Liver sinusoidal endothelial cells suppress BMP2 production in response to TGFβ pathway activation.

Background & aims TGFβ/BMP signalling in the liver plays a critical role in liver disease. Growth factors, such as BMP2, BMP6 and TGFβ1, are released from liver sinusoidal endothelial cells (LSECs) and signal in a paracrine manner to hepatocytes and hepatic stellate cells to control systemic iron homeostasis and fibrotic processes, respectively. The misregulation of the TGFβ/BMP pathway affects expression of the iron-regulated hormone hepcidin causing frequent iron overload and deficiency diseases. However, whether LSEC-secreted factors can act in an autocrine manner to maintain liver homeostasis was not addressed so far. Approach & results We analysed publicly available RNA-sequencing data of mouse LSECs for ligand-receptor interactions and identified members of the TGFβ family (BMP2, BMP6 and TGFβ1) as ligands with the highest expression levels in LSECs that may signal in an autocrine manner. We next tested the soluble factors identified via in silico analysis in optimized murine LSEC primary cultures and mice. Exposure of murine LSEC primary cultures to these ligands shows that autocrine responses to BMP2 and BMP6 are blocked despite high expression levels of the required receptor complexes, partially involving the inhibitor FKBP12. By contrast, LSECs respond efficiently to TGFβ1 treatment, which causes reduced expression of BMP2 via activation of ALK5. Conclusions These findings reveal that TGFβ1 signalling is functionally interlinked with BMP signalling in LSECs suggesting new druggable targets for the treatment of iron overload diseases associated with deficiency of the BMP2-regulated hormone hepcidin, such as Hereditary Hemochromatosis, β-thalassemia and chronic liver diseases.