The regulated cell death at the maternal-fetal interface: beneficial or detrimental?

Abstract

Regulated cell death (RCD) plays a fundamental role in placental development and tissue homeostasis. Placental development relies upon effective implantation and invasion of the maternal decidua by the trophoblast and an immune tolerant environment maintained by various cells at the maternal-fetal interface. Although cell death in the placenta can affect fetal development and even cause pregnancy-related diseases, accumulating evidence has revealed that several regulated cell death were found at the maternal-fetal interface under physiological or pathological conditions, the exact types of cell death and the precise molecular mechanisms remain elusive. In this review, we summarized the apoptosis, necroptosis and autophagy play both promoting and inhibiting roles in the differentiation, invasion of trophoblast, remodeling of the uterine spiral artery and decidualization, whereas ferroptosis and pyroptosis have adverse effects. RCD serves as a mode of communication between different cells to better maintain the maternal-fetal interface microenvironment. Maintaining the balance of RCD at the maternal-fetal interface is of utmost importance for the development of the placenta, establishment of an immune microenvironment, and prevention of pregnancy disorders. In addition, we also revealed an association between abnormal expression of key molecules in different types of RCD and pregnancy-related diseases, which may yield significant insights into the pathogenesis and treatment of pregnancy-related complications.

Fig. 1. Major molecular mechanisms of different types of regulated cell death.

A In apoptosis, the intrinsic pathway is mainly mediated by mitochondria. TNFα can stimulate the extrinsic pathway and induce apoptosis (left). If caspase-8 activity is inhibited, RIPK1 forms necrosomes with RIPK3 and MLKL, thereby triggering necroptosis (right). B Autophagy begins with the formation of phagophores. This process is regulated by ULKL and Beclin-1. The ATG12-ATG5-ATG16L1 complex and LC3-II recruit loads to cargo receptors, which is essential for the process of phagophore expansion to generate autophagosomes. C In the classical pyroptosis pathway, when cells are exposed to external stimuli, activated caspase-1 can cleave GSDMD to produce an N-terminal of GSDMD, which can form holes in the cell membrane to release mature IL-1β and IL-18 and induce pyroptosis. In the non-classical pyroptosis pathway, GSDMD is cleaved by caspase-4, -5, and -11. Pyroptosis can also trigger the release of HMGB1 and K⁺. D Iron accumulation and lipid peroxidation are important factors that trigger reactive oxygen species (ROS) production and ferroptosis. The ACSL4-LPCAT3-ALOXs pathway enables the production of phospholipid hydroperoxide (PLOOH) from polyunsaturated fatty acids (PUFAs), which is oxidized from fatty acids. In the most studied antioxidant system, the Xc-system-GSH-GPX4, GPX4 can scavenger oxygen free radicals and inhibit ferroptosis. Other antioxidant systems, such as CoQ10-AIFM2 and ESCRT-III membrane repair systems, also play important roles in inhibiting lipid peroxidation.

Fig. 2. Regulated cell death affects trophoblast differentiation, invasion and vascular remodeling.

A Apoptosis can promote the differentiation and fusion of cytotrophoblast cells to form syncytial trophoblasts; however, excessive apoptosis inhibits this differentiation process. Necroptosis can also affect trophoblast differentiation. Inhibition of ferroptosis can promote fusion. Pyroptosis- and autophagy-related proteins have been detected in syncytial trophoblasts. B Apoptosis and necroptosis in ESCs contribute to trophoblast invasion. Deficiency in autophagy or apoptosis in trophoblast cells can lead to shallow invasion. Pyroptotic cells can release HMGB1, which inhibits trophoblast invasion. Ferroptosis inhibits trophoblast invasion. C Trophoblast cells secrete cytokines to induce apoptosis of vascular endothelial smooth muscle cells and epithelial cells to promote arterial remodeling. Arterial remodeling also requires trophoblast autophagy. Necroptosis lead to failures in spiral artery remodeling. Trophoblastic plug dissolution is prone to trigger ferroptosis, which may affect spiral artery remodeling. Created with BioRender.com.

Fig. 3. Effect of regulated cell death on decidual immune cells and stromal cells.

A Natural killer (NK) cells can induce apoptosis of smooth muscle cells (SMCs) and endothelial cells (ECs) to promote vascular remodeling. Insufficient autophagy in extravillous trophoblasts (EVTs) or decidual stromal cells (DSCs) can affect the residence and function of NK cells. Galectin-1 secreted by NK cells and macrophages induces apoptosis of CD3⁺ T cells, while galectin-2 and TSLP inhibit the apoptosis of Treg and γδT cells respectively to maintain immune homeostasis. Ferroptosis facilitates the differentiation of macrophages into the M1 type and autophagy promotes the differentiation into the M2 type. Pyroptosis also affects the differentiation of M2 macrophages. B DSCs can induce the production of Th2 cytokines and promote immune tolerance. Autophagy can promote the decidualization of ESCs to DSCs but ferroptosis plays the opposite role. Lipopolysaccharide (LPS) stimulation can induce the apoptosis of DSCs, increase the secretion of Th1 inflammatory factors, and cause an inflammatory response. Decidual NK (dNK) cells, SGK1, and Tim-3 inhibit LPS-induced apoptosis. Before decidualization, DSCs also secrete pro-apoptotic molecules to induce the apoptosis of undifferentiated DSC. Created with BioRender.com.