Lung vascular injury leading to protein-rich edema formation is a hallmark of ALI and respiratory failure in critically ill patients. Little is known about the mechanisms of lung vascular endothelial regeneration following vascular injury. However, with an ever-growing understanding of Endothelial Progenitor Cells (EPCs) and our ability to identify and obtain them in sufficient numbers from induced Pluripotent Stem Cell-derived Endothelial Progenitor Cells (iPSC) or through direct reprogramming of somatic cells (fibroblasts), it is feasible to address the role EPCs in promoting vascular regeneration and to define the mechanism of vascular regeneration. In addition, we have developed a mouse reporter model employing the tamoxifen- inducible endothelial specific Scl-Cre (End-Scl-Cre-ER) which enables the rigorous tracing of endothelial lineage following endothelial injury. Using this approach we are also in the position of addressing mechanisms of intrinsic endothelial regeneration and restoration of lung vascular integrity. This proposal focuses on restoration of the injured lung endothelium by endogenous cells as well as transplantation of exogenous regenerative EPCs.
In Aim 1 we will investigate the efficacy and fate of transplanted iPSC-EPCs (induced pluripotent stem cells-derived endothelial progenitor cells) following lung vascular injury. We will test the hypothesis that iPSC-EPC transplantation prevents pulmonary edema and improves survival after lung injury by acutely restoring barrier function as well as through engraftment into the lung microvasculature, and thus restores lung fluid balance.
In Aim 2 we will study the lung vascular regenerative potential of mouse fibroblasts that have undergone lineage conversion into endothelial cells (Fib-EPCs). We will test the hypothesis that adult fibroblasts converted directly into functional proliferative EPCs using a novel microRNA strategy restore lung endothelial barrier function and fluid balance and prevent pulmonary edema.
In Aim 3 we will identify through endothelial lineage tracing populations of endogenous reparative cells and determine whether their activation promotes lung vascular regeneration and restoration of lung fluid balance. We will test the hypothesis that activation and proliferation of endogenous reparative endothelial cells restores lung endothelial barrier and fluid balance following vascular injury. The above studies will provide the essential frame-work needed to develop novel therapies for endothelial regeneration and recovery after lung vascular injury.
It is not known whether blood vessel progenitor cells are useful for treatment of lung vascular injury, a major cause of death of ICU patients with severe infections. The proposed studies will use a defined population of stem cell-derived progenitor cells and cells that have been directly converted from skin cells into blood vessel progenitor cells. The therapeutic benefits of these cells in repairing damaged vessels will be established and thus provide an important framework for patient studies using such cell types.
|Marsboom, Glenn; Rehman, Jalees (2018) Hypoxia Signaling in Vascular Homeostasis. Physiology (Bethesda) 33:328-337|
|Di, Anke; Xiong, Shiqin; Ye, Zhiming et al. (2018) The TWIK2 Potassium Efflux Channel in Macrophages Mediates NLRP3 Inflammasome-Induced Inflammation. Immunity 49:56-65.e4|
|Cheng, Kwong Tai; Xiong, Shiqin; Ye, Zhiming et al. (2017) Caspase-11-mediated endothelial pyroptosis underlies endotoxemia-induced lung injury. J Clin Invest 127:4124-4135|
|Tsang, Kit Man; Hyun, James S; Cheng, Kwong Tai et al. (2017) Embryonic Stem Cell Differentiation to Functional Arterial Endothelial Cells through Sequential Activation of ETV2 and NOTCH1 Signaling by HIF1?. Stem Cell Reports 9:796-806|
|Marsboom, Glenn; Chen, Zhenlong; Yuan, Yang et al. (2017) Aberrant caveolin-1-mediated Smad signaling and proliferation identified by analysis of adenine 474 deletion mutation (c.474delA) in patient fibroblasts: a new perspective on the mechanism of pulmonary hypertension. Mol Biol Cell 28:1177-1185|
|Yamada, Kaori H; Kang, Hojin; Malik, Asrar B (2017) Antiangiogenic Therapeutic Potential of Peptides Derived from the Molecular Motor KIF13B that Transports VEGFR2 to Plasmalemma in Endothelial Cells. Am J Pathol 187:214-224|
|Zhang, Lianghui; Jambusaria, Ankit; Hong, Zhigang et al. (2017) SOX17 Regulates Conversion of Human Fibroblasts Into Endothelial Cells and Erythroblasts by Dedifferentiation Into CD34+Progenitor Cells. Circulation 135:2505-2523|
|Gong, Haixia; Liu, Menglin; Klomp, Jeff et al. (2017) Method for Dual Viral Vector Mediated CRISPR-Cas9 Gene Disruption in Primary Human Endothelial Cells. Sci Rep 7:42127|
|Cantelmo, Anna Rita; Conradi, Lena-Christin; Brajic, Aleksandra et al. (2016) Inhibition of the Glycolytic Activator PFKFB3 in Endothelium Induces Tumor Vessel Normalization, Impairs Metastasis, and Improves Chemotherapy. Cancer Cell 30:968-985|
|Gong, Haixia; An, Shejuan; Sassmann, Antonia et al. (2016) PAR1 Scaffolds TGF?RII to Downregulate TGF-? Signaling and Activate ESC Differentiation to Endothelial Cells. Stem Cell Reports 7:1050-1058|
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