Targeting the vascular and perivascular niches as a regenerative therapy for lung and liver fibrosis.
Targeting the vascular and perivascular niches as a regenerative therapy for lung and liver fibrosis.
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针对血管和血管周围生态位作为肺和肝纤维化的再生疗法
DOI：
10.1126/scitranslmed.aai8710
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发表时间：
2017-08-30
影响因子：
17.1
通讯作者：
Ding BS
中科院分区：
文献类型：
--
作者：
Cao Z;Ye T;Sun Y;Ji G;Shido K;Chen Y;Luo L;Na F;Li X;Huang Z;Ko JL;Mittal V;Qiao L;Chen C;Martinez FJ;Rafii S;Ding BS
血管和血管周围细胞的靶向基因传递和酶抑制促进移植的实质细胞植入肺和肝脏修复。为了修复纤维化，肝脏等利基器官可以对急性损伤做出再生反应，但在慢性损伤期间，这种与生俱来的修复能力会不堪重负，导致疤痕和功能障碍。曹等人。研究了靶向微环境是否可以改善治疗性细胞植入，以恢复纤维化器官的再生。用双重疗法治疗小鼠-一种酶的抑制剂，在纤维化的成纤维细胞和病毒颗粒中上调，促进内皮特异性的生长因子分泌-改善肝细胞在纤维化肝脏中的植入和上皮细胞在纤维化肺中的植入。同时针对血管和血管周围区域可能是恢复纤维化器官再生的关键。慢性或压倒性损伤有时会损害肺和肝脏的再生能力。将实质干细胞原位移植到受损器官可能会恢复其自我修复能力。然而，实质细胞的植入经常受到疾病受者器官微环境的阻碍。我们发现，以血管壁龛和血管周围成纤维细胞为靶点，建立了“适宜的土壤”，以促进“种子”的结合，在这种情况下，实质细胞在受损的器官中植入。具体地说，异位诱导内皮细胞(EC)表达的旁分泌/血管内分泌肝细胞生长因子(HGF)和抑制血管周围NOX4[NADPH(还原形式的烟酰胺腺嘌呤二核苷酸磷酸)氧化酶4]协同使小鼠和人类实质细胞能够在受损器官中重建。反过来，小鼠内皮细胞(HGFIΔEC/IΔEC)中肝细胞生长因子的基因敲除在肝和肺再生过程中异常上调血管周围NOX4的表达。失调的HGF和NOX4通路颠覆了血管和血管周围细胞的功能，从上皮诱导的缝隙到抑制实质重建的微环境。在HGFIΔEC/IΔEC小鼠血管周围诱导NOX4重现了人和小鼠肝和肺纤维化的表型。因此，EC导向的HGF和NOX4抑制剂GKT137831促进了慢性损伤的肺和肝脏中小鼠和人的实质细胞的再生整合。我们的数据表明，靶向病变器官中功能障碍的血管周围和血管细胞可以绕过纤维化，并使修复细胞植入恢复肺和肝脏的再生。
Targeted gene delivery and enzyme inhibition in vascular and perivascular cells promote engraftment of transplanted parenchymal cells for lung and liver repair. 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. 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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影响因子：
17.1
作者：
Eming SA;Martin P;Tomic-Canic M
通讯作者：
Tomic-Canic M
影响因子：
82.9
作者：
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Ding BS
影响因子：
7.3
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通讯作者：
Kalinichenko, Vladimir V.
影响因子：
82.9
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影响因子：
64.8
作者：
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