regulatory T cells have demonstrated efficacy in humans. Ideally, cellular therapy for GVHD will not affect alloreactive immune responses against tumor cells. The importance of tissue damage in the pathophysiology of GVHD rationalizes the development of cells that support tissue homeostasis and repair, such as innate lymphoid cells. We discuss recent developments in the field of cellular therapy to prevent and treat acute and chronic GVHD, in the context of GVHD pathophysiology.
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Baron, Chloé S., Serine Avagyan, Song Yang, Aaron McKenna und Leonard Zon. „Abstract A27: Cellular barcoding of the leukemic niche reveals an apelin-mediated clonal expansion of niche endothelial and mesenchymal stromal cell clones“. Blood Cancer Discovery 4, Nr. 3_Supplement (01.05.2023): A27. http://dx.doi.org/10.1158/2643-3249.aml23-a27.
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Abstract Hematopoietic stem and progenitor cells (HSPCs) reside in niches that provide regulatory signals for their function. Perturbations such as acute leukemia induce cellular and molecular insults to the niche to support disease progression. Mutation of the MYC oncogene family is a frequent event leading to leukemogenesis. We developed a new zebrafish model of acute erythroid leukemia (AEL) by overexpression of human CMYC under the blood specific promotor draculin (drl). Analyses of drl:CMYC marrows demonstrated a significant expansion of progenitors and a decrease of erythroid, lymphoid and myeloid mature cells (fc=4.8, -4.5, -3.3, -6.5; p<0.000001). RNA-Sequencing of drl:CMYC marrows revealed an upregulation of the erythroid master regulator gata1a (fc=1.4, p=0.01) and fetal hemoglobins hbbe1.1/2 (fc=4.7, 2.9; p=0.0004). Primary and secondary transplantation of drl:CMYC marrows resulted in engraftment and disease propagation (7/7; 17/18). We used the cellular barcoding GESTALT technique to uniquely barcode single cells using CRISPR-CAS9 during embryonic development. We induced a round of barcoding at the one-cell stage and another one at 28 hours post-fertilization, the time of HSC birth. We injected these GESTALT embryos with drl:CMYC to induce AEL, barcode HSPCs and their niche to perform clone tracing. The number of HSPC clones was decreased by half compared to controls (p=0.008) indicative of a clonal expansion of the disease. We performed barcode and single-cell transcriptome profiling of flk1:GFP+ niche endothelial cells and found a significant decrease in the number of endothelial cells clones (fc= -3.5, p<0.05) paired with the identification of a novel AEL venous endothelial population upregulating 99 genes (fc>1; p<0.05) suggestive of angiogenesis likely supporting leukemogenesis. We sorted cxcl12a:dsRed+ niche stromal cells and found that AEL marrows have significantly less stromal clones (fc= -2.1, p<0.01) that are selectively amplified (>20% of the stromal compartment). We hypothesized that AEL expands a subset of stromal cells to promote disease progression and scRNA-Seq of 3,263 cxcl12a:dsRed+ stromal cells revealed an increased fraction of lepr+ mesenchymal stromal cells (MSCs, 66 vs 24% in controls). We hypothesized that AEL progenitors secrete a signal that can specifically remodel the marrow niche and we mined our scRNA-Sequencing data for a candidate ligand significantly upregulated in AEL cells compared to control HSPCs (fc>1; p<0.05) and paired receptors expressed on more than 20% of AEL associated endothelial and/or stromal cells. We identified the peptide hormone apelin expressed by the leukemia and tested if apelin alone could remodel the normal marrow niche endothelial and stromal cells by overexpressing apelin under the drl promotor. Adult marrow analyses revealed a decrease in the absolute number of stromal cells per marrow (fc= -2.2, p<0.001). Together our data support a model in which leukemia induces a clonal expansion of HSPC niche clones via apelin signaling to promote disease progression. Citation Format: Chloé S Baron, Serine Avagyan, Song Yang, Aaron McKenna, Leonard Zon. Cellular barcoding of the leukemic niche reveals an apelin-mediated clonal expansion of niche endothelial and mesenchymal stromal cell clones [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A27.
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Aggarwal, Vaishali, Radhika Srinivasan, Amanjit Bal, Pankaj Malhotra, Gaurav Prakash, Subhash Varma und Ashim Das. „Mutational Spectrum of Stromal Genes By Whole Exome Sequencing and Stromal-Cellular Interaction in Diffuse Large B-Cell Lymphoma“. Blood 126, Nr. 23 (03.12.2015): 2649. http://dx.doi.org/10.1182/blood.v126.23.2649.2649.
