Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis

Abstract

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.

Endothelial transcription factor KLF2 negatively regulates liver regeneration via induction of activin A

“…Because vascular density was not changed either upon endothelial-specific overexpression or deletion of KLF2, we hypothesized that KLF2 does not affect angiogenesis or endothelial cell survival, but regulates liver regeneration by controlling the endothelial secretome. Endothelial-mediated paracrine regulation of liver regeneration was shown to be critically controlled by the SDF-1 receptors CXCR4, which mediates the release of profibrotic cytokines, and CXCR7, which was shown to provide a proregenerative niche (4). Interestingly, we demonstrate that in vitro overexpression of KLF2 in ECs reciprocally regulates CXCR4 and CXCR7 expression on mRNA as well as protein level (Fig.…”

“…1 C and D). Hepatocyte proliferation was significantly elevated in CCL 4 -treated EC-KLF2-deficient mice compared with WT mice (Fig. 1E).…”

“…Moreover, stromal-derived factor-1 (SDF) and its receptors CXCR4 and CXCR7 control the balance between liver regeneration and fibrosis. CXCR7 signaling plays a crucial role in the release of hepatocyte growth factor (HGF), which is required for hepatocyte proliferation, whereas CXCR4 signaling leads to the release of TGF-β and subsequently to more liver fibrosis (4,5).…”

Biliary Epithelial Cells Are Not the Predominant Source of Hepatic CXCL12

“…8 Furthermore, differential expression of CXCL12 and its receptors promotes profibrotic changes within the hepatic vascular niche during injury. 26 Finally, in prostate and colon cancers, CXCR4 expression by tumor cells signifies their metastatic potential, and hepatic metastases of these tumors demonstrate a predilection for CXCL12-expressing niches within the liver. 27e29 Despite numerous reports demonstrating immunohistochemical evidence of CXCL12 expression by cholangiocytes, we show that human and murine cholangiocytes do not appear to secrete or express CXCL12.…”

Vessels of rejuvenation

“…The different structural and metabolic requirements of organs and tissues prompt the formation of specialized blood vessels during development 1 , which deliver molecules that instruct tissues on their fates 2,3 . This process requires crosstalk between organs and the vasculature: organs generate local growth factors that attract blood vessels toward metabolically active regions, and the vessels release molecules (known as angiocrine signals) that affect cell differentiation in the developing organs.…”