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Genetic Lineage Tracing Analysis of Endothelial Cells in Lung Vascular Injury Identifies Two Distinct Sources of Endothelial Regeneration
Author(s) -
Liu Menglin,
Gong Haixia,
Zhang Lianghui,
Xiong Shiqin,
Rehman Jalees,
Malik Asrar B
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.12.3
Subject(s) - microbiology and biotechnology , population , endothelium , regeneration (biology) , cd31 , endothelial stem cell , biology , lung , chemistry , cancer research , angiogenesis , medicine , endocrinology , biochemistry , environmental health , in vitro
Loss of pulmonary vascular endothelial cells (ECs) is a key pathogenic feature of acute lung injury (ALI). This compromises endothelial barrier function and leads to severe pulmonary edema. The process responsible for regeneration of lung endothelium is not well understood. Regeneration may be due to proliferation of resident ECs and also non‐ECs may be mobilized to repair the barrier. Here, we used an mT/mG (membrane Tomato/membrane GFP) double fluorescent transgenic mouse crossed with a tamoxifen (tam)‐inducible EC Cre mouse model. Tam induced the labeling of ECs with GFP whereas all other cells remained labeled with TomatoRed, allowing us to trace EC fate following endothelial injury. We found that lung vascular injury induced by endotoxin (LPS) produced ~50% loss of ECs which peaked at 24h post‐LPS. EC regeneration occurred rapidly and peaked within 5 days, thus mirroring restoration of lung vascular barrier function. Thereafter, tam was re‐injected to assess whether non‐ECs transdifferentiating to ECs could also account for the EC regeneration. The 2 nd tamoxifen labeling showed that half of ECs were derived from a non‐EC lineage. We identified a subpopulation of cells co‐expressing the endothelial surface marker CD31 and fibroblast‐specific protein 1 (FSP1) peaking at 1day post‐LPS and remained elevated during recovery, suggesting this population may contribute to replenishment of the endothelium. Inhibition of TGF‐β signaling promoted EC population recovery. Thus, there appear to be 2 mechanisms of EC recovery: a fibroblast subpopulation which transitions to ECs and acts in concert with proliferation of the native endothelium. Support or Funding Information This work was supported in part by the National Institutes of Health: RO1HL118068, RO1HL090152 and T32HL007829.