Correction: Dysregulation of decidual NK cell proliferation by impaired decidual cells: a potential contributor to excessive trophoblast invasion in placenta accreta spectrum
Year: 2025
Type: erratum
Abstract: List of abbreviations BMMSC Bone marrow-derived mesenchymal stem/stromal cell cAMP Cyclic adenosine monophosphate CTB Cytotrophoblast DC Dendritic cell dNK Decidual natural killer cell ER Estrogen receptor ESC Endometrial stromal cell EVT Extravillous trophoblast E2 Estradiol HLA Human leukocyte antigen IGFBP1 Insulin-like growth factor binding protein 1 iCTB Interstitial cytotrophoblast KIR Killer Ig-like Receptor MD-MSC Human placental maternal decidua-mesenchymal stem cell MMP Matrix metalloproteinase MPA Medroxyprogesterone acetate PA-MSC pathological MD-MSC from PAS patient PAS Placenta accreta spectrum PBMC Peripheral blood-derived mononuclear cell pNK Peripheral blood-derived natural killer cell PR Progesterone receptor PRL Prolactin P4 Progesterone SCARA5 Scavenger receptor class A type 5 SCT Syncytiotrophoblast TIMP Tissue inhibitors of metalloproteinase Introduction In the process of embryos implanting in the uterus, the interaction between the maternal decidual cells, leukocyte subpopulations like decidual natural killer (dNK) cells, and blastocyst trophoblasts is critical for healthy placental formation and successful pregnancy [1]. During blastocyst development, trophoblasts differentiate into cytotrophoblasts (CTBs), the subsequent syncytiotrophoblasts (SCTs), and extravillous trophoblasts (EVTs), forming the primitive syncytium and lacunae [2-3]. Studies demonstrate that decidual and dNK cells regulate trophoblast invasion by secreting factors, maintaining a delicate balance [4]. During pregnancy, decidual cells, part of the specialized endometrium, complete the decidual reaction post-implantation, supporting placentation through interactions with trophoblasts and producing specific proteins and factors [5]. Throughout pregnancy, dNK cells, with unique killer cell immunoglobulin-like receptors (KIR) expression and interactions with decidual cells, play a crucial role in immune tolerance at the maternal-fetal interface and placentation through interactions with EVTs [6]. The equilibrium among decidual, dNK, and trophoblast cells is vital in establishing an immune-regulated environment necessary for placental formation and fetal development, contributing significantly to maternal-fetal immune tolerance [7-8]. Various placental disorders, including the high-risk placenta accreta spectrum (PAS), are caused by disruptions in the regulation between these cells [9]. PAS is an abnormal placental development condition that encompasses placenta accreta, increta, and percreta and is a major cause of severe maternal morbidity and mortality [10]. PAS is particularly daunting for pregnant women and obstetricians due to the difficulty in early detection and the complexity of treatment even after diagnosis. The prevalence rate of PAS has increased in recent decades, from 1 in 1,250 births in the 1980s to as many as 1 in 272 births today [11]. From the cytological perspective, studies suggest that defects in the decidualization of endometrial stromal cells (ESCs) [12-13], altered immune responses in maternal tissues [14-15], or a combination of both conditions [16-18] are proposed as underlying factors contributing to excessive invasion of EVT. This can result in the pathologic adherence of the placenta and subsequent severe bleeding during delivery [19-21]. However, due to the lack of appropriate animal models and even cellular models, studying the intricate mechanisms governing the aberrant placentation of PAS has presented challenges. Thus, the precise etiology of PAS remains incompletely understood, especially when investigating the early and mid-stages of human pregnancy, during which EVTs interact with decidual cells and dNK cells. Therefore, understanding the complex interactions among decidual cells, EVTs, and immune cells, particularly dNK cells within the uterus, is essential for developing diagnostic and therapeutic approaches to address PAS and its potentially life-threatening complications. In our preliminary work, we isolated a unique cell population derived from the choriodecidual interface, where the decidua (developed from the endometrium) and the chorion (created from the trophoblast of the outer wall of the embryo) fuse. In order to clearly demonstrate the basic characteristics of MSCs, we adapted the results from previous studies (Su et al., 2017). These cells were identified from the precise decidua with the MSC markers (Supplementary Figure S1A) and differentiation potentials (Supplementary Figure S1B), known as human placenta maternal decidua-derived mesenchymal stem cells (MD-MSCs), replacing the previously confusing origin and nomenclature of human placenta choriodecidual membrane-derived mesenchymal stem cells (pcMSCs) [22]. They have shown significant potential for cell therapy due to their anti-inflammatory, immunomodulatory, and tissue repair capabilities [23]. Beyond their roles in regenerative medicine, this study aims to explore the physiological functions of MD-MSCs in the endometrium to gain new insights into complex placental diseases. Consequently, we developed an MD-MSC-based decidualization and co-culture system. This advanced system facilitates the assessment of EVT invasion and dNK cell induction, thereby overcoming the limitations of traditional in vitro methods. In this study, we established an