Blastocyst complementation and interspecies chimeras in gene edited pigs

Abstract

The only curative therapy for many endstage diseases is allograft organ transplantation. Due to the limited supply of donor organs, relatively few patients are recipients of a transplanted organ. Therefore, new strategies are warranted to address this unmet need. Using gene editing technologies, somatic cell nuclear transfer and human induced pluripotent stem cell technologies, interspecies chimeric organs have been pursued with promising results. In this review, we highlight the overall technical strategy, the successful early results and the hurdles that need to be addressed in order for these approaches to produce a successful organ that could be transplanted in patients with endstage diseases.

Chimeric Livers: Interspecies Blastocyst Complementation and Xenotransplantation for End-Stage Liver Disease

“…The technique is centered around the generation of cells and even whole organs of one animal species, the donor, through the use of another animal species in utero, the recipient. [73][74][75][76] When compared to other contemporary methods for organ regeneration, such as the previously discussed implementation of PHH transplantation for ESLD, blastocyst complementation has the benefit of requiring remarkably few PSCs, and most of the inductive cues required for hepatogenesis are already present within the developing blastocyst. [77][78][79] In reference to blastocyst complementation for hepatogenesis, genetic modification of the recipient species' blastocysts occurs such that key gene(s), such as the aforementioned Hhex, required for hepatogenesis and liver bud development are knocked out, and subsequently complemented with a microinjection of PSCs from the donor species -often ESCs or iPSCs (Figure 2).…”

“…ETV2, a master regulator of hematoendothelial lineages, has become a major target for the generation of human-pig chimeras with human-derived endothelial cells to minimize the likelihood of hyperacute graft rejection. 76 Due to its pivotal role in regulation and development of hematoendothelial lineages, deletion of ETV2 results in an absence of all blood and vasculature, thereby, ensuring the creation of an empty niche for interspecies blastocyst complementation. 144 Das et.…”