Summary Chemical or traumatic damage to the liver is frequently associated with aberrant healing(fibrosis) that overrides liver regeneration1–5. The mechanism by which hepatic niche cells differentially modulate regeneration and fibrosis during liver repair remains to be defined6–8. Hepatic vascular niche predominantly represented by liver sinusoidal endothelial cells (LSECs), deploys paracrine trophogens, known as angiocrine factors, to stimulate regeneration9–15. Nevertheless, it remains unknown how pro-regenerative angiocrine signals from LSECs is subverted to promote fibrosis16,17. 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 CXCR418–21in 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 (Cxcr7iΔEC/iΔEC) impaired liver regeneration by diminishing Id1-mediated production of angiocrine factors9–11. 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 cells22,23 and enforcing a pro-fibrotic vascular niche. EC-specific ablation of either Fgfr1 (Fgfr1iΔEC/iΔEC) or Cxcr4 (Cxcr4iΔEC/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 fibrosis1,2,4.

Summary To identify the pathways involved in adult lung regeneration, we have employed left unilateral pneumonectomy (PNX) model that promotes regenerative alveolarization in the remaining intact right lung lobes. Here, we show that PNX stimulates pulmonary capillary endothelial cells (PCECs) to produce paracrine (angiocrine) growth factors that induce proliferation of epithelial progenitor cells supporting alveologenesis. After PNX, endothelial-specific inducible genetic ablation of Vegfr2 and Fgfr1 in mice inhibited production of MMP14 impairing alveolarization. MMP14 via unmasking cryptic EGF-like ectodomain and activation of EGF-receptor (EGFR) expands epithelial progenitor cells. Neutralization of MMP14 impaired EGFR-ligand mediated alveolar regeneration. By contrast, administration of recombinant EGF, or intravascular transplantation of MMP14+ PCECs from wild-type mice, into pneumonectomized Vegfr2/Fgfr1 deficient mice restored alveologenesis and lung inspiratory volume and compliance function. This study shows that VEGFR2 and FGFR1 activation in PCECs by increasing MMP14-dependent bioavailability of EGFR-ligands initiates and sustains alveologenesis and holds promise to develop therapeutic strategies to promote lung regeneration.

Although the lung can undergo self-repair after injury, fibrosis in chronically injured or diseased lungs can occur at the expense of regeneration. Here we study how a hematopoietic-vascular niche regulates alveolar repair and lung fibrosis. Using intratracheal injection of bleomycin or hydrochloric acid in mice, we show that repetitive lung injury activates pulmonary capillary endothelial cells (PCECs) and perivascular macrophages, impeding alveolar repair and promoting fibrosis. Whereas the chemokine receptor CXCR7, expressed on PCECs, acts to prevent epithelial damage and ameliorate fibrosis after a single round of treatment with bleomycin or hydrochloric acid, repeated injury leads to suppression of CXCR7 expression and recruitment of vascular endothelial growth factor receptor 1 (VEGFR1)-expressing perivascular macrophages. This recruitment stimulates Wnt/β-catenin–dependent persistent upregulation of the Notch ligand Jagged1 (encoded by Jag1) in PCECs, which in turn stimulates exuberant Notch signaling in perivascular fibroblasts and enhances fibrosis. Administration of a CXCR7 agonist or PCEC-targeted Jag1 shRNA after lung injury promotes alveolar repair and reduces fibrosis. Thus, targeting of a maladaptbed hematopoietic-vascular niche, in which macrophages, PCECs and perivascular fibroblasts interact, may help to develop therapy to spur lung regeneration and alleviate fibrosis.