Reconstruction of intercellular communication and signaling impacting de novo HSC emergence using CellComm platform

Cellular transitions are shaped by cross-talk between cell-intrinsic and extrinsic factors. Signals derived from the cell’s microenvironment are integrated and processed by the cell to modulate gene expression programs to instruct cell function and fate. Recent advances in single-cell technologies and analytics have provided an unprecedented resolution to study intercellular communication and differentiation trajectories. Here, we developed CellComm, a systems biology platform to infer intercellular communication networks and transcriptional regulators downstream of cell surface receptors predicted to mediate cellular interactions. We applied CellComm to investigate how the unique cellular niche of the aorta-gonad-mesonephros (AGM) region is involved in hematopoietic stem cell emergence and identified key cell types and microenvironmental signals implicated in hematopoietic development. We extensively validated CellComm’s predictions in three different species - zebrafish, mouse and human - and found both known and novel genes involved in developmental hematopoiesis, such as Stat3, Nr0b2, Ybx1 and, surprisingly, App, which is often reported in neurodegenerative disorders. Strikingly, CellComm revealed extensive cross-talk of signaling pathways feeding into the same transcriptional regulators, indicating a tightly regulated developmental program ensuring dynamic adaptation to changes in the embryonic environment. Taken together, our work contributes to a better understanding on how the embryonic niche is involved in developmental hematopoiesis as well as provides a new algorithm and data resource for the scientific community. Single-cell RNA-sequecing of random sampling of the aorta-gonad-mesonephros region (AGM) complemented with sorted endothelial cells and immunophenotypic T1-preHSCs