<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Dissection of heterogeneous hematopoietic stem cell biology in the homeostatic and disease-associated states"^^ . "The hematopoietic stem cell (HSC) compartment is considered heterogeneous at both functional and molecular levels in its ability to continuously generate all mature blood cells throughout life. With age, clonal hematopoiesis can develop, where an HSC clone disproportionally contributes to the blood cell lineages. This phenomenon has been associated with an increased risk of various diseases.\r\n\r\nIn the first part of this dissertation, I utilized single cell transplantations and mathematical modeling to interrogate the functional potency of individual HSCs and their paired progeny, and assess cell-extrinsic mechanisms modulating the functionality of HSCs. A large-scale comprehensive analysis of single HSC transplants revealed reconstitution kinetics as a novel parameter capable of predicting HSC transplantation outcomes. My data demonstrated a significant correlation between slower reconstitution kinetics and stemness, alongside a “myeloid-biased” behavior. Conversely, fast-reconstituting clones exhibited exhaustion patterns and classical “lymphoid-biased” outputs. Secondary transplantations of single daughter HSCs revealed a profound decline in functional potential compared to their parent HSC. Moreover, daughter HSC clones acquired faster reconstitution kinetics, correlating with loss of sustained myelopoiesis, and overall HSC potency. Mathematical modeling of single cell transplantation outcomes led to the identification of cell-extrinsic feedback mechanisms regulating the activity of individual HSCs. These data highlighted that the functional outcome of a single HSC is, in part, influenced by the activity of the surrounding HSCs, unlike assumptions of intrinsic programs solely governing HSC heterogeneity. This finding was experimentally validated by altering the single cell transplantation scheme, so that the single HSC was surrounded by lymphoid-deficient Rag2-/- cells. Slow and rapid engraftment kinetics could still be detected, indicating that repopulation dynamics are mostly an intrinsic feature of the HSC clone. However, I no longer observed canonical “myeloid-biased” outcomes, denoting that, on the contrary, lineage output of single HSCs is highly dependent on that of neighboring clones.\r\n\r\nIn the second part of my dissertation, I investigated the role of Tet2 clonal hematopoiesis of indeterminate potential (CHIP) on the evolution of hepatocellular carcinoma (HCC) with a non-alcoholic fatty liver disease (NAFLD) etiology, with the underlying hypothesis that Tet2 CHIP is as a risk factor for this disease. Dietary-induced HCC represents the fastest rising cancer in the western world, predominantly affecting the elderly population. This disease frequently evolves from an advanced stage of NAFLD, which is primarily characterized by chronic liver inflammation driven by infiltrating-hematopoietic cells. In this project, I employed a mouse model of Tet2-driven CHIP, combined with the administration of a high caloric “Western diet”, able to induce liver damage and faithfully recapitulate the sequential evolution of NAFLD and HCC observed in humans. Long-term assessment of disease progression demonstrated a synergistic effect when combining a Western diet and Tet2 CHIP. This was evidenced by increased serum levels of the biomarkers alanine and aspartate aminotransferases (ALT, AST), higher histopathological NAFLD assessment score (NAS), and a higher incidence of transition to HCC from premalignant stages. Molecular characterization of Western diet liver homogenates further confirmed this synergy, revealing higher degree of fibrosis, inflammation and dysregulated metabolism in Tet2 CHIP livers compared to wild type (WT) counterparts. To this end, a substantial part of my thesis focused on elucidating the mechanisms via which Tet2 CHIP contributes to HCC development. A combination of functional and molecular analysis, including scRNA-seq, bulk RNA-seq and metabolomics, have revealed synergistic programs in Tet2 CHIP Western diet mice. \r\n\r\nTaken together, this dissertation advances the field of hematology from two angles; homeostatic and disease. It provides a comprehensive understanding on HSC heterogeneity using large-scale and fine experimental approaches and mathematical modeling. Additionally, it identifies Tet2 CHIP as a potential risk factor for diet-induced liver cancer, offering mechanistic insights which could be exploited for therapeutic interventions."^^ . "2025" . . . . . . . "Esther"^^ . "Rodríguez Correa"^^ . "Esther Rodríguez Correa"^^ . . . . . . "Dissection of heterogeneous hematopoietic stem cell biology in the homeostatic and disease-associated states (PDF)"^^ . . . "Dissection of heterogeneous hematopoietic stem cell biology in the homeostatic and disease-associated states (Other)"^^ . . . . . . "Dissection of heterogeneous hematopoietic stem cell biology in the homeostatic and disease-associated states (Other)"^^ . . . . . . "Dissection of heterogeneous hematopoietic stem cell biology in the homeostatic and disease-associated states (Other)"^^ . . . . . . "Dissection of heterogeneous hematopoietic stem cell biology in the homeostatic and disease-associated states (Other)"^^ . . . . . . "Dissection of heterogeneous hematopoietic stem cell biology in the homeostatic and disease-associated states (Other)"^^ . . . . . "HTML Summary of #35058 \n\nDissection of heterogeneous hematopoietic stem cell biology in the homeostatic and disease-associated states\n\n" . "text/html" . . . "500 Naturwissenschaften und Mathematik"@de . "500 Natural sciences and mathematics"@en . .