Authors
Jae Young Kim
Published in
Frontiers in transplantation. Volume 5. Pages 1968710. Epub Sep 28, 2026.
Abstract
Recent advances in genetic engineering have substantially reduced the major carbohydrate barriers to pig-to-human xenotransplantation. Deletion of GGTA1, CMAH, and B4GALNT2 decreases αGal, Neu5Gc, and B4GALNT2-dependent Sda-like xenoantigens and thereby attenuates preformed antibody binding and complement-mediated injury. However, removal of these major xenoantigens does not necessarily generate a human-compatible cell-surface glycome. In particular, CMAH knockout eliminates Neu5Gc but leaves a Neu5Ac-dominant sialome whose linkage, chemical modification, glycoconjugate carrier, density, and spatial presentation are not necessarily human-like. This review examines sialylation and glycan-dependent recognition as an underappreciated regulatory layer linking innate immunity, blood-cell homeostasis, complement regulation, and thromboinflammation in xenotransplantation. Two conceptual distinctions are emphasized. First, the direction and evidence depth of glycan-receptor recognition must be explicitly considered. The best-established Siglec-1-dependent xenogeneic interaction is a graft-versus-host pathway, in which donor porcine Siglec-1-positive macrophages capture recipient human erythrocytes. Conversely, direct receptor-level binding of human Siglec-1 to CMAH-deficient gene-edited pig erythrocytes has recently been demonstrated, providing evidence for the reciprocal host-versus-graft direction; however, whether this interaction drives recipient macrophage phagocytosis or in vivo clearance remains unresolved. Donor ASGR1-dependent uptake of human platelets provides another direct example of glycan-dependent recipient blood-cell clearance. Second, α2,3-linked Neu5Ac illustrates a fundamental functional trade-off in sialome engineering. Neu5Acα2,3Gal-containing glycans can serve as preferred ligands for Siglec-1-mediated capture, whereas α2,3-linked sialoglycans also contribute to Factor H-dependent recognition of self-associated surfaces and alternative complement regulation. Conversely, increasing α2,6-linked sialylation may reduce macrophage xenoreactivity and enhance inhibitory Siglec engagement but decrease α2,3-dependent Factor H recognition; thus, ST6GAL1 engineering should not be considered uniformly protective or equivalent to glycan "humanization". Other pathways, including CD24-Siglec-10 signaling, Siglec-9-mediated regulation of neutrophil activation and NETosis, and platelet Siglec signaling, provide additional mechanistic frameworks but remain incompletely validated in solid-organ xenotransplantation. We therefore propose that post-editing glycan compatibility should be evaluated according to receptor directionality, evidence depth, and functional trade-offs, rather than glycan abundance or donor genotype alone. Organ-, cell-, carrier-, and receptor-specific analyses integrating quantitative glycomics/glycoproteomics, human receptor and immune-cell assays, functional crossmatching, and ex vivo perfusion are needed to link donor genotype to post-editing glycan phenotype and guide precision optimization of xenograft compatibility.
PMID:
42865776
Bibliographic data and abstract were imported from PubMed on 13 Oct 2026.
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