Reducing immunoreactivity of porcine bioprosthetic heart valves by genetically-deleting three major glycan antigens, GGTA1/β4GalNT2/CMAH

Zhang, Runjie; Wang, Ying; Chen, Lei; Wang, Ronggen; Chu, Li; Li, Xiaoxue; Fang, Bin; Ren, Xueyang; Ruan, Miaomiao; Liu, Jiying; Xiong, Qiang; Zhang, Lining; Jin, Yong; Zhang, Manling; Liu, Xiaorui; Li, Lin; Chen, Qiang; Pan, Dengke; Li, Rongfeng; Cooper, David K. C.; Yang, Haiyuan; Dai, Yifan

doi:10.1016/j.actbio.2018.03.055

Cited by 72 publications

(53 citation statements)

References 40 publications

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“…Until now, large animals with similar anatomy, size and physiology to humans but lacking the ability to generate kidney organs have not been available. Previous studies have shown that CRISPR/Cas9 can be successfully used to generate target mutations in pigs . Here, we efficiently disrupted the SIX1 and SIX4 genes in pigs by altering the protein coding sequence, and we demonstrated that both SIX1 and SIX4 gene knockout in pig foetuses result in disruption of their nephrogenesis phenotype, thereby providing an empty organ niche for the potential generation of human kidneys in pigs.…”

Section: Discussionmentioning

confidence: 81%

Disabling of nephrogenesis in porcine embryos via CRISPR/Cas9‐mediated SIX1 and SIX4 gene targeting

Wang

Liu

Zhao

et al. 2019

Xenotransplantation

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SIX1 and SIX4 genes play critical roles in kidney development. We evaluated the effect of these genes on pig kidney development by generating SIX1 −/− and SIX1 −/− /SIX4 −/− pig foetuses using CRISPR/Cas9 and somatic cell nuclear transfer. We obtained 3 SIX1 −/− foetuses and 16 SIX1 −/− /SIX4 −/− foetuses at different developmental stages. The SIX1 −/− foetuses showed a migration block of the left kidney and a smaller size for both kidneys. The ureteric bud failed to form the normal branching and collecting system. Abnormal expressions of kidney development-related genes (downregulation of PAX2, PAX8, and BMP4 and upregulation of EYA1 and SALL1) were also observed in SIX1 −/− foetal kidneys and confirmed in vitro in porcine kidney epithelial cells (PK15) following SIX1 gene deletion. The SIX1 −/− /SIX4 −/− foetuses exhibited more severe phenotypes, with most foetuses showing retarded development at early stages of gestation. The kidney developed only to the initial stage of metanephros formation. These results demonstrated that SIX1 and SIX4 are key genes for porcine metanephros development. The creation of kidney-deficient porcine foetuses provides a platform for generating human kidneys inside pigs using blastocyst complementation. K E Y W O R D S blastocyst complementation, CRISPR/Cas9, kidney development, pig, SIX1, SIX4

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Section: Discussionmentioning

confidence: 81%

Disabling of nephrogenesis in porcine embryos via CRISPR/Cas9‐mediated SIX1 and SIX4 gene targeting

Wang

Liu

Zhao

et al. 2019

Xenotransplantation

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“…Besides the dietary exposure to Neu5Gc, humans can also encounter Neu5Gc that is expressed on exogenous glycosylated biotherapeutics, 106,[134][135][136] biodevices, or xenografts, 104,[137][138][139][140][141][142] that are given to human patients. In this case, circulating anti-Neu5Gc antibodies could reduce efficacy of therapy, [134][135][136] elicit an increased and diversified anti-Neu5Gc response that can remain long-lasting, 143,144 or possibly mediate xenograft failure or rejection.…”

Section: Con S Equen Ce S Of Neu5g C and Anti -Neu5g C Antibod Ie Smentioning

confidence: 99%

Evolution of sialic acids: Implications in xenotransplant biology

Paul

Padler‐Karavani

2018

Xenotransplantation

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All living cells are covered with a dense "sugar-coat" of carbohydrate chains (glycans) conjugated to proteins and lipids. The cell surface glycome is determined by a non-template driven process related to the collection of enzymes that assemble glycans in a sequential manner. In mammals, many of these glycans are topped with sialic acids (Sia), a large family of acidic sugars. The "Sialome" is highly diverse owing to various Sia types, linkage to underlying glycans, range of carriers, and complex spatial organization. Presented at the front of cells, Sia play a major role in immunity and recognition of "self" versus "non-self," largely mediated by the siglecs family of Sia-binding host receptors. Albeit many mammalian pathogens have evolved to hijack this recognition system to avoid host immune attack, presenting a fascinating host-pathogen evolutionary arms race. Similarly, cancer cells exploit Sia for their own survival and propagation. As part of this ongoing fitness, humans lost the ability to synthesize the Sia type N-glycolylneuraminic acid (Neu5Gc), in contrast to other mammals. While this loss had provided an advantage against certain pathogens, humans are continuously exposed to Neu5Gc through mammalian-derived diet (eg, red meat), consequently generating a complex immune response against it. Circulating anti-Neu5Gc antibodies together with Neu5Gc on some human tissues mediate chronic inflammation "xenosialitis" that exacerbate various human diseases (eg, cancer and atherosclerosis). Similarly, Neu5Gc-containing xenografts are exposed to human anti-Neu5Gc antibodies with implications to sustainability. This review aimed to provide a glimpse into the evolution of Sia and their implications to xenotransplantation.

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“…These results suggest that the deletion of Neu5Gc epitope in pigs is crucial for increasing xenograft survival time. In vitro evidence has also suggested that inactivation of the B4GalNT2 gene reduce human antibody binding (34,128). These data indicate that TKO pig organs have proven to be a major advancement compared with GTKO and DKO xenografts following transplantation into human.…”

Section: Deleting Xenoreactive Antigensmentioning

confidence: 97%