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Abstract Introduction: Morphological sub-classification of DLBCL into germinal center B-cell-like (GCB) and activated B-cell like (ABC) lacks sufficient reproducibility for risk stratification and predicting survival based on International Prognostic Index (IPI). The importance of stromal cells and their cross-talk with lymphoma cells is important in lymphomagenesis and progression. We postulate that mutations in stromal genes may regulate the rate of tumor progression in DLBCL and understanding the stromal-cellular interaction in DLBCL may help evolve better markers of prognostication and identify novel therapeutic targets. Methods: The study was approved by the Institute ethics committee and patients were enrolled after an informed consent. Frozen samples from 6 cases which included 4 cases of de novo nodal DLBCL (2 cases each of GCB and ABC subtypes as per Han's algorithm) and two control cases of non-neoplastic reactive lymphoid hyperplasia were subjected to AmpliSeqExome - Whole Exome Sequencing(WES) using Ion TorrentTM and compared against human reference genome (hg19). Torrent suiteTM 4.4 version (Life Technologies) and Ion ReporterTM software was used to perform tumor vs normal analysis by choosing variants for missense, frameshift insertions/ deletions, stoploss and single nucleotide variations (SNP). Filtering for common SNPs were done by UCSC common SNPs followed by inclusion in dbSNP and COSMIC and further filtered by predictive functional scores of SIFT < 0.05 and Polyphen (0.15 - 1.0). Variants were visualized using Integrated Genome Viewer (IGV) software. Bioinformatics analysis was done using PANTHER, STRING and PCViz and data mined for mutations in extracellular matrix genes. Selected genes were validated in DLBCL cases using Sanger sequencing BigDye terminator v3.1 cycle sequencing kit (Life Technologies) and ABI PRISM 3130 analyzer (Life Technologies). Further, in-vitro experiments were carried out to evaluate the effect of the conditioned media of CD19- stromal cells on the CD19+ lymphoma cells. Fresh tissue from 5 cases of nodal DLBCL were collected in RPMI 1640, 20% FBS and 1% penicillin and streptomycin and subjected to primary culture at 37°C and 5% CO2 humidified atmosphere. After 24 hours, the cultured cells were sorted into CD19+ and CD19- cells (BD FACSAriaTM) which were re-cultured for 24 hours separately. After this, the conditioned media of CD19- cells (comprising stromal cells predominantly) was transferred onto CD19+ cells and incubated for further 48 hours. Thereafter, cytokine (IL-6, IL-10, TNF-α, IFN-γ, IL-2, IL-4, IL-17) analysis of conditioned media in comparison to mock controls was performed using BD THI/THII kit (560484). Results: Analysis of filtered mutated genes using Panther revealed thirty four genes coding for extracellular matrix mutated specifically in GCB subtype and 26 mutated genes in ABC DLBCL. These genes were then analyzed for association in STRING. STRING identified LAMC3, AGRN, LAMA2, LAMB2, COL5A2, COL13A1,FN1,TGFB3, LTBP1 andADAMTS16 in GCB phenotype whereas LAMB1,LAMA3,COL4A2, COL28A1,COL5A3, IBSP, FGA, MUC6, MUC2, MUC5B,SPARCL1, VWF, GAS6 and USH2A were mutated in ABC DLBCL (Figure 1A and B). Mutations of COL5A2, COL13A1, LAMB2, MUC2, MUC6, and MUC5B were further validated using Sanger sequencing in individual DLBCL cases. This advocated the role of collagen scaffolding and laminin cross-linking in DLBCL progression. In vitro experiments for effect of stromal cells on the secreted cytokine profile revealed increased IL-6, IL-10, TNF-α, IFN-γ, IL-4, IL-17 levels respectively in the media of CD19+ sorted lymphoma cells upon addition of conditioned media of CD19-stromal cells in comparison to controls. Conclusion: Mutational profile of COL5A2, COL13A1, LAMB2, MUC2, MUC6, and MUC5B stromal genes in DLBCL may help in refinement of risk stratification based on morphology. The cross-talk between neoplastic cells and interacting tumor microenvironment cells has implications for therapy in DLBCL. GCB Mutation Profile ABC Mutation Profile Figure 1. Stromal gene signature profile in ABC and GCB subsets of DLBCL. Figure 1. Stromal gene signature profile in ABC and GCB subsets of DLBCL. Figure 2. Association among Stromal genes in GCB and ABC subtypes of DLBCL using STRING. Figure 2. Association among Stromal genes in GCB and ABC subtypes of DLBCL using STRING. Figure 3. Figure 3. Disclosures No relevant conflicts of interest to declare.
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Belli, Carmen, Gabriele Antonarelli, Matteo Repetto, Luca Boscolo Bielo, Edoardo Crimini und Giuseppe Curigliano. „Targeting Cellular Components of the Tumor Microenvironment in Solid Malignancies“. Cancers 14, Nr. 17 (01.09.2022): 4278. http://dx.doi.org/10.3390/cancers14174278.
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Cancers are composed of transformed cells, characterized by aberrant growth and invasiveness, in close relationship with non-transformed healthy cells and stromal tissue. The latter two comprise the so-called tumor microenvironment (TME), which plays a key role in tumorigenesis, cancer progression, metastatic seeding, and therapy resistance. In these regards, cancer-TME interactions are complex and dynamic, with malignant cells actively imposing an immune-suppressive and tumor-promoting state on surrounding, non-transformed, cells. Immune cells (both lymphoid and myeloid) can be recruited from the circulation and/or bone marrow by means of chemotactic signals, and their functionality is hijacked upon arrival at tumor sites. Molecular characterization of tumor-TME interactions led to the introduction of novel anti-cancer therapies targeting specific components of the TME, such as immune checkpoint blockers (ICB) (i.e., anti-programmed death 1, anti-PD1; anti-Cytotoxic T-Lymphocyte Antigen 4, anti-CTLA4). However, ICB resistance often develops and, despite the introduction of newer technologies able to study the TME at the single-cell level, a detailed understanding of all tumor-TME connections is still largely lacking. In this work, we highlight the main cellular and extracellular components of the TME, discuss their dynamics and functionality, and provide an outlook on the most relevant clinical data obtained with novel TME-targeting agents, with a focus on T lymphocytes, macrophages, and cancer-associated fibroblasts.
Dissertationen zum Thema "Cellule stromale lymphoïde"
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Barbier, Nicolas. „Étude du rôle des mécanismes épigénétiques dans la transition des cellules stromales mésenchymateuses en fibroblastes associés au cancer et dans l’acquisition de leurs propriétés pro-tumorales dans le lymphome folliculaire“. Electronic Thesis or Diss., Université de Rennes (2023-....), 2024. http://www.theses.fr/2024URENB011.
