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

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. Here, we show that targeting both the vascular niche and perivascular fibroblasts establishes “hospitable soil” to foster 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 NADPH Oxidase 4 (NOX4) synergistically enabled reconstitution of mouse and human parenchymal cells in damaged organs. Reciprocally, genetic knockout of Hgf in mouse ECs (HgfiΔEC/iΔEC) aberrantly upregulated 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 fibrotic livers and lungs. 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.

Are Liver Pericytes Just Precursors of Myofibroblasts in Hepatic Diseases? Insights from the Crosstalk between Perivascular and Inflammatory Cells in Liver Injury and Repair

“…In that work, amphiregulin was found to activate cell surface integrin-α V complexes which, in turn, convert latent TGF-β into its active form with consequent promotion of proliferation of pericytes and their differentiation into myofibroblast-like cells [96]. In the absence of hepatocyte growth factor derived from endothelial cells, perivascular fibroblasts upregulate expression of NADPH oxidase 4 [97], which has been shown to generate ROS in monocytes and macrophages [98] and can increase damage by ROS production. During the progression of experimental liver injury, TGF-β is observable in myofibroblasts and macrophages in fibrotic areas, as well as in hepatocytes; in contrast, TGF-β is no longer observable in these regions during the recovery phase [82].…”

Transforming growth factor–β in tissue fibrosis

“…The high prevalence of perivascular fibrosis in a wide range of conditions affecting several different organs (including the heart, lung, and liver; Cao et al, 2017;Frangogiannis, 2019), and the common localization of TGF-βs in the microvasculature of fibrotic lesions (Huh et al, 2009), suggest a potential role for TGF-β-driven modulation of vascular cells in the pathogenesis of fibrotic diseases. Endothelial cells and mural cells may acquire a fibrogenic phenotype in response to TGF-β, expressing ECM proteins or secreting fibroblast-activating mediators.…”

SHIP‐1, a target of miR‐155, regulates endothelial cell responses in lung fibrosis

“…11,14 Several studies proposed the concept that lung endothelial cells and endothelial-mesenchymal transition (EndoMT) play important roles in the pathogenesis of pulmonary fibrosis. [15][16][17][18] However, the role of endothelial cells and the function and relationship of endothelial miR-155 and SHIP-1 in lung fibrosis remain unknown. We hypothesized that endothelial miR-155 mediates fibrotic responses in the lung through EndoMT; Endothelial SHIP-1, a target of miR-155, is essential in controlling fibrotic responses in the lung.…”