Reduced human platelet uptake by pig livers deficient in the asialoglycoprotein receptor 1 protein. (27th February 2015)

• Record Type: Journal Article
• Authors: Paris, Leela L.; Estrada, Jose L.; Li, Ping; Blankenship, Ross L.; Sidner, Richard A.; Reyes, Luz M.; Montgomery, Jessica B.; Burlak, Christopher; Butler, James R.; Downey, Susan M.; Wang, Zheng‐Yu; Tector, Matthew; Tector, A. Joseph
• Is Part Of: Xenotransplantation. Volume 22:Number 3(2015:May/Jun.)
• Page Start: 203
• Page End: 210
• Publication Date: 2015-02-27
• Subjects: Xenografts -- Periodicals; Transplantation of organs, tissues, etc -- Periodicals; 617.95
• DOI: 10.1111/xen.12164
• Languages: English
• ISSNs: 0908-665X

Abstract

<abstract abstract-type="main" id="xen12164-abs-0001"> <title>Abstract</title> <sec id="xen12164-sec-0001" sec-type="section"> <title>Background</title> <p>The lethal thrombocytopenia that accompanies liver xenotransplantation is a barrier to clinical application. Human platelets are bound by the asialoglycoprotein receptor (ASGR) on pig sinusoidal endothelial cells and phagocytosed. Inactivation of the <italic>ASGR1</italic> gene in donor pigs may prevent xenotransplantation‐induced thrombocytopenia.</p> </sec> <sec id="xen12164-sec-0002" sec-type="section"> <title>Methods</title> <p>Transcription activator‐like effector nucleases (TALENs) were targeted to the ASGR1 gene in pig liver‐derived cells. ASGR1 deficient pig cells were used for somatic cell nuclear transfer (SCNT). <italic>ASGR1</italic> knock out (ASGR1<sup>−/−</sup>) fetal fibroblasts were used to produce healthy <italic>ASGR1</italic> knock out piglets. Human platelet uptake was measured in ASGR1<sup>+/+</sup> and ASGR1<sup>−/−</sup> livers.</p> </sec> <sec id="xen12164-sec-0003" sec-type="section"> <title>Results</title> <p>Targeted disruption of the <italic>ASGR1</italic> gene with TALENs eliminated expression of the receptor. ASGR1‐/‐ livers phagocytosed fewer human platelets than domestic porcine livers during perfusion.</p> </sec> <sec id="xen12164-sec-0004" sec-type="section"> <title>Conclusions</title> <p>The use of TALENs in liver‐derived cells followed by SCNT enabled the production of healthy homozygous <italic>ASGR1</italic> knock out pigs. Livers from ASGR1‐/‐ pigs exhibit decreased human platelet uptake. Deletion of the ASGR1 gene is a viable strategy to diminish platelet destruction in pig‐to‐human xenotransplantation.</p> </sec> </abstract>