Endothelial-derived angiocrine signals induce and sustain regenerative lung alveolarization

Bi Sen Ding, Daniel J. Nolan, Peipei Guo, Alexander O. Babazadeh, Zhongwei Cao, Zev Rosenwaks, Ronald Crystal, Michael Simons, Thomas N. Sato, Stefan Worgall, Koji Shido, Sina Y. Rabbany, Shahin Rafii

Research output: Contribution to journalArticle

242 Citations (Scopus)

Abstract

To identify pathways involved in adult lung regeneration, we employ a unilateral pneumonectomy (PNX) model that promotes regenerative alveolarization in the remaining intact lung. We show that PNX stimulates pulmonary capillary endothelial cells (PCECs) to produce angiocrine growth factors that induce proliferation of epithelial progenitor cells supporting alveologenesis. Endothelial cells trigger expansion of cocultured epithelial cells, forming three-dimensional angiospheres reminiscent of alveolar-capillary sacs. After PNX, endothelial-specific inducible genetic ablation of Vegfr2 and Fgfr1 in mice inhibits production of MMP14, impairing alveolarization. MMP14 promotes expansion of epithelial progenitor cells by unmasking cryptic EGF-like ectodomains that activate the EGF receptor (EGFR). Consistent with this, neutralization of MMP14 impairs EGFR-mediated alveolar regeneration, whereas administration of EGF or intravascular transplantation of MMP14 + PCECs into pneumonectomized Vegfr2/Fgfr1-deficient mice restores alveologenesis and lung inspiratory volume and compliance function. VEGFR2 and FGFR1 activation in PCECs therefore increases MMP14-dependent bioavailability of EGFR ligands to initiate and sustain alveologenesis.

Original languageEnglish
Pages (from-to)539-553
Number of pages15
JournalCell
Volume147
Issue number3
DOIs
Publication statusPublished - 28 Oct 2011
Externally publishedYes

Fingerprint

Endothelial cells
Lung
Endothelial Cells
Epidermal Growth Factor Receptor
Epidermal Growth Factor
Epithelial Cells
Regeneration
Stem Cells
Ablation
Intercellular Signaling Peptides and Proteins
Pneumonectomy
Chemical activation
Biological Availability
Compliance
Transplantation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Ding, B. S., Nolan, D. J., Guo, P., Babazadeh, A. O., Cao, Z., Rosenwaks, Z., ... Rafii, S. (2011). Endothelial-derived angiocrine signals induce and sustain regenerative lung alveolarization. Cell, 147(3), 539-553. https://doi.org/10.1016/j.cell.2011.10.003

Endothelial-derived angiocrine signals induce and sustain regenerative lung alveolarization. / Ding, Bi Sen; Nolan, Daniel J.; Guo, Peipei; Babazadeh, Alexander O.; Cao, Zhongwei; Rosenwaks, Zev; Crystal, Ronald; Simons, Michael; Sato, Thomas N.; Worgall, Stefan; Shido, Koji; Rabbany, Sina Y.; Rafii, Shahin.

In: Cell, Vol. 147, No. 3, 28.10.2011, p. 539-553.

Research output: Contribution to journalArticle

Ding, BS, Nolan, DJ, Guo, P, Babazadeh, AO, Cao, Z, Rosenwaks, Z, Crystal, R, Simons, M, Sato, TN, Worgall, S, Shido, K, Rabbany, SY & Rafii, S 2011, 'Endothelial-derived angiocrine signals induce and sustain regenerative lung alveolarization', Cell, vol. 147, no. 3, pp. 539-553. https://doi.org/10.1016/j.cell.2011.10.003
Ding BS, Nolan DJ, Guo P, Babazadeh AO, Cao Z, Rosenwaks Z et al. Endothelial-derived angiocrine signals induce and sustain regenerative lung alveolarization. Cell. 2011 Oct 28;147(3):539-553. https://doi.org/10.1016/j.cell.2011.10.003
Ding, Bi Sen ; Nolan, Daniel J. ; Guo, Peipei ; Babazadeh, Alexander O. ; Cao, Zhongwei ; Rosenwaks, Zev ; Crystal, Ronald ; Simons, Michael ; Sato, Thomas N. ; Worgall, Stefan ; Shido, Koji ; Rabbany, Sina Y. ; Rafii, Shahin. / Endothelial-derived angiocrine signals induce and sustain regenerative lung alveolarization. In: Cell. 2011 ; Vol. 147, No. 3. pp. 539-553.
@article{3355587b418f403cb51d314a5c319c96,
title = "Endothelial-derived angiocrine signals induce and sustain regenerative lung alveolarization",
abstract = "To identify pathways involved in adult lung regeneration, we employ a unilateral pneumonectomy (PNX) model that promotes regenerative alveolarization in the remaining intact lung. We show that PNX stimulates pulmonary capillary endothelial cells (PCECs) to produce angiocrine growth factors that induce proliferation of epithelial progenitor cells supporting alveologenesis. Endothelial cells trigger expansion of cocultured epithelial cells, forming three-dimensional angiospheres reminiscent of alveolar-capillary sacs. After PNX, endothelial-specific inducible genetic ablation of Vegfr2 and Fgfr1 in mice inhibits production of MMP14, impairing alveolarization. MMP14 promotes expansion of epithelial progenitor cells by unmasking cryptic EGF-like ectodomains that activate the EGF receptor (EGFR). Consistent with this, neutralization of MMP14 impairs EGFR-mediated alveolar regeneration, whereas administration of EGF or intravascular transplantation of MMP14 + PCECs into pneumonectomized Vegfr2/Fgfr1-deficient mice restores alveologenesis and lung inspiratory volume and compliance function. VEGFR2 and FGFR1 activation in PCECs therefore increases MMP14-dependent bioavailability of EGFR ligands to initiate and sustain alveologenesis.",
author = "Ding, {Bi Sen} and Nolan, {Daniel J.} and Peipei Guo and Babazadeh, {Alexander O.} and Zhongwei Cao and Zev Rosenwaks and Ronald Crystal and Michael Simons and Sato, {Thomas N.} and Stefan Worgall and Koji Shido and Rabbany, {Sina Y.} and Shahin Rafii",
year = "2011",
month = "10",
day = "28",
doi = "10.1016/j.cell.2011.10.003",
language = "English",
volume = "147",
pages = "539--553",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "3",

