Date: Tuesday, June 4, 2019
Session Time: 6:00pm-7:00pm
Presentation Time: 6:00pm-7:00pm
Location: Hall C & D
*Purpose: The clinical relevance and tissue-specific role of Notch1 activation, a highly conserved transmembrane receptor involved in cell fate decision, proliferation and regeneration, in orthotopic liver transplantation (OLT) remains to be elucidated. We utilized a clinically-relevant mouse OLT model, and screened human liver transplant biopsies (Bx) to dissect the role of hepatic Notch1 signaling in IR-stressed OLT.
*Methods: In the clinical arm, hepatic Bx were obtained from liver transplant patients (n=60) at 2h post-reperfusion (prior to abdominal closure). The expression of Notch1 intracellular domain (NICD) target gene was evaluated by Western blots. In the experimental arm, WT or myeloid-specific Notch1 deficient (mN1-KO) livers (C57/BL6) subjected to extended (18h) ex-vivo cold storage were transplanted into syngeneic WT recipients; OLT and sera samples were collected at 6h post-reperfusion. Some mouse recipients were treated with a putative Notch1 activator, Serelaxin (SER, 5μg/kg i.v. at reperfusion).
*Results: Post-reperfusion NICD levels in clinical OLT Bx correlated negatively with mRNA levels coding for TLR4 (r=-0.334, p=0.013), CXCL10 (r=-0.286, p=0.034) and Cathepsin G (neutrophil marker; r=-0.343, p=0.010); as well as with sAST (r=-0.381, p=0.003) and sALT (r=-0.367, p=0.004) levels at POD1. Liver Bx with high-NCID levels (n=30) were characterized by decreased expression of TLR4/CXCL10/Cathepsin G (p<0.05), along with lower sAST (252±37 vs 858±373 IU/L, p=0.029) and sALT (256±34 vs 434±65 IU/L, p=0.037) at POD1; and showed improved rejection-free OLT survival (3-years: 87% vs 68%, p=0.076, median follow-up of 1287 days) as compared to low-NICD group (n=30). Treatment of mouse OLT with SER: 1/ increased NICD expression; 2/ decreased sAST levels (1315±520 vs 3204±1539 IU/L, n=10/10, p<0.001), Suzuki's histological grading (p<0.05), frequency of TUNEL+ cells (p<0.05); 3/ inhibited neutrophil/macrophage infiltration (p<0.05); 4/ depressed CXCL10/MCP1/CXCL2 mRNA levels (p<0.05); and 5/ improved overall survival (2-weeks: 60% vs 31%, p=0.016), all documenting the therapeutic potential of OLT-specific Notch1 activation. In marked contrast to WT liver grafts, myeloid-deficient Notch1 livers (mN1-KO>WT) suffered exaggerated IR-damage, evidenced by sALT (9127±4276 vs 4633±2678 IU/L, n=7/7, p=0.020), Suzuki’s histological grading (p<0.05), frequency of TUNEL+ cells (p<0.05); increased neutrophil/macrophage infiltration (p<0.05); and enhanced CXCL10/MCP1/CXCL2 (p<0.05) mRNA levels.
*Conclusions: This translational study highlights the cytoprotective role of hepatic Notch1 activation, especially in donor liver Kupffer cells, to regulate innate immune-driven inflammation response and preserve OLT function. These findings provide the rationale for Notch1 inducing novel therapeutic strategies in IR-stressed liver transplant recipients.
To cite this abstract in AMA style:Kadono K, Kageyama S, Hirao H, Nakamura K, Ito T, Dery KJ, Oncel D, Ke B, Kaldas FM, Busuttil RW, Kupiec‐Weglinski JW. Notch1 Signaling Protects Liver Grafts from Ischemia Reperfusion Injury: From Mouse to Human [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/notch1-signaling-protects-liver-grafts-from-ischemia-reperfusion-injury-from-mouse-to-human/. Accessed February 18, 2020.
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