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

Research output: Contribution to journalArticle

Zhongwei Cao, Tinghong Ye, Yue Sun, Gaili Ji, Koji Shido, Yutian Chen, Lin Luo, Feifei Na, Xiaoyan Li, Zhen Huang, Jane L. Ko, Vivek Mittal, Lina Qiao, Chong Chen, Fernando J. Martinez, Shahin Rafii, Bi Sen Ding

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.

Original languageEnglish (US)
Article numberaai8710
JournalScience Translational Medicine
Volume9
Issue number405
DOIs
StatePublished - Aug 30 2017

PMID: 28855398

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Targeting the vascular and perivascular niches as a regenerative therapy for lung and liver fibrosis. / Cao, Zhongwei; Ye, Tinghong; Sun, Yue; Ji, Gaili; Shido, Koji; Chen, Yutian; Luo, Lin; Na, Feifei; Li, Xiaoyan; Huang, Zhen; Ko, Jane L.; Mittal, Vivek; Qiao, Lina; Chen, Chong; Martinez, Fernando J.; Rafii, Shahin; Ding, Bi Sen.

In: Science Translational Medicine, Vol. 9, No. 405, aai8710, 30.08.2017.

Research output: Contribution to journalArticle

Harvard

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 2017, 'Targeting the vascular and perivascular niches as a regenerative therapy for lung and liver fibrosis' Science Translational Medicine, vol. 9, no. 405, aai8710. https://doi.org/10.1126/scitranslmed.aai8710

APA

Cao, Z., Ye, T., Sun, Y., Ji, G., Shido, K., Chen, Y., ... Ding, B. S. (2017). Targeting the vascular and perivascular niches as a regenerative therapy for lung and liver fibrosis. Science Translational Medicine, 9(405), [aai8710]. https://doi.org/10.1126/scitranslmed.aai8710

Vancouver

Cao Z, Ye T, Sun Y, Ji G, Shido K, Chen Y et al. Targeting the vascular and perivascular niches as a regenerative therapy for lung and liver fibrosis. Science Translational Medicine. 2017 Aug 30;9(405). aai8710. https://doi.org/10.1126/scitranslmed.aai8710

Author

Cao, Zhongwei ; Ye, Tinghong ; Sun, Yue ; Ji, Gaili ; Shido, Koji ; Chen, Yutian ; Luo, Lin ; Na, Feifei ; Li, Xiaoyan ; Huang, Zhen ; Ko, Jane L. ; Mittal, Vivek ; Qiao, Lina ; Chen, Chong ; Martinez, Fernando J. ; Rafii, Shahin ; Ding, Bi Sen. / Targeting the vascular and perivascular niches as a regenerative therapy for lung and liver fibrosis. In: Science Translational Medicine. 2017 ; Vol. 9, No. 405.

BibTeX

@article{4a4e9f1cd6ba4237a88c60919e663fbe,
title = "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. 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.",
author = "Zhongwei Cao and Tinghong Ye and Yue Sun and Gaili Ji and Koji Shido and Yutian Chen and Lin Luo and Feifei Na and Xiaoyan Li and Zhen Huang and Ko, {Jane L.} and Vivek Mittal and Lina Qiao and Chong Chen and Martinez, {Fernando J.} and Shahin Rafii and Ding, {Bi Sen}",
year = "2017",
month = "8",
day = "30",
doi = "10.1126/scitranslmed.aai8710",
language = "English (US)",
volume = "9",
journal = "Science Translational Medicine",
issn = "1946-6234",
publisher = "American Association for the Advancement of Science",
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RIS

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T1 - Targeting the vascular and perivascular niches as a regenerative therapy for lung and liver fibrosis

AU - Cao, Zhongwei

AU - Ye, Tinghong

AU - Sun, Yue

AU - Ji, Gaili

AU - Shido, Koji

AU - Chen, Yutian

AU - Luo, Lin

AU - Na, Feifei

AU - Li, Xiaoyan

AU - Huang, Zhen

AU - Ko, Jane L.

AU - Mittal, Vivek

AU - Qiao, Lina

AU - Chen, Chong

AU - Martinez, Fernando J.

AU - Rafii, Shahin

AU - Ding, Bi Sen

PY - 2017/8/30

Y1 - 2017/8/30

N2 - 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.

AB - 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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U2 - 10.1126/scitranslmed.aai8710

DO - 10.1126/scitranslmed.aai8710

M3 - Article

VL - 9

JO - Science Translational Medicine

T2 - Science Translational Medicine

JF - Science Translational Medicine

SN - 1946-6234

IS - 405

M1 - aai8710

ER -

ID: 32617217