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Le lymphome folliculaire (FL) est le lymphome non-hodgkinien indolent le plus fréquent qui représente 20 à 25% des cas. Le FL est dans 90% des cas caractérisé par la translocation chromosomique t(14;18) des lymphocytes B, qui entraine la surexpression de BCL-2. Pour se développer, le FL est dépendant de son microenvironnement qui fournit notamment des signaux de survie et de prolifération aux lymphocytes B. Ce microenvironnement est composé en partie de cellules stromales lymphoïdes (LSC), qui, dans un contexte physiologique, structurent l’organe et soutiennent la mise en place de réactions immunitaires dans les centres germinatifs. En revanche, dans un contexte pathologique, ces cellules vont acquérir un phénotype pro-tumoral et sécréter des chimiokines telle que CXCL12, dérégulant l’homéostasie du tissus. Les mécanismes impliqués dans la transition de ces cellules vers un phénotype de type fibroblaste associé au cancer ne sont, à ce jour, pas connus. Au cours de mon projet de thèse, j’ai mis en évidence le rôle de KDM6B, une déméthylase spécifique de la marque H3K27, dans la différenciation des LSC physiologiques et pathologiques. J’ai également identifié une nouvelle voie de signalisation impliquée dans la différenciation pathologique des LSC, impliquant le facteur de transcription STAT1 sous l’influence de l’IL-4 sécrétée par les lymphocytes TFH. L’impact de l’activation de cette voie sur les lymphocytes B de FL reste encore à décrireFollicular lymphoma (FL) is the most common indolent non-Hodgkin's lymphoma, accounting for 20-25% of cases. In 90% of cases, FL is characterized by the chromosomal translocation t(14;18) in B lymphocytes, causing BCL-2 overexpression. FL is dependent on its microenvironment, which supplies survival and proliferation signals to the B cells. This microenvironment includes lymphoid stromal cells (LSC), which, in a physiological context, structure the organ and support the development of immune reactions in the germinal centers. However, in a pathological context, these cells acquire a protumoral phenotype and secrete chemokines such as CXCL12, deregulating tissue homeostasis. The exact process through which these cells transform into cancer- associated fibroblasts isn't fully understood. My project has therefore highlighted the role of KDM6B, a specific déméthylase of H3K27, in the differentiation of physiological and pathological LSCs. I also identified a new signaling pathway involved in LSCs pathological differentiation, involving the transcription factor STAT1, under the influence of IL-4 secreted by TFH. It remains to be described how activation of this pathway affects FL B cells
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Misiak, Jan. „The interactions of stromal cells and follicular helper T cells resulting in a B-cell supporting, IL4-producing phenotype in the context of follicular lymphoma“. Thesis, Rennes 1, 2016. http://www.theses.fr/2016REN1B030.
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Un microenvironnement riche en IL-4 a été mis en évidence dans le lymphome folliculaire (FL). Cette IL-4 impliquée dans la croissance tumorale a été démontrée comme principalement secrétée par les lymphocytes T follicular helper (Tfh). Dans cette étude, nous étudions l’interaction bidirectionnelle entre les cellules fibroblastiques réticulaires (FRC) dont le réseau est augmenté dans le FL et les lymphocytes Tfh par analyse des profils d’expression génique, et co-culture in vitro des lymphocytes Tfh primaires avec des cellules fibroblastiques humaines de type FRC-like. Nous démontrons que les cellules FRC-like augmentent in vitro la croissance des sous-populations de Tfh. De plus, nous avons mis en évidence une augmentation spécifique de la sécrétion d’IL-4 par les précurseurs Tfh (pre-Tfh) co-cultivés avec les cellules FRC-like, augmentation d’IL-4 impliquant les voies Notch et ICAM1/LFA1. Cette observation est particulièrement intéressante dans le contexte du FL car les lymphocytes pre-Tfh de FL comparés à des lymphocytes pre-Tfh d’amygdales non tumorales sont caractérisés par un profil d’expression génique enrichi en gènes des voies Notch et des intégrines en plus d’une surexpression d’IL-4. En conclusion, notre description de l’interaction entre les cellules stromales et les sous-populations Tfh démontrent une modification du profil cytokinique des Tfh au stade précurseur qui pourrait expliquer le profil cytokinique retrouvé dans le microenvironnement du FL, et apporter de nouveaux éléments pour la mise en évidence de nouvelles cibles thérapeutiquesThe enrichment of the microenvironment with tumor-promoting interleukin 4 (IL4) has been implicated in the pathogenesis of follicular lymphoma (FL) and was found to be conferred mainly by T follicular helper (Tfh) cells. In this study, we investigated the bidirectional crosstalk of fibroblastic reticular cells that are expanded in FL and Tfh cells with the analysis of gene expression profiles of the respective, and an in-vitro co-culture model of human induced FRC-like cells. We demonstrated that FRC-like cells enhance the growth of Tfh cell subsets in vitro. Crucially, we uncovered a specific upregulation of IL-4 secretion by precursor Tfh (pre-Tfh) cells co-cultured with FRC-like cells. Additionally, we demonstrated that Notch and ICAM1/LFA1 are two pathways involved in IL-4 secretion following FRClike cell / Tfh cell crosstalk. This observation was particularly interesting in FL context, because FL pre-Tfh cells display an enriched Notch and integrin gene expression profile as well as an overexpression of IL-4, compared to their tonsil counterpart. Altogether, we described new interactions between stromal cells and Tfh subsets and uncovered a specific cytokine profile modification at pre-Tfh stage after contact with FRC-like cells that could explain the high levels of IL-4 in FL and provide a novel target for therapy
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Pandey, Shubham. „Identification of Interleukin 4 - CXCL12 supportive loop in follicular lymphoma“. Thesis, Rennes 1, 2016. http://www.theses.fr/2016REN1B031/document.
