Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 9, Issue 405, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aai8710
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Funding
- National Scientist Development Grant from the American Heart Association [12SDG1213004]
- National Heart, Lung, and Blood Institute [R01HL097797, R01HL119872, R01HL130826]
- National Natural Science Foundation of China [91639117]
- National Key Research and Development Program focused on Stem Cell and Translational Research [2016YFA0101600]
- Empire State Stem Cell Board and New York State Department of Health [C024180, C026438, C026878, C028117]
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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 (Hgf(i Delta EC/i Delta EC)) 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 Hgf(i Delta EC/i Delta EC) 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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