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

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.

[1]  J. Dufour,et al.  Mouse Sertoli Cells Inhibit Humoral-Based Immunity , 2022, International journal of molecular sciences.

[2]  Ping Liu,et al.  Endothelial cell heterogeneity and microglia regulons revealed by a pig cell landscape at single-cell level , 2022, Nature Communications.

[3]  J. Dufour,et al.  The Good, the Bad and the Ugly of Testicular Immune Regulation: A Delicate Balance Between Immune Function and Immune Privilege. , 2021, Advances in Experimental Medicine and Biology.

[4]  J. Dufour,et al.  Neonatal Pig Sertoli Cells Survive Xenotransplantation by Creating an Immune Modulatory Environment Involving CD4 and CD8 Regulatory T Cells , 2020, Cell transplantation.

[5]  Ming-hui Zhao,et al.  The Complement C3a and C3a Receptor Pathway in Kidney Diseases , 2020, Frontiers in Immunology.

[6]  S. Quake,et al.  Molecular and genetic regulation of pig pancreatic islet cell development , 2020, Development.

[7]  B. Tönshoff.  Immunosuppressants in Organ Transplantation. , 2019, Handbook of experimental pharmacology.

[8]  J. Thurman,et al.  The Role of Complement in Organ Transplantation , 2019, Front. Immunol..

[9]  P. Nilsson,et al.  The Role of Complement in Liver Injury, Regeneration, and Transplantation , 2019, Hepatology.

[10]  D. Cooper,et al.  The complex functioning of the complement system in xenotransplantation , 2019, Xenotransplantation.

[11]  C. Garlanda,et al.  The Long Pentraxin PTX3 as a Link Between Innate Immunity, Tissue Remodeling, and Cancer , 2019, Front. Immunol..

[12]  C. Lindskog,et al.  The adult human testis transcriptional cell atlas , 2018, Cell Research.

[13]  M. Pirooznia,et al.  Complement receptor CD46 co-stimulates optimal human CD8+ T cell effector function via fatty acid metabolism , 2018, Nature Communications.

[14]  M. Kolev,et al.  Complement and the Regulation of T Cell Responses. , 2018, Annual review of immunology.

[15]  M. Kolev,et al.  Intracellular complement − the complosome − in immune cell regulation , 2017, Molecular Immunology.

[16]  L. Trouw,et al.  Production of complement components by cells of the immune system , 2017, Clinical and experimental immunology.

[17]  J. Dufour,et al.  Xenotransplanted Pig Sertoli Cells Inhibit Both the Alternative and Classical Pathways of Complement-Mediated Cell Lysis While Pig Islets Are Killed , 2016, Cell transplantation.

[18]  B. Gao,et al.  Hepatocytes: a key cell type for innate immunity , 2015, Cellular and Molecular Immunology.

[19]  Uday Kishore,et al.  Emerging and Novel Functions of Complement Protein C1q , 2015, Front. Immunol..

[20]  Lubka T. Roumenina,et al.  Complement System Part II: Role in Immunity , 2015, Front. Immunol..

[21]  G. von Heijne,et al.  Tissue-based map of the human proteome , 2015, Science.

[22]  C. Drouet,et al.  Human complement C3 deficiency: Th1 induction requires T cell-derived complement C3a and CD46 activation. , 2014, Molecular immunology.

[23]  T. Woodruff,et al.  C5L2: a controversial receptor of complement anaphylatoxin, C5a , 2013, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[24]  Ming O. Li,et al.  Signaling through C5a receptor and C3a receptor diminishes function of murine natural regulatory T cells , 2013, The Journal of experimental medicine.

[25]  C. Garlanda,et al.  PTX3 as a paradigm for the interaction of pentraxins with the complement system. , 2013, Seminars in immunology.

[26]  E. Shevach,et al.  Absent C3a and C5a receptor signaling into CD4+ T cells enables auto-inductive TGF-β1 signaling and induction of Foxp3+ T regulatory cells , 2012, Nature Immunology.

[27]  Wen-chao Song,et al.  Review: Complement and its regulatory proteins in kidney diseases , 2010, Nephrology.

[28]  G. Korbutt,et al.  Sertoli Cell Line Lacks the Immunoprotective Properties Associated with Primary Sertoli Cells , 2008, Cell transplantation.

[29]  G. Korbutt,et al.  Comparison of Successful and Unsuccessful Islet/Sertoli Cell Cotransplant Grafts in Streptozotocin-Induced Diabetic Mice , 2007, Cell transplantation.

[30]  Jinhua Lu,et al.  The regulatory roles of C1q. , 2007, Immunobiology.

[31]  J. Atkinson,et al.  T-cell regulation: with complements from innate immunity , 2007, Nature Reviews Immunology.

[32]  Andrea Carpentieri,et al.  Structure and function of the long pentraxin PTX3 glycosidic moiety: fine-tuning of the interaction with C1q and complement activation. , 2006, Biochemistry.

[33]  G. Korbutt,et al.  Neonatal Porcine Sertoli Cells Inhibit Human Natural Antibody-Mediated Lysis1 , 2005, Biology of reproduction.

[34]  G. Korbutt,et al.  Long‐term survival of neonatal porcine Sertoli cells in non‐immunosuppressed rats , 2003, Xenotransplantation.

[35]  Alex E. Lash,et al.  Gene Expression Omnibus: NCBI gene expression and hybridization array data repository , 2002, Nucleic Acids Res..

[36]  Wuding Zhou,et al.  Intrarenal synthesis of complement. , 2001, Kidney international.

[37]  M. Walport,et al.  The Complement Factsbook , 1999 .

[38]  G. Korbutt,et al.  Cotransplantation of Allogeneic Islets With Allogeneic Testicular Cell Aggregates Allows Long-Term Graft Survival Without Systemic Immunosuppression , 1997, Diabetes.

[39]  G. Korbutt,et al.  Large scale isolation, growth, and function of porcine neonatal islet cells. , 1996, The Journal of clinical investigation.

[40]  A. Bengtsson,et al.  The Role of Complement , 1993 .

[41]  K. Yancey,et al.  Analysis of the interaction of human C5a and C5a des Arg with human monocytes and neutrophils: flow cytometric and chemotaxis studies. , 1989, The Journal of investigative dermatology.

[42]  M. M. Bradford.  A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. , 1976, Analytical biochemistry.