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Le lymphome folliculaire (FL) est le lymphome B indolent le plus fréquent. Outre des altérations géniques récurrentes, le micro-environnement tumoral, et notamment les cellules stromales lymphoides,joue un rôle majeur dans le développement de ce cancer. Cependant, la caractérisation in-situ des cellules stromales lymphoïdes chez l'homme tout comme les facteurs menant à la polarisation du stroma en un stroma protumoral ont été peu étudiés. Dans cette thèse, nous avons montré, que les cellules stromales présentes dans les ganglions et la moelle osseuse envahis des patients atteints de FL surexpriment fortement la chimiokine CXCL12. Nous avons ensuite tenté de comprendre les mécanismes responsables de cette induction. Alors que les cellules B tumorales induisent une surexpression de la chimiokine CCL2 dans les cellules stromales de façon dépendante de leur synthèse de TNF, elles ne contribuent pas à l'induction de CXCL12. A l'inverse, le principal compartiment TCD4 impliqué dans la croissance tumorale du FL, les cellules T follicular helper (TFH), augmentent l'expression de CXCL12 dans les cellules stromales. Le taux d'IL-4, la principale cytokine produite par les TFH de FL, est d'ailleurs corrélé à celui de CXCL12 au sein de ma niche tumorale du FL. De plus, à l’aide d'un modèle de différenciation en stroma lymphoide, nous avons démontré que l’IL4 induit l’expression de CXCL12 par les cellules stromale in vitro. Cette production est augmentée quand les cellules stromales sont déjà engagées vers la voie de différentiation lymphoide par un traitement TNF/LT qui favorise l'activation de STAT6 par l'IL-4. Nous avons validé ces résultats dans un modèle de formation d'organe lymphoide ectopique chez la souris. Enfin, CXCL12 induit la migration et l'adhésion au stroma des B de FL via l'activation de cascades de signalisations qui peuvent être abrogées par l'utilisation d'un inhibiteur de Btk utilisé en clinique, l'Ibrutinib. Ces résultats sont en faveur de l'intérêt de considérer la boucle IL-4/CXCL12 pour développer de nouvelles stratégies thérapeutiques dans cette pathologie constamment fataleFollicular lymphoma (FL) is the most frequent indolent B-cell lymphoma. Beside recurrent genetic alterations, tumor microenvironment, including lymphoid stromal cells, has been shown to play a key role in FL development. However, in situ characterization of lymphoid stromal cells is still lacking in humans and there are very few studies focusing on the factors that could lead to stroma polarization in normal and pathological context. In this thesis, we showed first that in FL, lymph node (LN) and bone marrow (BM) infiltrating stromal cells highly express the chemokine CXCL12. We next focused on the mechanisms underlying this upregulation. Interestingly, whereas malignant FL B cells induced overexpression of CCL2 in stromal cells in a TNF-dependent manner, they did not contribute to CXCL12 induction. Conversely, FL-infiltrating follicular helper T cells (FL-TFH), the key FL-supportive T-cell subset could trigger CXCL12 expression in stromal cells. IL-4 is the main FL-TFH-derived cytokine and showed a positive correlation with CXCL12 expression inside FL cell niches. Moreover, based on our in vitro lymphoid stroma differentiation model, we demonstrated that IL-4 promoted CXCL12 expression in stromal cells, together with a phenotype close to that identified in situ within FL cell niche. Such IL4 dependent CXCL12 regulation is more pronounced in stromal cells already committed towards lymphoid stromal cells by a prestimulation by TNF/LT in association with an increased STAT6 activation. These data were validated in a model of ectopic lymphoid organ formation in mice. Finally, CXCL12 induced FL B-cell migration, and adhesion to stromal cells through the activation of a signaling pathway that could be abrogated by the Btk inhibitor Ibrutinib. These data argue for considering IL-4/CXCL12 axis as a potential therapeutic target to disrupt FL protective cell niche in this still fatal malignancy
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Grégoire, Murielle. „Polynucléaires neutrophiles, cellules stromales, lymphocytes B : interaction tripartite dans la niche des lymphomes B“. Thesis, Rennes 1, 2014. http://www.theses.fr/2014REN1S156/document.
