Humanized von Willebrand factor reduces platelet sequestration in ex vivo and in vivo xenotransplant models.
Humanized von Willebrand factor reduces platelet sequestration in ex vivo and in vivo xenotransplant models.
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DOI：
10.1111/xen.12712
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发表时间：
2021-11
影响因子：
3.9
通讯作者：
Pierson, Richard N., III
中科院分区：
文献类型：
--
作者：
Connolly, Margaret R.;Kuravi, Kasinath;Burdorf, Lars;Sorrells, Lori;Morrill, Benson;Cimeno, Arielle;Vaught, Todd;Dandro, Amy;Sendil, Selin;Habibabady, Zahra A.;Monahan, Jeffery;Li, Tiezheng;LaMattina, John;Eyestone, Willard;Ayares, David;Phelps, Carol;Azimzadeh, Agnes M.;Pierson, Richard N., III
跨物种器官移植为解决人体器官短缺提供了可能。虽然人血管性血友病因子 (vWF) 激活人血小板需要通过剪切应力激活 vWF，但人血小板和猪 vWF (pvWF) 之间的接触会导致自发的血小板粘附和激活。这种非生理相互作用可能导致血小板减少症和凝血途径失调，这通常与非人灵长类动物的猪器官异种移植有关。经过基因改造以减少抗体和补体依赖性排斥反应的猪 (GTKO.hCD46) 被设计为通过用人 cDNA 直向同源物替换编码糖蛋白 Ib 结合位点的 pvWF 基因区域来表达人源化 pvWF (h*pvWF)。这种修改纠正了暴露于猪血浆时的非生理性人血小板聚集，同时保留了胶原蛋白在体外的血小板活化作用。患有 h*pvWF 的猪的器官在用人血离体灌注肺 (p≤ .01) 和肝 (4 小时内 p≤ .038) 期间以及猪-狒狒肺移植 (p≤ .007) 期间，血小板隔离减少。典型血小板粘附途径的阻断并不能阻止残余血小板的隔离和活化。 h*pvWF 修饰可防止猪 vWF 对人类或狒狒血小板产生生理上不适当的激活，从而解决了异种移植中观察到的血小板减少和血小板激活的原因之一。
The transplantation of organs across species offers the potential to solve the shortage of human organs. While activation of human platelets by human von Willebrand factor (vWF) requires vWF activation by shear stress, contact between human platelets and porcine vWF (pvWF) leads to spontaneous platelet adhesion and activation. This non-physiologic interaction may contribute to the thrombocytopenia and coagulation pathway dysregulation often associated with xenotransplantation of pig organs in nonhuman primates. Pigs genetically modified to decrease antibody and complement-dependent rejection (GTKO.hCD46) were engineered to express humanized pvWF (h*pvWF) by replacing a pvWF gene region that encodes the glycoprotein Ib-binding site with human cDNA orthologs. This modification corrected for non-physiologic human platelet aggregation on exposure to pig plasma, while preserving in vitro platelet activation by collagen. Organs from pigs with h*pvWF demonstrated reduced platelet sequestration during lung (p≤ .01) and liver (p≤ .038 within 4 h) perfusion ex vivo with human blood and after pig-to-baboon lung transplantation (p≤ .007). Residual platelet sequestration and activation were not prevented by the blockade of canonical platelet adhesion pathways. The h*pvWF modification prevents physiologically inappropriate activation of human or baboon platelets by porcine vWF, addressing one cause of the thrombocytopenia and platelet activation observed with xenotransplantation.
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影响因子：
3.9
作者：
Burdorf, Lars;Harris, Donald;Pierson, Richard N., III
通讯作者：
Pierson, Richard N., III
影响因子：
3.9
作者：
Burdorf L;Riner A;Rybak E;Salles II;De Meyer SF;Shah A;Quinn KJ;Harris D;Zhang T;Parsell D;Ali F;Schwartz E;Kang E;Cheng X;Sievert E;Zhao Y;Braileanu G;Phelps CJ;Ayares DL;Deckmyn H;Pierson RN 3rd;Azimzadeh AM;Dandro A;Karavi K
通讯作者：
Karavi K
DOI：
10.1007/978-1-0716-0255-3_12
发表时间：
2020-01-01
期刊：
XENOTRANSPLANTATION: METHODS AND PROTOCOLS, 2ND EDITION
影响因子：
--
作者：
Burdorf, Lars;Azimzadeh, Agnes M.;Pierson, Richard N., III
通讯作者：
Pierson, Richard N., III
影响因子：
8.8
作者：
Cantu, E.;Balsara, K. R.;Davis, R. D.
通讯作者：
Davis, R. D.
影响因子：
3.9
作者：
Kim, Young Tae;Lee, Hyun Joo;Kang, Hee Jung
通讯作者：
Kang, Hee Jung