}

TY - JOUR

T1 - Endothelial-derived angiocrine signals induce and sustain regenerative lung alveolarization

AU - Ding, Bi Sen

AU - Nolan, Daniel J.

AU - Guo, Peipei

AU - Babazadeh, Alexander O.

AU - Cao, Zhongwei

AU - Rosenwaks, Zev

AU - Crystal, Ronald

AU - Simons, Michael

AU - Sato, Thomas N.

AU - Worgall, Stefan

AU - Shido, Koji

AU - Rabbany, Sina Y.

AU - Rafii, Shahin

PY - 2011/10/28

Y1 - 2011/10/28

N2 - To identify pathways involved in adult lung regeneration, we employ a unilateral pneumonectomy (PNX) model that promotes regenerative alveolarization in the remaining intact lung. We show that PNX stimulates pulmonary capillary endothelial cells (PCECs) to produce angiocrine growth factors that induce proliferation of epithelial progenitor cells supporting alveologenesis. Endothelial cells trigger expansion of cocultured epithelial cells, forming three-dimensional angiospheres reminiscent of alveolar-capillary sacs. After PNX, endothelial-specific inducible genetic ablation of Vegfr2 and Fgfr1 in mice inhibits production of MMP14, impairing alveolarization. MMP14 promotes expansion of epithelial progenitor cells by unmasking cryptic EGF-like ectodomains that activate the EGF receptor (EGFR). Consistent with this, neutralization of MMP14 impairs EGFR-mediated alveolar regeneration, whereas administration of EGF or intravascular transplantation of MMP14 + PCECs into pneumonectomized Vegfr2/Fgfr1-deficient mice restores alveologenesis and lung inspiratory volume and compliance function. VEGFR2 and FGFR1 activation in PCECs therefore increases MMP14-dependent bioavailability of EGFR ligands to initiate and sustain alveologenesis.

AB - To identify pathways involved in adult lung regeneration, we employ a unilateral pneumonectomy (PNX) model that promotes regenerative alveolarization in the remaining intact lung. We show that PNX stimulates pulmonary capillary endothelial cells (PCECs) to produce angiocrine growth factors that induce proliferation of epithelial progenitor cells supporting alveologenesis. Endothelial cells trigger expansion of cocultured epithelial cells, forming three-dimensional angiospheres reminiscent of alveolar-capillary sacs. After PNX, endothelial-specific inducible genetic ablation of Vegfr2 and Fgfr1 in mice inhibits production of MMP14, impairing alveolarization. MMP14 promotes expansion of epithelial progenitor cells by unmasking cryptic EGF-like ectodomains that activate the EGF receptor (EGFR). Consistent with this, neutralization of MMP14 impairs EGFR-mediated alveolar regeneration, whereas administration of EGF or intravascular transplantation of MMP14 + PCECs into pneumonectomized Vegfr2/Fgfr1-deficient mice restores alveologenesis and lung inspiratory volume and compliance function. VEGFR2 and FGFR1 activation in PCECs therefore increases MMP14-dependent bioavailability of EGFR ligands to initiate and sustain alveologenesis.

UR - http://www.scopus.com/inward/record.url?scp=80155137529&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80155137529&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2011.10.003

DO - 10.1016/j.cell.2011.10.003

M3 - Article

C2 - 22036563

AN - SCOPUS:80155137529

VL - 147

SP - 539

EP - 553

JO - Cell

JF - Cell

SN - 0092-8674

IS - 3

ER -