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Les polynucléaires neutrophiles ont longtemps été considérés comme des cellules n’intervenant que dans la réponse immune innée. Cependant, au cours de ces dernières années, de nombreuses publications suggèrent que ces cellules, retrouvées au sein du microenvironnement de nombreux cancers, pourraient également jouer un rôle dans la tumorigénèse et la progression tumorale. Ces études mettent en évidence leur fréquence comme marqueur pronostique dans différents cancers solides, mais peu de travaux se sont intéressés à la caractérisation fonctionnelle de ces cellules dans la progression tumorale. Dans de nombreux cancers dont les lymphomes B issus du centre germinatif, les cellules tumorales, qui sont incapables de proliférer et de survivre seules, sont dépendantes de leur microenvironnement de soutien. Dans cette étude, nous avons évalué la fonctionnalité des polynucléaires neutrophiles dans la croissance des lymphomes B. Ainsi, nous avons démontré pour la première fois que les polynucléaires neutrophiles soutiennent directement la croissance et la survie des cellules tumorales de lymphomes B. De plus, un dialogue bidirectionnel existe entre les polynucléaires neutrophiles et les cellules stromales. D’une part, les cellules stromales soutiennent la survie des polynucléaires neutrophiles, qui en retour induisent les caractéristiques d’un stroma lymphoïde. L’induction de ce phénotype permet aux cellules stromales d’acquérir de meilleures capacités de soutien envers les cellules tumorales. Cette étude confirme donc que les polynucléaires neutrophiles sont une composante importante du microenvironnement tumoral, et pourraient devenir une nouvelle cible thérapeutique pour le traitement des lymphomes B issus du centre germinatifFor long time, neutrophils have only been considered as cells involved in the innate immune response. More recently, in descriptive publications, neutrophils were found in the microenvironment of many solid cancers, hypothesizing that they could also play a role in tumorigenesis and cancer progression. These studies highlighted the prognostic value of their frequency, but few of them focused on the functional characterization of these cells in tumor growth. In many cancers, including germinal centre-derived B-cell lymphomas, tumor cells are dependent on their microenvironment to proliferate and survive. In this study, we focused on the role of neutrophils in the progression of B-cell lymphomas, and for the first time we demonstrated that neutrophils directly support the growth and survival of tumor Bcells. In addition, we highlighted the existence of bidirectional cooperation between neutrophils and stromal cells. In one hand stromal cells support the survival of neutrophils. On the other hand, neutrophils induce a lymphoid stroma phenotype which is well known to enhance their supportive effect on tumor cells. This study demonstrates that neutrophils are a significant component of the tumor microenvironment and may be considered as a potential therapeutic target for the treatment of B-cell lymphomas
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Lemoine, François. „Etudes des interactions entre les cellules stromales et les progeniteurs lymphoides b“. Paris 7, 1989. http://www.theses.fr/1989PA077206.
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Le but de cette these est d'etudier les mecanismes regulant la proliferation des cellules pre-b normales et de determiner leur alteration au cours de la transformation maligne des cellules pre-b. Differentes etudes realisees a partir de modeles animaux ou de cultures a long terme indiquent que les cellules stromales jouent un role cle. Aussi un certain nombre de lignees stromales supportant la croissance des cellules pre-b de meme que des lignees cellulaires pre-b ont ete isolees, clonees et caracterisees. Certaines de ces lignees pre-b ont ete transformees soit spontanement soit par le virus abelson. Ces differentes lignees utilisees dans des experiences de cocultures ont montre que les cellules stromales secretaient un facteur stimulant pre-b correspondant a une molecule de 10 kd differente des facteurs de croissance hematopoietiques deja connus. Le role des composants de la matrice extracellulaire dans le controle de la croissance cellulaire pre-b par le stroma a aussi ete etudiee. Il a ete trouve que les cellules pre-b attachaient specifiquement a la fibronectine et que celle-ci bien qu'elle ne puisse pas supporter la proliferation cellulaire pre-b contribuait toutefois a la stimulation de la croissance pre-b par le stroma. L'etude de populations pre-b transformees montrent que l'ensemble de ces mecanismes sont alteres. Ainsi, les cellules pre-b apres transformation secretent une nouvelle activite autocrine de 3 kd capable egalement de stimuler les cellules pre-b normales et perdent considerablement leur propriete d'adhesion a la fibronectine
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Bresler, Priscillia. „Étude de la régulation des cellules lymphoïdes innées par les lymphocytes T chez la souris“. Electronic Thesis or Diss., Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCB078.
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Plusieurs rapports de la littérature ont relaté que la composition, la fréquence et l'activité des ILC sont fortement impactées dans le contexte d'un déficit du système immunitaire adaptatif chez la souris. Cependant les mécanismes par lesquels l'immunité adaptative régule l'homéostasie des ILC restent en grande partie inconnus. L'objectif de ma thèse a été dans un premier temps d'évaluer l'implication des lymphocytes T dans cette régulation au sein de tissus lymphoïdes tels que les ganglions périphériques et mésentériques et dans l'intestin grêle. Dans un deuxième temps, j'ai entrepris d'identifier les mécanismes de régulation impliqués dans le dialogue entre ILC et lymphocytes T et de déterminer leur spécificité tissulaire. Au cours de ma thèse j'ai pu confirmer que la régulation des ILC3 NKp46+ sécrétrices d'IL-22 de la lamina propria de l'intestin par les lymphocytes T CD4+ repose sur la capacité de ces derniers à participer au confinement des bactéries commensales. Par ailleurs, j'ai également mis en évidence un rôle encore peu étudié des lymphocytes T CD4+ dans la régulation de la fréquence et de l'activité des ILC de type 2 dans les ganglions mésentériques. Ce dernier est indépendant de l'activation des lymphocytes T CD4+ par les antigènes du microbiote et repose en partie sur la régulation indirecte de l'expression de l'alarmine IL-33. En effet, j'ai montré que l'expression du gène codant l'IL-33 est augmentée dans les ganglions mésentériques en absence de lymphocytes T et que la neutralisation de l'IL-33 à court terme a pour effet de réduire significativement la fréquence des ILC2 et leur production de cytokines dans les ganglions mésentériques de souris dépourvues de lymphocytes T. Une collaboration avec le laboratoire de Lucie Peduto à l'Institut Pasteur a permis de montrer que les lymphocytes T pourraient indirectement