Research ArticleFibrosis

Targeting the vascular and perivascular niches as a regenerative therapy for lung and liver fibrosis

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Science Translational Medicine  30 Aug 2017:
Vol. 9, Issue 405, eaai8710
DOI: 10.1126/scitranslmed.aai8710

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To fix fibrosis, nix the niche

Organs such as the liver can mount a regenerative response to acute injury, but during chronic injury, this innate repair capacity is overwhelmed, leading to scarring and dysfunction. Cao et al. investigated whether targeting the microenvironment could improve therapeutic cell engraftment to reinstate regeneration in fibrotic organs. Treating mice with a dual therapy—an inhibitor of an enzyme up-regulated in fibrotic fibroblasts and viral particles that promoted endothelial-specific secretion of a growth factor—improved hepatocyte engraftment in fibrotic livers and epithelial cell engraftment in fibrotic lungs. Targeting both the vascular and perivascular regions could be key for restoring regeneration to fibrotic organs.

Abstract

The regenerative capacity of lung and liver is sometimes impaired by chronic or overwhelming injury. Orthotopic transplantation of parenchymal stem cells to damaged organs might reinstate their self-repair ability. However, parenchymal cell engraftment is frequently hampered by the microenvironment in diseased recipient organs. We show that targeting both the vascular niche and perivascular fibroblasts establishes “hospitable soil” to foster the incorporation of “seed,” in this case, the engraftment of parenchymal cells in injured organs. Specifically, ectopic induction of endothelial cell (EC)–expressed paracrine/angiocrine hepatocyte growth factor (HGF) and inhibition of perivascular NOX4 [NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase 4] synergistically enabled reconstitution of mouse and human parenchymal cells in damaged organs. Reciprocally, genetic knockout of Hgf in mouse ECs (HgfiΔEC/iΔEC) aberrantly up-regulated perivascular NOX4 during liver and lung regeneration. Dysregulated HGF and NOX4 pathways subverted the function of vascular and perivascular cells from an epithelially inductive niche to a microenvironment that inhibited parenchymal reconstitution. Perivascular NOX4 induction in HgfiΔEC/iΔEC mice recapitulated the phenotype of human and mouse liver and lung fibrosis. Consequently, EC-directed HGF and NOX4 inhibitor GKT137831 stimulated regenerative integration of mouse and human parenchymal cells in chronically injured lung and liver. Our data suggest that targeting dysfunctional perivascular and vascular cells in diseased organs can bypass fibrosis and enable reparative cell engraftment to reinstate lung and liver regeneration.

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