The broad, long-term objective of this proposal is to define the mechanism by which the chemokine SDF1 through activation of its receptor CXCR4, contributes to the revascularization of the regenerating lungs. In particular, we plan to determine as to how left lung pnueomonectomy through upregulation of SDF-1 supports the mobilization and incorporation of pro-angiogenic CXCR4+VEGFR1+ hematopoietic cells thereby promoting neo-angiogenesis of the regenerating right lung. We have shown that VEGF family of angiogenic factors promote recruitment of CD133+VEGFR2+ vascular progenitor cells from bone marrow (BM) to the neo-vessels. Signaling through VEGFR2 is essential for the proliferation and differentiation of vascular progenitors. We have also demonstrated that functional VEGFR1 and CXCR4 are co-expressed on the subsets of hematopoietic progenitors cells, supporting mobilization of these cells from the BM's microenvironment. Recruitment of pro-angiogenic CXCR4+VEGFR1+ cells to the regenerating vessels facilitates incorporation of VEGFR2 into functional vasculature. Mobilization and incorporation of BM-derived progenitor cells is a dynamic process and requires activation of a cascade of molecular events that drives recruitment of these cells from unique BM niches. Angiogenic factors, including Placental Growth Factor (P1GF), which exclusively signals through VEGFR1, induce expression of metalloproteinase-9 (MMP-9), which in turn promote the release of soluble Kit-ligand (sKitL, stem cell factor). Increase in bio-available sKitL enhances cycling and morility of CXCR4+VEGFR1+ cells, setting up the stage for mobilization to the circulation. We have preliminary evidence demonstrating that in mice, left lung pneumonectomy results in mobilization and incorporation of hemangiogenic progenitor cells into regenerating lung. Based on these studies, we hypothesize that the regenerating lung through plasma elevation of SDF-1 and VEGFs support the recruitment of marrow derived pro-angiogenic CXCR4+VEGFR1+ hematopoietic cells thereby facilitating incorporation of VEGFR2+ endothelial cells into functional regenerating lung vasculature. This hypothesis will be tested through studying the following specific aims: 1) Determine the temporal, and spatial recruitment patterns and functional contribution of CXCR4+VEGFR1+ progenitors during lung regeneration and compare their incorporation pattern into mice with diminished hemangiogenic potential including, Idl^TdS""""""""'"""""""", P1GF""""""""'"""""""", VEGF^/"""""""", and VEGFigg""""""""'"""""""" mice. 2) Assess the physiological significance of SDF-1 and VEGFs in accelerating lung revascularization through recruitment of CXCR4+VEGFR1+ cells. 3) Evaluate the contribution of BM-derived VEGFR2+, and VEGFR1+CXCR4+ cells to revascularization during lung regeneration. The proposed studies will take advantage of the expertise of Dr. RG Crystal (PI) in lung regeneration and emphysema models and the applicant's experience in hematopoiesis and endothelial cell biology to define the mechanism and identify molecular mediators that support recruitment of CXCR4+VEGFR1+ progenitors thereby supporting regeneration of pulmonary vasculature. These studies will lay the foundation for designing clinical protocols to deliver BM derived cells, including CXCR4-t-VEGFRl+ and VEGFR2+ cells, or to introduce SDF-1 and angiogenic factors, to enhance lung revascularization in patients suffering from emphysema and COPD.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Weill Medical College of Cornell University
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Strulovici-Barel, Yael; Staudt, Michelle R; Krause, Anja et al. (2016) Persistence of circulating endothelial microparticles in COPD despite smoking cessation. Thorax 71:1137-1144
Barjaktarevic, Igor Z; Crystal, Ronald G; Kaner, Robert J (2016) The Role of Interleukin-23 in the Early Development of Emphysema in HIV1(+) Smokers. J Immunol Res 2016:3463104
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Gomi, Kazunori; Arbelaez, Vanessa; Crystal, Ronald G et al. (2015) Activation of NOTCH1 or NOTCH3 signaling skews human airway basal cell differentiation toward a secretory pathway. PLoS One 10:e0116507
Wang, Guoqing; Wang, Rui; Strulovici-Barel, Yael et al. (2015) Persistence of smoking-induced dysregulation of miRNA expression in the small airway epithelium despite smoking cessation. PLoS One 10:e0120824
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Hessel, Justina; Heldrich, Jonna; Fuller, Jennifer et al. (2014) Intraflagellar transport gene expression associated with short cilia in smoking and COPD. PLoS One 9:e85453
Shaykhiev, Renat; Crystal, Ronald G (2014) Early events in the pathogenesis of chronic obstructive pulmonary disease. Smoking-induced reprogramming of airway epithelial basal progenitor cells. Ann Am Thorac Soc 11 Suppl 5:S252-8
Brekman, Angelika; Walters, Matthew S; Tilley, Ann E et al. (2014) FOXJ1 prevents cilia growth inhibition by cigarette smoke in human airway epithelium in vitro. Am J Respir Cell Mol Biol 51:688-700
Gao, Chuan; Tignor, Nicole L; Salit, Jacqueline et al. (2014) HEFT: eQTL analysis of many thousands of expressed genes while simultaneously controlling for hidden factors. Bioinformatics 30:369-76

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