Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis

Chemical or traumatic damage to the liver is frequently associated with aberrant healing(fibrosis) that overrides liver regeneration(1–5). The mechanism by which hepatic niche cells differentially modulate regeneration and fibrosis during liver repair remains to be defined(6–8). Hepatic vascular niche predominantly represented by liver sinusoidal endothelial cells (LSECs), deploys paracrine trophogens, known as angiocrine factors, to stimulate regeneration(9–15). Nevertheless, it remains unknown how pro-regenerative angiocrine signals from LSECs is subverted to promote fibrosis(16,17). Here, by combining inducible endothelial cell (EC)-specific mouse gene deletion strategy and complementary models of acute and chronic liver injury, we revealed that divergent angiocrine signals from LSECs elicit regeneration after immediateinjury and provoke fibrosis post chronic insult. The pro-fibrotic transition of vascular niche results from differential expression of stromal derived factor-1 (SDF-1) receptors, CXCR7 and CXCR4(18–21)in LSECs. After acute injury, CXCR7 upregulation in LSECs acts in conjunction with CXCR4 to induce transcription factor Id1, deploying pro-regenerative angiocrine factors and triggering regeneration. Inducible deletion of Cxcr7 in adult mouse LSECs (Cxcr7(iΔEC/iΔEC)) impaired liver regeneration by diminishing Id1-mediated production of angiocrine factors(9–11). By contrast, after chronic injury inflicted by iterative hepatotoxin (carbon tetrachloride) injection and bile duct ligation, constitutive FGFR1 signaling in LSECs counterbalanced CXCR7-dependent pro-regenerative response and augmented CXCR4 expression. This predominance of CXCR4 over CXCR7 expression shifted angiocrine response of LSECs, stimulating proliferation of desmin(+)hepatic stellate-like cells(22,23) and enforcing a pro-fibrotic vascular niche. EC-specific ablation of either Fgfr1 (Fgfr1(iΔEC/iΔEC)) or Cxcr4 (Cxcr4(iΔEC/iΔEC)) in mice restored pro-regenerative pathway and prevented FGFR1-mediated maladaptive subversion of angiocrine factors. Similarly, selective CXCR7 activation in LSECs abrogated fibrogenesis. Thus, we have demonstrated that in response to liver injury, differential recruitment of pro-regenerative CXCR7/Id1 versus pro-fibrotic FGFR1/CXCR4 angiocrine pathways in vascular niche balances regeneration and fibrosis. These results provide a therapeutic roadmap to achieve hepatic regeneration without provoking fibrosis(1,2,4).