réguler l'expression de l'IL-33 au sein du compartiment stromal des ganglions mésentériques. Il reste cependant à déterminer les mécanismes par lesquels les lymphocytes T régulent l'expression de l'IL-33 dans les cellules stromales des tissus lymphoïdes. Enfin, l'intervention d'autres facteurs environnementaux dépendants des lymphocytes T reste également à évaluer. Des expériences préliminaires indiquent que les lymphocytes B pourraient jouer un rôle non-redondant dans la régulation des ILC2 par les lymphocytes T dans un contexte de reconstitution du système immunitaire adaptatifMany articles in the literature report that the composition, the frequency and the activity of ILCs are strongly affected when the adaptive immune system is deficient in mice. However, the mechanisms by which adaptive immunity regulates the homeostasis of ILCs remain largely unknown. The objective of my thesis was to address the role played by T cells in this regulation within lymphoid tissues such as peripheral and mesenteric lymph nodes and in the small intestine. I also characterised some of the regulatory mechanisms involved in this dialogue between ILCs and T cells and determined their tissue specificity. During my thesis, I confirmed that the regulation of gut resident ILC3 by CD4+ T cells is based on their ability to participate in the containment and diversification of bacterial communities colonizing the gut. In addition, I have also highlighted the role of CD4+ T cells in the regulation of the frequency and activity of type 2 ILCs in the mesenteric lymph nodes. The latter does not rely on the activation of CD4+ T cells by the gut microbiota. Indeed, I showed that the expression of the gene encoding IL-33 is increased in the mesenteric lymph nodes of T cell deficient mice and that the short-term neutralization of IL-33 signalling in vivo significantly reduces the frequency of type 2 ILCs in the mLNs of these mice. In collaboration with Lucie Peduto's team, we showed that T lymphocytes indirectly regulate the expression of IL-33 by mesenteric lymph nodes stromal cells. However, the mechanisms underlying these interactions remain to be elucidated. Finally, the role of other T-cell dependent environmental factors remains to be characterised. Indeed, our preliminary results indicate that T-B cooperation may be instrumental in the regulation of mesenteric lymph nodes resident ILC2 while it is redundant in the regulation of gut resident type 3 ILCs by CD4+ T cells
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Crompot, Emerence. „Caractérisation phénotypique et impact fonctionnel des vésicules extracellulaires issues de cellules stromales mésenchymateuses sur les lymphocytes B de Leucémie Lymphoïde Chronique“. Doctoral thesis, Universite Libre de Bruxelles, 2017. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/245872.
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La Leucémie Lymphoïde Chronique (LLC) est la leucémie la plus fréquente des pays occidentaux. Cette maladie est caractérisée par l’accumulation de lymphocytes B (LB) monoclonaux (CD5+/CD19+/CD23+) dans le sang, la moelle et les organes lymphoïdes secondaires. Malgré d’importants progrès durant cette dernière décennie, la LLC reste incurable avec les traitements classiques. De manière intéressante, son évolution clinique est hétérogène :certains patients ne présenteront aucun symptôme alors que d’autres évolueront rapidement nécessitant une intervention thérapeutique. De nombreuses interactions entre les cellules leucémiques et le microenvironnement (ME) médullaire, composé entre autres de cellules stromales mésenchymateuses (CSM) sécrétant une matrice extracellulaire, jouent un rôle important dans la survie cellulaire et la résistance à la chimiothérapie. Actuellement la nature des communications entre le clone leucémique et son ME n’est pas encore complétement élucidée. Notre objectif est d’étudier l’impact des vésicules extracellulaires (VEs abréviées ici EVs) (microparticules et exosomes) du ME, spécifiquement des CSM, sur les LB de LLC. Dans la 1ère partie de ce travail, nous nous sommes intéressés à la caractérisation des microparticules (MPs) par cytométrie en flux (CMF). Cette technique est un des meilleurs moyens de déterminer le phénotype des MPs, elle permet d’étudier les vésicules de 300 nm à 1 µm, excluant donc les exosomes, dont la taille est inférieure à 100 nm. Nous avons ainsi pu caractériser les MPs provenant de plaquettes et d’érythrocytes grâce à la présence respective des antigènes CD41/61 et du CD235a. Par contre, concernant les antigènes classiques des cellules mononucléées (CD3-14-19-20-56), aucun antigène n’a pu être détecté sur les MPs provenant des lymphocytes T (LT), des monocytes, des LB normaux et leucémiques et des cellules ‘’natural killer’’ (NK). Le signal positif obtenu dans certains cas était la conséquence d’un marquage aspécifique. Nous avons dès lors proposé un contrôle négatif supplémentaire qui ne se limite pas à l’utilisation d’isotypes mais qui se base sur des marquages croisés. Grâce à ce travail, nous avons démontré que les MPs dérivant de cellules positives pour un antigène donné n’étaient pas automatiquement positives pour ce dernier. Dans la seconde partie du travail, nous avons étudié les MPs et les exosomes provenant du ME médullaire, regroupés sous le terme EVs. Nous avons démontré que leur intégration dans les LB de LLC est très rapide et qu’elle permet une diminution de l’apoptose ainsi qu’une augmentation de la viabilité et de la migration des cellules leucémiques. Les EVs augmentent leur chimiorésistance vis-à-vis de différents agents leucémiques. A l’aide de la technologie Affymetrix, nous avons comparé les profils d’expression génique des LB leucémiques, ayant reçu ou non des EVs du ME. Ces analyses ont mis en évidence 805 gènes différentiellement exprimés entre les deux conditions. Une grande partie de la signature obtenue suite à l’intégration des EVs, partage de nombreuses similitudes avec des signatures de LB de LLC ayant eu un contact avec des cellules nourricières ou ayant reçu différents stimuli. Le point commun parmi ces différentes signatures est l’activation de la voie du ‘’B-cell receptor’’ (BCR) ;les EVs de CSM semblent en effet avoir la capacité d’induire dans les LB de LLC une réponse semblable à celle d’une activation BCR. Dans cette étude, nous avons démontré que le ME médullaire, en plus d’interagir par contact direct avec les LB de LLC et par la production de facteurs solubles, est également capable d’influencer le comportement des cellules leucémiques via la production d’EVs. Nos données suggèrent un rôle important des EVs dans la survie cellulaire et l’évolution de la LLC et ouvrent donc la porte à de nouvelles cibles thérapeutiques.Doctorat en Sciences biomédicales et pharmaceutiques (Médecine)
info:eu-repo/semantics/nonPublished
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Camara, Abdouramane. „Control of lymphoid organ CD169+ macrophage differentiation by stromal cells through the RANK-RANKL axis“. Thesis, Strasbourg, 2019. http://www.theses.fr/2019STRAJ102.
