Placental trophoblast syncytialization potentiates macropinocytosis via mTOR signaling to adapt to reduced amino acid supply

Abstract

During pregnancy, the appropriate allocation of nutrients between the mother and the fetus is dominated by maternal–fetal interactions, which is primarily governed by the placenta. The syncytiotrophoblast (STB) lining at the outer surface of the placental villi is directly bathed in maternal blood and controls feto–maternal exchange. The STB is the largest multinucleated cell type in the human body, and is formed through syncytialization of the mononucleated cytotrophoblast. However, the physiological advantage of forming such an extensively multinucleated cellular structure remains poorly understood. Here, we discover that the STB uniquely adapts to nutrient stress by inducing the macropinocytosis machinery through repression of mammalian target of rapamycin (mTOR) signaling. In primary human trophoblasts and in trophoblast cell lines, differentiation toward a syncytium triggers macropinocytosis, which is greatly enhanced during amino acid shortage, induced by inhibiting mTOR signaling. Moreover, inhibiting mTOR in pregnant mice markedly stimulates macropinocytosis in the syncytium. Blocking macropinocytosis worsens the phenotypes of fetal growth restriction caused by mTOR-inhibition. Consistently, placentas derived from fetal growth restriction patients display: 1) Repressed mTOR signaling, 2) increased syncytialization, and 3) enhanced macropinocytosis. Together, our findings suggest that the unique ability of STB to undergo macropinocytosis serves as an essential adaptation to the cellular nutrient status, and support fetal survival and growth under nutrient deprivation.

Cellular and molecular atlas of the placenta from a COVID‐19 pregnant woman infected at midgestation highlights the defective impacts on foetal health

“…Abnormal formation or function of STB during pregnancy may hinder material and gas exchange between the mother and the foetus and thus impair foetal growth, implicating in the aetiology of pregnancy complications, such as preeclampsia and foetal growth restriction. 42 This may be the reason for the low foetal weight in this COVID‐RS case. In addition, HLA‐C and HLA‐G in the EVT subset, which is critical to establish protective immunity at the maternal–foetal interface, are downregulated in COVID‐RS placenta, indicating the impairment in immune tolerance to the foetus.…”

Amino acids suppress macropinocytosis and promote release of CSF1 receptor in macrophages

“…Similarly, in amino acid-deficient environments, mTORC1 is dissociated from lysosomes, preventing its function as a metabolic hub to promote various anabolic processes (Efeyan, Zoncu and Sabatini, 2012). Inhibition of mTORC1 in human trophoblasts was recently shown to enhance macropinocytosis (Shao et al, 2021). GCN2 or mTORC1 may regulate CSF1R expression at the cell surface.…”

Pregnancy and pandemics: Interaction of viral surface proteins and placenta cells

“…The ability of the syncytiotrophoblast (ST) to perform macropinocytosis has been shown in recent studies [ 56 ]. It has been reported that about 10% of trophoblast cells from term placentas could be infected in vitro with VacV [ 57 ].…”