Acute respiratory distress syndrome (ARDS) is a complex, multi-factorial syndrome with an unacceptable
high mortality rate. Endothelial injury characterized by persistently increased lung microvascular
permeability resulting in protein-rich lung edema is a hallmark of ARDS. In both animal models of acute
lung injury induced by sepsis and ARDS patients, there are mounting evidence demonstrate loss of
endothelial cells (ECs). Recent studies provide some information that ECs play predominant role in lung
endothelial regeneration. However, the pulmonary vascular ECs are quite heterogenous. It is unknown
whether all resident ECs contribute to endothelial regeneration following sepsis-induced vascular injury.
The most important question in the field is whether there is a special endothelial stem cells responsible
for endothelial regeneration and vascular repair following sepsis-induced lung injury. Our supporting data
show that there is a novel rare subpopulation of ECs responsible for lung endothelial regeneration and
vascular repair following sepsis-induced lung injury. These cells express many of the genes essential for
cell cycle progression and proliferation and also some of the stem cell genes, however, not the markers
of recently identified vascular endothelial stem cells/progenitor cells such as Apelin, CD157 and EPCR.
Based on their unique expression of 2 genes, we named this rare subpopulation of ECs as UC+
endothelial stem cells (UC+ESCs). Genetic depletion of UC+ESCs in mouse lungs led to inhibited
endothelial regeneration and impaired vascular repair resulting in persistent inflammatory lung injury.
Thus, we hypothesize that UC+ESCs are the long-sought endothelial stem cells responsible for
endothelial regeneration and vascular repair following inflammatory lung injury induced by sepsis
challenge. The proposed studies will address the following Specific Aims. Studies in AIM 1 will determine
the fundamental role of UC+ESCs in vascular repair and resolution of inflammatory lung injury induced
by sepsis challenge via genetic depletion of UC+ESCs. Two complementary sepsis models including i.p.
LPS and cecal ligation and puncture (CLP) which induces polymicrobial sepsis will be used. AIM 2 will
define the role of UC+ESCs in regenerating endothelial subpopulation(s) and the molecular mechanisms
of UC+ESC proliferation and expansion following sepsis challenge. These studies will define a novel
rare endothelial stem cell subpopulation responsible for endothelial regeneration following sepsis-
induced inflammatory lung injury and provide a paradigm shift in our understanding of the cellular
mechanisms of endothelial regeneration and vascular repair. We believe successful completion of the
studies will lead to novel therapeutic strategy to harness this specific intrinsic endothelial stem cell
subpopulation for the prevention and effective treatment of ARDS induced by sepsis.
