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^iΔEC/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 Hgf^iΔEC/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.

慢性或压倒性损伤有时会损害肺和肝的再生能力。实质干细胞的原位移植到受损器官可能会恢复其自我修复能力。然而，在受病器官中的微环境经常阻碍实质细胞的植入。我们表明，针对血管生境和血管周成纤维细胞都建立了“好客的土壤”，以促进“种子”的掺入，在这种情况下，是在受损器官中植入实质细胞。具体来说，异位诱导内皮细胞（EC）表达的旁分泌/血管分泌肝细胞生长因子（HGF）和抑制血管周围NOX4 [NADPH（烟酰胺腺嘌呤二核苷酸磷酸的还原形式）氧化酶4]协同使小鼠和人类实质细胞在受损器官中得以重建。相反，基因敲除HGF在小鼠内皮细胞（HGF ^iΔEC/iΔEC肝和肺再生期间）异常上调血管周围NOX4。异常调节的HGF和NOX4通路将血管和血管周细胞的功能从上皮诱导性生态位转变为抑制实质重建的微环境。血管周围NOX4诱导HGF ^iΔEC/iΔEC小鼠概括了人和小鼠肝和肺纤维化的表型。因此，EC指导的HGF和NOX4抑制剂GKT137831刺激了慢性损伤的肺和肝中小鼠和人类实质细胞的再生整合。我们的数据表明，在患病器官中靶向功能异常的血管周围和血管细胞可以绕过纤维化，并使修复性细胞移植能够恢复肺和肝的再生。