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Immunological and functional features of decellularized xenogeneic heart valves after transplantation into GGTA1-KO pigs.

ABSTRACT: Decellularization of xenogeneic heart valves might lead to excellent regenerative implants, from which many patients could benefit. However, this material carries various xenogeneic epitopes and thus bears a considerable inherent immunological risk. Here, we investigated the regenerative and immunogenic potential of xenogeneic decellularized heart valve implants using pigs deficient for the galactosyltransferase gene (GGTA1-KO) as novel large animal model. Decellularized aortic and pulmonary heart valves obtained from sheep, wild-type pigs or GGTA1-KO pigs were implanted into GGTA1-KO pigs for 3, or 6 months, respectively. Explants were analyzed histologically, immunhistologically (CD3, CD21 and CD172a) and anti-αGal antibody serum titers were determined by ELISA. Xenogeneic sheep derived implants exhibited a strong immune reaction upon implantation into GGTA1-KO pigs, characterized by massive inflammatory cells infiltrates, presence of foreign body giant cells, a dramatic increase of anti-αGal antibody titers and ultimately destruction of the graft, whereas wild-type porcine grafts induced only a mild reaction in GGTA1-KO pigs. Allogeneic implants, wild-type/wild-type and GGTA1-KO/GGTA1-KO valves did not induce a measurable immune reaction. Thus, GGTA1-KO pigs developed a 'human-like' immune response toward decellularized xenogeneic implants showing that immunogenicity of xenogeneic implants is not sufficiently reduced by decellularization, which detracts from their regenerative potential.

SUBMITTER: Ramm R

PROVIDER: S-EPMC8329474 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Immunological and functional features of decellularized xenogeneic heart valves after transplantation into GGTA1-KO pigs.

Ramm Robert R Goecke Tobias T Köhler Peter P Tudorache Igor I Cebotari Serghei S Ciubotaru Anatol A Sarikouch Samir S Höffler Klaus K Bothe Friederike F Petersen Björn B Haverich Axel A Niemann Heiner H Hilfiker Andres A

Regenerative biomaterials 20210803 5

Decellularization of xenogeneic heart valves might lead to excellent regenerative implants, from which many patients could benefit. However, this material carries various xenogeneic epitopes and thus bears a considerable inherent immunological risk. Here, we investigated the regenerative and immunogenic potential of xenogeneic decellularized heart valve implants using pigs deficient for the galactosyltransferase gene (GGTA1-KO) as novel large animal model. Decellularized aortic and pulmonary hea ...[more]

PMID: 35928180

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Project description:Tissue-engineered heart valves are proposed as novel viable replacements granting longer durability and growth potential. However, they require extensive in vitro cell-conditioning in bioreactor before implantation. Here, the propensity of non-preconditioned decellularized heart valves to spontaneous in body self-regeneration was investigated in a large animal model. Decellularized porcine aortic valves were evaluated for right ventricular outflow tract (RVOT) reconstruction in Vietnamese Pigs (n = 11) with 6 (n = 5) and 15 (n = 6) follow-up months. Repositioned native valves (n = 2 for each time) were considered as control. Tissue and cell components from explanted valves were investigated by histology, immunohistochemistry, electron microscopy, and gene expression. Most substitutes constantly demonstrated in vivo adequate hemodynamic performances and ex vivo progressive repopulation during the 15 implantation months without signs of calcifications, fibrosis and/or thrombosis, as revealed by histological, immunohistochemical, ultrastructural, metabolic and transcriptomic profiles. Colonizing cells displayed native-like phenotypes and actively synthesized novel extracellular matrix elements, as collagen and elastin fibers. New mature blood vessels, i.e. capillaries and vasa vasorum, were identified in repopulated valves especially in the medial and adventitial tunicae of regenerated arterial walls. Such findings correlated to the up-regulated vascular gene transcription. Neoinnervation hallmarks were appreciated at histological and ultrastructural levels. Macrophage populations with reparative M2 phenotype were highly represented in repopulated valves. Indeed, no aspects of adverse/immune reaction were revealed in immunohistochemical and transcriptomic patterns. Among differentiated elements, several cells were identified expressing typical stem cell markers of embryonic, hematopoietic, neural and mesenchymal lineages in significantly higher number and specific topographic distribution in respect to control valves. Following the longest follow-up ever realized in preclinical models, non-preconditioned decellularized allogeneic valves offer suitable microenvironment for in vivo cell homing and tissue remodeling. Manufactured with simple, timesaving and cost-effective procedures, these promising valve replacements hold promise to become an effective alternative, especially for pediatric patients.

Project description:BackgroundValve replacement surgery is the definitive management strategy for patients with severe valvular disease. However, valvular conduits currently in clinical use are associated with significant limitations. Tissue-engineered (decellularized) heart valves are alternative prostheses that have demonstrated promising early results. The purpose of this systematic review and meta-analysis is to perform robust evaluation of the clinical performance of decellularized heart valves implanted in either outflow tract position, in comparison with standard tissue conduits.MethodsSystematic searches were conducted in the PubMed, Scopus, and Web of Science databases for articles in which outcomes between decellularized heart valves surgically implanted within either outflow tract position of human subjects and standard tissue conduits were compared. Primary endpoints included postoperative mortality and reoperation rates. Meta-analysis was performed using a random-effects model via the Mantel-Haenszel method.ResultsSeventeen articles were identified, of which 16 were included in the meta-analysis. In total, 1418 patients underwent outflow tract reconstructions with decellularized heart valves and 2725 patients received standard tissue conduits. Decellularized heart valves were produced from human pulmonary valves and implanted within the right ventricular outflow tract in all cases. Lower postoperative mortality (4.7% vs. 6.1%; RR 0.94, 95% CI: 0.60-1.47; P = 0.77) and reoperation rates (4.8% vs. 7.4%; RR 0.55, 95% CI: 0.36-0.84; P = 0.0057) were observed in patients with decellularized heart valves, although only reoperation rates were statistically significant. There was no statistically significant heterogeneity between the analyzed articles (I2 = 31%, P = 0.13 and I2 = 33%, P = 0.10 respectively).ConclusionsDecellularized heart valves implanted within the right ventricular outflow tract have demonstrated significantly lower reoperation rates when compared to standard tissue conduits. However, in order to allow for more accurate conclusions about the clinical performance of decellularized heart valves to be made, there need to be more high-quality studies with greater consistency in the reporting of clinical outcomes.

Dataset Information

Immunological and functional features of decellularized xenogeneic heart valves after transplantation into GGTA1-KO pigs.

Publications

Immunological and functional features of decellularized xenogeneic heart valves after transplantation into GGTA1-KO pigs.

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