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Hematopoietic stem cell (HSC)-independent lymphopoiesis has been elucidated in murine embryos. However, our understanding regarding human embryonic counterparts remains limited. Here, we demonstrated the presence of human yolk sac-derived lymphoid-biased progenitors (YSLPs) expressing CD34 , IL7R , LTB , and IRF8 at Carnegie stage 10, much earlier than the first HSC emergence. The number and lymphopoietic potential of these progenitors were both significantly higher in the yolk sac than the embryo proper at this early stage. Importantly, single-cell/bulk culture and CITE-seq have elucidated the tendency of YSLP to differentiate into innate lymphoid cells and dendritic cells. Notably, lymphoid progenitors in fetal liver before and after HSC seeding displayed distinct transcriptional features, with the former closely resembling those of YSLPs. Overall, our data identified the origin, potential, and migratory dynamics of innate lymphoid-biased multipotent progenitors in human yolk sac before HSC emergence, providing insights for understanding the stepwise establishment of innate immune system in humans. [Display omitted] • Progenitors with non-NK lymphoid potential exist in human yolk sac before HSC onset • Human yolk sac lymphoid progenitors before HSC emergence show ILC and DC potential • ILC potential before HSC onset is stronger in human yolk sac than in embryo proper • Early fetal liver lymphoid progenitors share characteristics with those from yolk sac Liu et al. demonstrated the presence of yolk sac-derived lymphoid progenitors expressing IL7R and IRF8 well before HSC emergence in human embryos, which showed differentiation bias toward innate lymphoid cells and dendritic cells. They shared transcriptional profiles with lymphoid progenitors in the fetal liver before HSC colonization. [ABSTRACT FROM AUTHOR]

Intrahepatic cholangiocarcinoma (ICC) is the second most common liver malignancy. ICC typically features remarkable cellular heterogeneity and a dense stromal reaction. Therefore, a comprehensive understanding of cellular diversity and the interplay between malignant cells and niche cells is essential to elucidate the mechanisms driving ICC progression and to develop therapeutic approaches. Herein, we performed single-cell RNA sequencing (scRNA-seq) analysis on unselected viable cells from 8 human ICCs and adjacent samples to elucidate the comprehensive transcriptomic landscape and intercellular communication network. Additionally, we applied a negative selection strategy to enrich fibroblast populations in 2 other ICC samples to investigate fibroblast diversity. The results of the analyses were validated using multiplex immunofluorescence staining, bulk transcriptomic datasets, and functional in vitro and in vivo experiments. We sequenced a total of 56,871 single cells derived from human ICC and adjacent tissues and identified diverse tumor, immune, and stromal cells. Malignant cells displayed a high degree of inter-tumor heterogeneity. Moreover, tumor-infiltrating CD4 regulatory T cells exhibited highly immunosuppressive characteristics. We identified 6 distinct fibroblast subsets, of which the majority were CD146-positive vascular cancer-associated fibroblasts (vCAFs), with highly expressed microvasculature signatures and high levels of interleukin (IL)-6. Functional assays indicated that IL-6 secreted by vCAFs induced significant epigenetic alterations in ICC cells, particularly upregulating enhancer of zeste homolog 2 (EZH2) and thereby enhancing malignancy. Furthermore, ICC cell-derived exosomal miR-9-5p elicited high expression of IL-6 in vCAFs to promote tumor progression. Our single-cell transcriptomic dataset delineates the inter-tumor heterogeneity of human ICCs, underlining the importance of intercellular crosstalk between ICC cells and vCAFs, and revealing potential therapeutic targets. Intrahepatic cholangiocarcinoma is an aggressive and chemoresistant malignancy. Better understanding the complex transcriptional architecture and intercellular crosstalk of these tumors will help in the development of more effective therapies. Herein, we have identified important interactions between cancer cells and cancer-associated fibroblasts in the tumor stroma, which could have therapeutic implications. • Single cell transcriptomic datasets are a valuable resource to dissect cellular diversity and intercellular crosstalk of human ICCs. • Malignant cells displayed remarkable inter-tumor heterogeneity and Tregs revealed highly immunosuppressive characteristics. • Six distinct fibroblast subsets were defined in ICCs and adjacent tissues. • CD146+ vCAFs, comprising most of the fibroblasts, had tight interactions with malignant cells through IL-6/IL-6R axis. • Tumor exosomal miR-9-5p elicited IL-6 expression in vCAFs, contributing to ICC progression via upregulation of EZH2. [ABSTRACT FROM AUTHOR]

JNK, p38 and Akt signalings have been shown to be activated by granulocyte-macrophage colony-stimulating factor (GM-CSF) and are pivotal for GM-CSF-mediated survival, proliferation and differentiation of macrophages and their progenitors. However, the detailed mechanism of how these signalings is activated by GM-CSF is not fully elucidated. We report here that E3 ligase TRAF6 is required for the GM-CSF-induced activation of JNK, p38 and Akt. GM-CSF triggers autoubiquitination of TRAF6 and TRAF6 knocked down results in impaired activation of JNK and p38 signaling. TRAF6 is also required for GM-CSF-induced ubiquitination and activation of Akt. These findings reveal novel roles of TRAF6 in GM-CSF signaling. [ABSTRACT FROM AUTHOR]