Cancer Research Programme Image The generation of hematopoietic stem cells from embryonic aortic (hemogenic) endothelial cells is a multi-step \ndynamic process. Extrinsic regulators (hypoxia, growth factors) and intrinsic factors (transcription, epigenetic) \ndirect the program for endothelial cell-to-hematopoietic stem cell transdifferentiation.\n The Dzierzak group has several linked programs of research: Molecular programs intrinsic to HSC generation and regeneration We are building on our previous and current novel reporter mouse models to image in real-time and identify the intrinsic regulators of endothelial cell-to-hematopoietic stem cell transition. Single cell ranscriptomics and genetic models are being used to identify mechanisms of action. Of particular interest are transcription factors (Gata2, Runx1) and other molecules (Gpr56, AhR) that show association with leukemias. Niche cells and extrinsic regulators of HSC generation and regeneration Extrinsic regulators such as BMP4, Hedgehog, inflammatory molecules and cytokines are our main area of focus. The role of early myeloid cells as part of the HCS generative niche is also being examined. Mouse embryo explant cultures, lineage tracing and genetic models are being used to examine the cell types and functions within the hemogenic niches. Following the identification and validation of bona fide extrinsic regulators, the homologues will be tested on human non-hematopoietic cells. Ex vivo production of therapeutic hematopoietic cells Using information from programs 1 and 2, we will culture various non-hematopoietic cells types in differentiation protocols and/or reprogramming protocols to induce hemogenic endothelial cell, hematopoietic progenitor and HSC generation. Reporter mouse cells are used in the first instance, followed by use of human somatic and/or iPS cells. Embryonic and induced pluripotent stem cell models are also being used for the production of functional innate immune cell types such as mast cells, to provide insight into disease and therapeutic strategies. Image Confocal microscopic imaging of Ly6a-gfp transgenic mouse aorta immunostained for ckit (hematopoietic cell marker) and CD31 (endothelial and hematopoietic cell marker) reveals the four populations of cells present during the time of endothelial-to-hematopoietic transdifferentiation - hematopoietic cells (HC), newly generated hematopoietic stem cells (HSC), endothelial cells (EC) and hemogenic endothelial cells (HEC). \n Image Therapies for blood-related deficiencies and genetic diseases rely on \nsources of normal hematopoietic stem cells (HSC), progenitors and/or differentiated blood cells. Reprogramming of patient-specific somatic cells with pivotal transcription factor genes or growth factors, either directly to HSCs or indirectly through induced pluripotent cells (iPS), holds great promise for hematologic regeneration strategies. \n\n This article was published on 2024-09-23
