Dataset Information

The Sertoli Cell Complement Signature: A Suspected Mechanism in Xenograft Survival.

ABSTRACT: The complement system is an important component of transplant rejection. Sertoli cells, an immune regulatory testicular cell, survive long-term when transplanted across immunological barriers; thus, understanding the mechanisms behind this unique survival would be of great benefit to the transplantation field. This study focused on Sertoli cell inhibition of complement as relevant in xenotransplantation. Neonatal pig Sertoli cells (NPSCs) survived activated human complement in vitro while neonatal pig islet (NPI) aggregates and pig aortic endothelial cell (PAEC) survival were diminished to about 65% and 12%, respectively. PAECs cultured in NPSC-conditioned media and human complement demonstrated a 200% increase in survival suggesting that NPSCs secrete complement-inhibiting substances that confer protection. Bioinformatic and molecular analyses identified 21 complement inhibitors expressed by NPSCs with several significantly increased in NPSCs compared to NPIs or PAECs. Lastly, RNA sequencing revealed that NPSCs express 25 other complement factors including cascade components and receptors. Overall, this study identified the most comprehensive Sertoli cell complement signature to date and indicates that the expression of a variety of complement inhibitors ensures a proper regulation of complement through redundant inhibition points. Understanding the regulation of the complement system should be further investigated for extending xenograft viability.

SUBMITTER: Washburn RL

PROVIDER: S-EPMC9916409 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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The Sertoli Cell Complement Signature: A Suspected Mechanism in Xenograft Survival.

Washburn Rachel L RL Martinez-Marin Dalia D Korać Ksenija K Sniegowski Tyler T Rodriguez Alexis R AR Chilton Beverly S BS Hibler Taylor T Pruitt Kevin K Bhutia Yangzom D YD Dufour Jannette M JM

International journal of molecular sciences 20230118 3

The complement system is an important component of transplant rejection. Sertoli cells, an immune regulatory testicular cell, survive long-term when transplanted across immunological barriers; thus, understanding the mechanisms behind this unique survival would be of great benefit to the transplantation field. This study focused on Sertoli cell inhibition of complement as relevant in xenotransplantation. Neonatal pig Sertoli cells (NPSCs) survived activated human complement in vitro while neonat ...[more]

PMID: 36768217

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Project description:Xenotransplantation has vast clinical potential but is limited by the potent immune responses generated against xenogeneic tissue. Immune-privileged Sertoli cells (SCs) survive xenotransplantation long term (≥90 days) without immunosuppression, making SCs an ideal model to identify xenograft survival mechanisms. Xenograft rejection includes the binding of natural and induced antibodies and the activation of the complement cascade. Using an in vitro cytotoxicity assay, wherein cells were cultured with human serum and complement, we demonstrated that neonatal pig SCs (NPSCs) are resistant to complement-mediated cell lysis and express complement inhibitory factors, membrane cofactor protein (MCP; CD46), and decay- accelerating factor (DAF; CD55) at significantly higher levels than neonatal pig islets (NPIs), which served as non-immune-privileged controls. After xenotransplantation into naive Lewis rats, NPSCs survived throughout the study, while NPIs were rejected within 9 days. Serum antibodies, and antibody and complement deposition within the grafts were analyzed. Compared to preformed circulating anti-pig IgM antibodies, no significant increase in IgM production against NPSCs or NPIs was observed, while IgM deposition was detected from day 6 onward in both sets of grafts. A late serum IgG response was detected in NPSC (days 13 and 20) and NPI (day 20) recipients. Consistently, IgG deposition was first detected at days 9 and 13 in NPSC and NPI grafts, respectively. Interestingly, C3 was deposited at days 1 and 3 in NPI grafts and only at day 1 in NPSC grafts, while membrane attack complex (MAC) deposition was only detected in NPI grafts (at days 1-4). Collectively, these data suggest NPSCs actively inhibit both the alternative and classical pathways of complement-mediated cell lysis, while the alternative pathway plays a role in rejecting NPIs. Ultimately, inhibiting the alternative pathway along with transplanting xenogeneic tissue from transgenic pigs (expressing human complement inhibitory factors) could prolong the survival of xenogeneic cells without immunosuppression.

Dataset Information

The Sertoli Cell Complement Signature: A Suspected Mechanism in Xenograft Survival.

Publications

The Sertoli Cell Complement Signature: A Suspected Mechanism in Xenograft Survival.

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