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种间囊胚互补与嵌合实体人类器官的生成

Interspecies Blastocyst Complementation and the Genesis of Chimeric Solid Human Organs.

作者信息

Bigliardi Elena, Shetty Anala V, Low Walter C, Steer Clifford J

机构信息

Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455, USA.

Molecular, Cellular, Developmental Biology, and Genetics Graduate Program, University of Minnesota, Minneapolis, MN 55455, USA.

出版信息

Genes (Basel). 2025 Feb 12;16(2):215. doi: 10.3390/genes16020215.

Abstract

Solid organ transplantation remains a life-saving treatment for patients worldwide. Unfortunately, the supply of donor organs cannot meet the current need, making the search for alternative sources even more essential. Xenotransplantation using sophisticated genetic engineering techniques to delete and overexpress specific genes in the donor animal has been investigated as a possible option. However, the use of exogenous tissue presents another host of obstacles, particularly regarding organ rejection. Given these limitations, interspecies blastocyst complementation in combination with precise gene knockouts presents a unique, promising pathway for the transplant organ shortage. In recent years, great advancements have been made in the field, with encouraging results in producing a donor-derived organ in a chimeric host. That said, one of the major barriers to successful interspecies chimerism is the mismatch in the developmental stages of the donor and the host cells in the chimeric embryo. Another major barrier to successful chimerism is the mismatch in the developmental speeds between the donor and host cells in the chimeric embryos. This review outlines 19 studies in which blastocyst complementation was used to generate solid organs. In particular, the genesis of the liver, lung, kidney, pancreas, heart, thyroid, thymus and parathyroids was investigated. Of the 19 studies, 7 included an interspecies model. Of the 7, one was completed using human donor cells in a pig host, and all others were rat-mouse chimeras. While very promising results have been demonstrated, with great advancements in the field, several challenges continue to persist. In particular, successful chimerism, organ generation and donor contribution, synchronized donor-host development, as well as ethical concerns regarding human-animal chimeras remain important aspects that will need to be addressed in future research.

摘要

实体器官移植仍然是全球患者的一种挽救生命的治疗方法。不幸的是,供体器官的供应无法满足当前需求,因此寻找替代来源变得更加重要。利用复杂的基因工程技术在供体动物中删除和过表达特定基因的异种移植已被作为一种可能的选择进行研究。然而,使用外源组织带来了一系列其他障碍,特别是在器官排斥方面。鉴于这些局限性,种间囊胚互补与精确的基因敲除相结合为解决移植器官短缺问题提供了一条独特且有前景的途径。近年来,该领域取得了巨大进展,在嵌合宿主中产生供体来源的器官方面取得了令人鼓舞的结果。也就是说,成功的种间嵌合体的主要障碍之一是嵌合胚胎中供体细胞和宿主细胞发育阶段的不匹配。成功嵌合体的另一个主要障碍是嵌合胚胎中供体细胞和宿主细胞发育速度的不匹配。本综述概述了19项利用囊胚互补来生成实体器官的研究。特别研究了肝脏、肺、肾、胰腺、心脏、甲状腺、胸腺和甲状旁腺的起源。在这19项研究中,7项包括种间模型。在这7项中,1项是使用人类供体细胞在猪宿主中完成的,其他所有都是大鼠 - 小鼠嵌合体。虽然已经取得了非常有前景的结果,该领域也有了很大进展,但仍有几个挑战持续存在。特别是,成功的嵌合体形成、器官生成和供体贡献、供体 - 宿主发育同步,以及关于人 - 动物嵌合体的伦理问题仍然是未来研究需要解决的重要方面。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c044/11854981/430ba797c059/genes-16-00215-g001.jpg

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