Chronic alcohol consumption-mediated immune dysregulation elevates the risk of multiple diseases, yet how these immunological alterations manifest across tissues remains poorly understood. Here, we investigated the impact of chronic alcohol consumption on hematopoiesis and immune homeostasis across the bone marrow (BM), spleen (SP), and peripheral blood (PB) using female C57BL/6 mice fed a Lieber-DeCarli liquid diet with 6% (v/v) ethanol for 6 weeks. Alcohol consumption induced a mild hepatic injury, evidenced by increased liver weight, elevated plasma levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and hepatic steatosis without fibrosis. Immune phenotyping by high-dimensional spectral flow cytometry showed that, in the BM, alcohol expanded myeloid-biased multipotent progenitors 2 and 3 (MPP2 and MPP3), granulocyte-monocyte progenitors (GMPs), and macrophages. Conversely, the SP exhibited reduced abundance and proliferative activity of lineage-negative c-KIT-positive (LK) and megakaryocyte-erythroid progenitor (MEP) populations, resulting in impaired erythropoiesis. Despite these tissue-specific alterations, PB exhibited comparatively subtle and more variable changes than the BM and SP. These findings demonstrate that alcohol-mediated hematopoietic remodeling is tissue-specific and may not be fully captured by PB analyses. They further highlight the potential need for improved tissue-informed biomarkers and diagnostic approaches to detect and monitor alcohol-mediated immune remodeling beyond PB.
Generating functional haematopoietic stem cells (HSCs) from human pluripotent stem cells remains a major goal for both regenerative medicine and the study of early human blood development. Achieving this requires a clear understanding of how HSC identity is established during embryogenesis and how these developmental cues can be recreated in vitro. Recent work from Prof. Hanna Mikkola's group has defined transcriptional signatures and niche interactions that mark the emergence and maturation of human HSCs in vivo. Complementary studies from Professor Elizabeth Ng's team have developed human pluripotent stem cell-based systems that recapitulate key stages of this ontogeny, generating haemogenic endothelium and HSC‑like cells capable of long‑term multilineage engraftment. In this perspective, drawing on the recent ISEH NIC webinar presented by Profs. Mikkola and Ng, we integrate insights from both developmental and engineered systems to outline shared principles of human HSC formation and highlight opportunities to refine in vitro strategies for producing fully functional HSCs. Teaser Abstract What can human development teach us about building haematopoietic stem cells in the laboratory? Inspired by presentations from Profs. Mikkola and Ng at the 2025 ISEH NIC webinar, this perspective highlights the developmental and engineering principles that underpin human HSC formation and considers how these insights are advancing efforts to generate durable, engraftable HSCs for translational and regenerative applications.
