2It is essential for early human life that immunological responses to developing embryos are 3 tightly regulated. An imbalance in the activation and regulation of the human complement 4 system occurs in pregnancy complications, such as pre-eclampsia and recurrent miscarriage. 5We hereby present the first full analysis of the expression and deposition of complement 6 molecules in human pre-implantation embryos. Thus far, immunological imbalance has been 7 considered in stages of pregnancy following implantation. We here show that complement 8 activation and deposition takes place on developing human embryos already at the pre-9 implantation stage. Using confocal microscopy, we observed deposition of activation products 10 such as C1q, C3 and C5 on healthy developing embryos, which highlights the need for strict 11 complement regulation. The early embryos express the complement membrane inhibitors 12 CD46, CD55 and CD59 and bind the soluble regulators C4bp and factor H. These findings 13show that complement targets human embryos, and indicate potential adverse pregnancy 14 outcomes, if regulation of activation fails. In addition, single-cell RNA sequencing of embryos 15 at oocyte, zygote, 4-cell and 8-cell stages showed expression of complement genes, e.g. C1s, 16C2, C3, C5, factor B and factor D. This shows that the embryonic cells themselves have the 17 capacity to express C3 and C5, which may become activated and function as mediators of 18 cellular signaling. The specific local embryonic expression of complement components, 19regulators, and deposition of activation products on the surface of embryos suggests that 20 complement has immunoregulatory functions and may impact cellular homeostasis and 21 differentiation at the earliest stage of human life. 22 23 Keywords 24Complement, embryo, development, pre-implantation 25 26 Statement of significance 27While canonical functions of the complement system relate to pathogen-defence, it is known 28 to drive certain immune pathologies. The work here described shows, for the first time, 29 expression and localization of a full range of complement molecules in human pre-implantation 30 embryos. We demonstrate complement attack against early embryos, and show presence of 31 embryonic defence mechanisms. Furthermore, we reveal early embryonic production of 32 complement activators, suggesting non-canonical roles in cell signalling and development. Our 33 findings thus reveal a fundamental role for complement at the earliest stages of human 34 embryogenesis. Our data opens up for future studies into the role of complement, both in 35 relation to infertility and pregnancy complications, as well as basic cellular processes during 36 early human development. 37 38 3
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