P1331: DISTINCT REACTIVITY TO ENVIRONMENTAL FACTORS OF YS VERSUS HSC DERIVED PROGENITORS DICTATE HEMATOPOIESIS IN THE MOUSE FETAL LIVER

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Topic: 23. Hematopoiesis, stem cells and microenvironment Background: During embryogenesis, the hematopoietic system is formed by waves of progenitors that arise from the yolk sac (YS) and dorsal aorta (DA). These waves converge to the fetal liver (FL), where they display distinct dynamics of proliferation and differentiation. New evidence by ourselves and others show that YS, but not hematopoietic stem cell (HSC)-derived progenitors, drives hematopoiesis during the fetal period. Aims: Our aim is to identify how these two progenitor types respond to environmental cues to understand embryonic hematopoiesis. Methods: We evaluated the FL stromal compartment by spectral flow cytometry and single-cell gene expression, from mid-to-late gestation. We performed 3D immunofluorescence of the FL to identify the different stromal and hematopoietic populations and developed a cell-segmentation pipeline to extract single-cell positions and perform neighborhood analysis, resulting in a network representation of the FL. For the localization of cytokine expressing cells we used Kitl- and Cxcl12-reporter mice. Results: Here, we analyzed the FL microenvironment and found that at early stages both YS and DA-derived progenitors accumulate at the periphery of the FL where Kitl is mainly produced by mesothelial cells and hepatoblasts. Also, whereas certain hematopoietic cytokines (Csf1, Tpo and Kitl) are expressed by multiple cell types, Epo and Il7 are exclusively expressed by hepatoblasts, suggesting a critical role for these cells. Cytokine levels increase from E12 to E14 and decrease thereafter, indicating that the microenvironment is most supportive for hematopoiesis at earlier stages. At E14, while YS-derived progenitors remain concentrated at the periphery, DA-derived progenitors spread throughout the parenchyma in response to increased Cxcl12 levels in perivascular cells, compatible with their later migration to the bone marrow. Summary/Conclusion: Overall, we identified a new component of the FL microenvironment: the mesothelium and the periphery region. We hypothesize that low cytokine levels accommodate both the differentiation of YS-progenitors and the expansion of the HSC compartment due to their distinct sensitivity to environmental cues. Keywords: Fetal, Hematopoietic stem and progenitor cells, Hematopoietic microenvironment

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