Stromal Cell-Derived Factor 2: A Novel Protein that Interferes in Endoplasmic Reticulum Stress Pathway in Human Placental Cells

Abstract

Endoplasmic reticulum (ER) stress results from changes in ER homeostasis and folding of proteins. ER stress initiates cellular adaptive mechanisms to rescue cell homeostasis or, if that does not work, to elicit apoptosis. We have previously shown that mouse SDF2 is sublocalized in the ER, is ubiquitously expressed, and shows strong similarities with stromal cell-derived factor (SDF) 2L1 and SDF2-like from Arabidopsis, ER proteins involved in chaperone network and protein folding. Thus, we hypothesized that SDF2 plays a role in the ER stress and unfolded protein response. In this study, we investigated the possible role of SDF2 in the human placenta. Expression of SDF2 was present throughout gestation and was expressed by several cell types. Second-trimester cytotrophoblast cells (CTBs) in the differentiation process, monitored through chorionic gonadotropin production, showed upregulation of SDF2 protein. SDF2 expression, however, was significantly diminished in placentas from neonates small for gestational age and in hypoxic in vitro conditions (P ≤ 0.001, 2% O2), suggesting a link with cellular stress. ER stress-induced cells—CTB and BeWo—also showed SDF2 downregulation in different time points, emphasizing this relationship. SDF2 downregulation was also followed by an increase in binding immunoglobulin protein (BiP) expression, an ER protein-associated chaperone acting as a sensor for misfolded proteins and an ER stress cell survival marker. In line with this, SDF2 siRNA resulted in significant anticipation of BiP expression. Downregulation of SDF2 also interfered with C/EBP homologous protein expression, one of the highest inducible genes during ER stress. These findings suggest that SDF2 may be an important regulatory factor by which trophoblast cells can control cell survival under ER stress. In conclusion, this study identifies a novel factor with the ability to interfere with ER stress proteins, which may contribute to the understanding of ER stress associated with placental-related diseases of pregnancy.

Mosaic autosomal aneuploidies are detectable from single-cell RNAseq data

“…The activation of the unfolded protein response is also linked with aneuploidy [ 27 ]. Three of the differentially expressed genes have roles in this pathway: Calnexin ( Canx ), Pdia3 [ 28 ], and Sdf2 [ 29 ]. Sdf2 differential expression is additionally associated with human oocyte aneuploidy [ 30 ].…”

Genes and Pathways Affecting Sheep Productivity Traits: Genetic Parameters, Genome-Wide Association Mapping, and Pathway Enrichment Analysis

“…It has been reported that SMAD proteins have roles in maintaining the structural and functional integrity of the oviduct and uterus. They are essential for the establishment and maintenance of pregnancy ( Rodriguez et al, 2016 ). Another signaling pathway is Notch signaling which exerts effects throughout the pregnancy and plays an important role in placental angiogenesis, normal placental function, and trophoblast function ( Zhao and Lin, 2012 ).…”

Serum From Preeclamptic Women Triggers Endoplasmic Reticulum Stress Pathway and Expression of Angiogenic Factors in Trophoblast Cells

“…Stromalderived factor 2 (SDF2) has also been related to the activation of UPR pathways. Previous studies suggested that SDF2 expression is associated with controlling cell survival/apoptosis mediated by the PERK arm (Lorenzon-Ojea et al, 2016). In addition, SDF2 was upregulated in the most severe cases of this disease (Lorenzon-Ojea et al, 2020;Lorenzon et al, 2021).…”