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Au-delà de leurs rôles de sentinelles, de reconnaissance du danger et d’initiation des réponses protectrices, les signaux et le mécanisme qui gouvernent la formation des macrophages CD169 + sinusoïdaux ganglionnaires sont mal connus. Au cours de ma thèse, j’ai montré que la cytokine Receptor Activator of NF-kB Ligand (RANKL) est requise pour la formation de ces macrophages dès l’embryogenèse jusqu’aux quatre semaines après la naissance. Celle-ci est contrôlée par les cellules endothéliales lymphatiques (LECs) activées par RANKL produite par les cellules mésenchymateuses. Chez l’adulte, les LECs activées par RANKL sont encore nécessaires pour la reconstitution des populations de ces macrophages en cas de déplétion transitoire induite par un stimulus inflammatoire. En complément à cela, j’ai aussi démontré l’importance générale du double signal RANKL & lymphotoxine LTα1β2 dans la formation des macrophages non-ostéoclastiques de la rate et de la moelle osseuseLymph node CD169 + sinusoidal macrophages are sentinel cells that recognize the danger signals and initiate the protective immune responses. However, the signals and the mechanism underlying their formation are not well known. During my thesis, I have shown that the cytokine Receptor Activator of NF-kB Ligand (RANKL) is required for their differentiation, starting from the embryogenesis up to four weeks after birth. The lymphatic endothelial cells (LECs) activated by RANKL expressed by mesenchymal cells form the niches for the primary differentiation of these macrophages. Yet, in adults, RANKL-activated LECs are required for their niche replenishment after transient depletion induced by an inflammatory stimulus. Beyond lymph node, my research has revealed a general requirement of the double signal RANKL & lymphotoxin LTα1β2 for the differentiation of non-osteoclastic CD169 + macrophages of spleen and bone marrow
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Stzepourginski, Igor. „Identification of lymph node and intestinal lymphoid stromal cell subsets with key roles in immunity and homeostasis“. Paris 7, 2014. http://www.theses.fr/2014PA077148.
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Les cellules stromales lymphoïdes (LSCs) sont des cellules non-hématopoïétiques essentielles à l'initiation et au maintien de réponses immunitaires performantes. Caractérisées par l'expression de la podoplanine (gp38), les LSCs sont présentes à l'état basal dans les organes lymphoïdes secondaires et sont induites par l'inflammation dans tous les tissus périphériques. Dans l'intestin, les cellules exprimant gp38 constituent la majorité des cellules non-hématopoïétiques de la lamina propria. Nous avons montré que l'expression de gp38 définit une population très hétérogène de cellules aux fonctions parfois très distinctes des LSCs. Les cellules gp38+CD34- sont des myofibroblastes sous-épithéliaux situés dns les villi et spécialisés dans la différentiation d l'épithélium. Situées dans les cryptes, les cellules gp38+CD34+VCAM+ sont similaires aux LSCs des ganglions lymphatiques : elles se développent peu après le sevrage et promeuvent l'attraction et la survie des lymphocytes. En revanche les cellules gp38+CD34+VCAM- sont programmées lors du développement embryonnaire et jouent un rôle déterminant dans le maintien de l'activité des cellules souches intestinales. Afin d'identifier les précurseurs des LSCs pendant l'inflammation, nous avons développé une souris transgénique permettant de suivre la descendance des cellules exprimant le récepteur à la lymphotoxine-beta (LTβR), une protéine essentielle au développement des ganglions lymphatiques et à la maturation des LSCs. Nous avons montré pour la première fois qu'une sous-popultion de péricytes exprimant LTβR génère des LSCs dans le ganglion pendant l'inflammationLymphoid stromal cells (LSCs) are non-hemaopoietic cells pivotal in building and maintaining efficient immune responses. LSCs are described as podoplanin (gp38)- expressing cells and are present in secondary lymphoid organs at steady state. Moreover, LSCs are induced by inflammation and some tumors in the periphery. In the intestinal lamina propria, gp38+LSCs compose the majority of the non-hematopoietic cells at steady state. We showed that gp38+intestinal stromal cells are very heterogeneous and contain cells distinct from LSCs that populate different niches in the lamina propria. Gp38+CD34- stromal cells are subepithelial myofibroblasts located in the upper lamina propria that promote the differentiation of epithelial cells. In the crypts, gp38+CD34+VCAM+ stromal cells are the equivalent of LSCs found in lymphoid organs : they develop around weaning to attract lymphocytes into the lamina propria and promote their survival. However, gp38+CD34+VCAM- stromal cells develop during ontogeny and maintain the activity of intestinal epithelial stem cells in the crypts. In order to identify LSC progenitors during inflammation we developed a transgenic mouse model allowing for the fate-mapping of cells expressing lymphotoxin beta receptor (LTβR), a key protein involved in the development of lymphoid organs and LSC maturation. We showed for the first time that a subset of pericytes expressing LTβR give rise to LSCs during inflammation-induced expansion of the lymph node
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Passaro, Diana. „Dissection of phenotypic traits and molecular mechanisms underlying Cn/NFAT pathway activation in T-ALL“. Paris 7, 2013. http://www.theses.fr/2013PA077263.
