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Circulatory Extracellular Vesicles from Lung Allograft Recipients with Chronic Lung Allograft Dysfunction Can Induce LKB1 Dependent Epithelial-Mesenchymal Transition

M. Rahman, S. Angara, A. Arjuna, M. Smith, R. Bremner, T. Mohanakumar

Norton Thoracic Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ

Meeting: 2020 American Transplant Congress

Abstract number: 206

Keywords: Epithelial cells, Lung transplantation, Rejection

Session Information

Session Name: Basic: Acute Rejection

Session Type: Oral Abstract Session

Date: Saturday, May 30, 2020

Session Time: 3:15pm-4:45pm

 Presentation Time: 3:15pm-3:27pm

Location: Virtual

*Purpose: Extracellular vesicles (EVs) play important role in physiological and pathological conditions. Recently we demonstrated that circulating exosomes (EVs) with lung self-antigens (SAgs) play important role in acute and chronic lung allograft dysfunction (CLAD). A tumor suppressor gene, LKB1, is mutated in up to one-third of lung adenocarcinomas, is responsible for proliferation, invasion, and tumor progression. The goal of this study is to determine the role of exosomes isolated from LTxRs diagnosed with CLAD in the induction of epithelial mesenchymal transition (EMT) in LKB1 dependent manner for the pathogenesis of CLAD.

*Methods: EVs were isolated from LTxRs with bronchiolitis obliterans syndrome (BOS), or time matched stable, using Total Exosome Isolation kit followed by 0.2 micron filtration and size distribution (<200nm) using Nano-sight, concentration by BCA. Human lung epithelial cells (BEAS-2B) were incubated with 100 microgram of EVs from BOS or stable. We examined the role of LKB1 in BOS-EVs induced EMT by knocking down with siRNA in a hypoxia/reperfusion in vitro model. Lung SAgs and EMT markers (Vimentin, α-SMA) were measured by Western blot and band intensity calculated by densitometry.

*Results: BOS plasma contained higher amount of EVs compared to stable (2000000 vs 1200000 particles/ml, p=<0.0005) and contained higher levels of SAgs, Kα1-Tubulin (Kα1T) (2811 vs 1215, p=<0.005), and Collagen V (Col-V) (2138 vs 716, p=<0.005) compared to stable. BOS-EVs induced morphological changes of the BEAS-2B. Co-culture of EVs from BOS, but not stable, induced vimentin (2412 vs 1521, p=<0.05), α-SMA protein (1121 vs 521, p=<0.05) LKB1 knock-down increased Kα1T (3412 vs 1221, p=<0.05), Col-V (2132 vs 1121, p=<0.05), α-SMA (2322 vs 632, p=<0.05), and vimentin (1923 vs 821, p=<0.05) following hypoxia/reperfusion compared to non-targeting siRNA. These results demonstrate that circulating EVs from BOS LTxRs can play an important role in inducing EMT leading to the pathogenesis seen in CLAD.

*Conclusions: Our data also supports a significant role for the tumor suppressor gene LKB1 in this process. Therefore, circulating exosomes released from the transplanted lungs can inactivate the tumor suppressor gene LKB1 leading to upregulation of vimentin and α-SMA resulting in EMT leading to CLAD, a novel molecular mechanism for induction of EMT following lung transplantation.

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To cite this abstract in AMA style:

Rahman M, Angara S, Arjuna A, Smith M, Bremner R, Mohanakumar T. Circulatory Extracellular Vesicles from Lung Allograft Recipients with Chronic Lung Allograft Dysfunction Can Induce LKB1 Dependent Epithelial-Mesenchymal Transition [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/circulatory-extracellular-vesicles-from-lung-allograft-recipients-with-chronic-lung-allograft-dysfunction-can-induce-lkb1-dependent-epithelial-mesenchymal-transition/. Accessed May 28, 2025.

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