Haemodynamic control of zonated liver function via instructive vascular Wnt signalling.

The vascular endothelium forms a systemically disseminated organ that translates micromilieu factors into instructive cues, designated as angiocrine signalling. While vascular control of organ function mechanisms have been discovered in essentially all major organs, the mechanisms of translating milieu factors into angiocrine signalling mechanisms remain largely elusive. Here, focussing on the well-established angiocrine Wnt signalling-regulated liver metabolic zonation paradigm, we identified blood flow-induced haemodynamic stress as a biophysical sensor that governs the angiocrine expression profile of liver sinusoidal endothelial cells (LSEC). Combining single-cell RNA sequencing with spatial proteomics, we generated a high-resolution crosstalk map of LSEC and hepatocytes from LSEC Wnt-deficient mutant mice and littermate controls. Intriguingly, vascular Wnt receptors, in parallel with angiocrine Wnt ligands, were specifically enriched in pericentral LSEC, enforcing the spatially coordinated vascular Wnt functions. Consequently, vascular Wnt further modulated angiocrine gene signatures, LSEC morphology, and the expression of gap junctional molecules in an autocrine manner. Taken together, the data define LSEC as a dynamic cellular decoder that translates biophysical forces into instructive angiocrine signals via activating promiscuous vascular Wnt factors.