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En dépit de leur efficace réponse initiale de la chimiothérapie, la rechute reste fréquente chez les patients atteints de LAL-T. Les résultats précédents du laboratoire ont révélé que Cn a une fonction pro-oncogène dans les LAL-T. L'utilisation d'un modèle murin de LAL-T induite par ICN1, dans lequel la suppression de Cn est restreinte aux cellules leucémiques, nous avons démontré que Cn est intrinsèquement requise pour la capacité des cellules leucémiques à propager la maladie activité LIC). De plus, le traitement avec la vincristine et l'inactivation de Cn coopèrent pour induire une rémission long terme des LAL-T. Au niveau phénotypique, la suppression de Cn modifie les interactions fonctionnelles entre cellules leucémiques et stroma ex vivo, résultant en réduits survie, prolifération, migration et potentiel clonogénique. Au niveau moléculaire, l'analyse transcriptomique a révélé que la suppression de Cn est associée à la dérégulation d'expression de > 400 gènes. Nous avons analysé les conséquences de la régulation positive de CDKN1A induite par la suppression de Cn, montrant qu'elle participe probablement au blocage du cycle cellulaire observé dans les cellules leucémiques Cn-déficientes. Nous avons également constaté que l'expression de surface de CXCR4 est négativement régulée suite à la suppression de Cn, un mécanisme que nous avons trouvé impliqué dans la réduction de motilité de cellules Cn-déficientes. Enfin, en utilisant des LAL-T induite par ICN1 dans lesquelles les gènes NFATcl, NFATc2 et NFATc3 peuvent être inactivés, nous avons démontré un rôle pour NFAT dans la survie, prolifération, motilité et activité LIC des cellules leucémiquesDespite their initial efficient response to induction chemotherapy, relapse remains frequent in patients with T-ALL. Previous results from the laboratory revealed that Cn is active and has a pro-oncogenic fonction in mouse models of human T-ALL. Using an ICN1-induced T-ALL mouse model, in which conditional Cn genetic deletion is restricted to leukemic cells, we demonstrated that Cn is intrinsically required for the ability of leukemic cells to propagate the disease (LIC activity). Importantly, combination of vincristine treatment with Cn inactivation cooperated to induce long-term remission of ICN1-induced T-ALL. Phenotypically, Cn deletion altered the functional interactions between leukemic cells and the supportive MS5 stromal cell line ex vivo, resulting in reduced leukemic cell survival, proliferation, migration and clonogenic potential. At the molecular level, transcriptomic analysis revealed that Cn deletion was associated with the deregulation of the expression of >400 genes. We analysed the consequences of Cdkn la (p21) up-regulation upon Cn deletion, showing that it likely participates to the cell cycle arrest observed in Cn-deficient leukemic cells. We also found that expression of Cxcr4 was down-regulated at the surface of leukemic cells upon Cn deletion, a mechanism that we found responsible of the decreased motility of Cn-deficient leukemic cells. Finally, using ICN1- induced T-ALL mouse m odel in which NFATc 1, NFATc2 and NFATc3 genes could be conditionally inactivated, we demonstrated a role for NFAT in the survival, proliferation, motility and LIC activity of leukemic cells
Buchteile zum Thema "Cellule stromale lymphoïde"
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Mueller, C. G., S. Nayar, J. Campos und F. Barone. „Molecular and Cellular Requirements for the Assembly of Tertiary Lymphoid Structures“. In Stromal Immunology, 55–72. Cham: Springer International Publishing, 2018. http://dx.doi.org/10.1007/978-3-319-78127-3_4.
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Zhang, Leisheng, Xiaorong Bai, Shan Huang, Jiechao Ma, Yuan Meng, Xiaoming Feng, Tiankang Guo und Hui Cai. „Hematopoietic Stem Cells in Regenerative Medicine“. In Stem Cells in Clinical Application and Productization, 29–57. BENTHAM SCIENCE PUBLISHERS, 2024. http://dx.doi.org/10.2174/9789815196627124010006.
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Hematopoietic stem cells (HSCs) are a common origin of blood cells and the intermediate progenitor cells and precursor cells including the myeloid or lymphoid lineages, which are the footstones of short-term and long-term blood regeneration. HSCs are precisely orchestrated by the constituents in the hematopoietic microenvironment in the bone marrow niches such as stromal cells, immune cells, and cytokines. The dysfunction and genetic variations of HSCs might lead to hematopoietic abnormality, haematopoietic equilibrium and even hematologic malignancies. Meanwhile, the cellular and molecular mechanisms of HSC maintenance and differentiation according to the niche are of great importance for disease administration via hematopoietic stem cell transplantation (HSCT). In the chapter, we mainly focus on the works of literature on the definition, biological phenotypes, preclinical investigation and clinical trials of HSCs, which will collectively facilitate the clinical application of HSCT and the relative regenerative medicine for hematological diseases and immune diseases in future.