MD-MSC-based co-culture system and utilized pathological MD-MSCs from patients with PAS (PA-MSCs) to investigate the underlying mechanism of PAS. Our findings suggest that MD-MSCs can potentially induce pNK cells to convert into dNK-like cells with lower cytolytic ability and enhanced expression of KIR2DL4, one of the polymorphic KIRs that interacts with HLA-G on EVTs [24]. Moreover, we observed that dNK-like cells proliferate significantly when co-cultured with PA-MSCs and exhibit a greater capacity to promote trophoblast invasion when co-cultured with MD-MSCs. This discovery highlights the potential contribution of aberrant dNK cell numbers and decidualization defects to PAS development. This study proposes a novel approach to studying the intricate interactions among decidual, dNK, and trophoblast cells in vitro and offers new insights into the mechanism of PAS. Materials and Methods Isolation and culture of MD-MSCs and PA-MSCs MD-MSCs and PA-MSCs cells were obtained from the term placenta undergoing cesarean sections at Taipei Medical University Hospital and Dr. Jin-Chung Shih from National Taiwan University Hospital, respectively. All procedures were approved by the Institutional Review Board (IRB: 202308101RINC). The diagnostic criteria for selecting pathological placentas as clinical specimens in this study are outlined in Supplementary Table 1. Additionally, histopathological confirmation of PAS was performed, with Supplementary Fig. 4 illustrating interstitial cytotrophoblast (iCTB) invasion into the in the cell the decidual was and with a of and at the was and in with growth factor and were and cells were after cells were with with fetal and for In vitro decidualization in vitro decidualization and induction, MD-MSCs or PA-MSCs were in a and to for the cells were with the combination of and 1 or and 1 for 5 The and the expression of decidualization markers were at 5 Throughout the decidualization the of the cells were a on the after for protein and were from and at Decidual cell MD-MSCs were in a and to decidualization a decidualization cells were with and with in for at cells They were with at a of 5 to the cell the of cell and the cell was at a of 1 for 5 cells were observed to and was to cell The and of cells from were to cell was from MD-MSCs and PA-MSCs the The of was the was the system to the The were utilized for the were in on a detection system. the expression of the was The specific for can in Supplementary Table The was from the obtained from of The for was as the of the the of the was as the between the of the and The in expression for to the was the for in The and of the were from a of or the of as and Insulin-like growth factor binding protein 1 the cell culture was and at for at to cellular The was with a and at for subsequent the of receptor class A type 5 protein the cells were with a The cell was and at for The was to a new and at the PRL and IGFBP1 specific were as the Human Prolactin and Human IGFBP1 in with the the the SCARA5 were an appropriate in tissue sections The human decidual tissue sections from and PAS placenta were and at the of National Taiwan The sections were in a to the for the the sections were with in and through of in of was in for were with for 5 and with at with to were was for at was for for was to cell were with The on the is in Supplementary Table were the expression by the of and SCARA5 expression in MD-MSCs and cells were and with a in for at was for 5 at cells were with and SCARA5 at for KIR2DL4, and HLA-G expression the were cells were in with 1 and for subsequent was an and were invasion the invasion MD-MSCs and PA-MSCs were and in a these cells treatment with decidualization a trophoblast cell was with an to trophoblast cells can and through this appropriate for invasion These with a in a co-culture the were and cells on the of the were a the trophoblasts were a to the of the trophoblast invasion Peripheral mononuclear cells and natural killer cells pNK cells were obtained from human approved procedures by the cells were isolated from human the for Peripheral was in a and at for to from cells. The was at for by at for to PBMC cells were with the of and in a at for The PBMC was to a new with and at for were by the cell in and at for the The cell was and a cell was A of cells were in a and in a with for pNK cell and a the of pNK cells was by by the expression of the pNK cell pNK cells were for subsequent for pNK cell and dNK-like cells The pNK cells and dNK-like cells by MD-MSCs were to the In the trophoblasts were into a a the pNK cells and dNK-like cells were to co-culture with the The of cells to cells were at and for the cells were with the cell culture and the trophoblasts were the and for The cytolytic ability of cells was the dNK-like cell MD-MSCs and PA-MSCs were in at a of and for These cells were with decidualization a decidualization pNK cells were at a of into the establishing with and the decidual cells. During the co-culture the cells were at specific and the of dNK-like cells, the was This of cell on insights into cell and cellular and MD-MSCs and PA-MSCs were in treatment with decidualization the of these cells was the and utilized for The was by The obtained was the This and for for the of on and The presented on the are as which have to the expression expression were the were was The were presented as of the were with or by or A of was significant MD-MSCs a cell type with the for in vitro In this study, we have a of known as MD-MSCs. These cells were from the decidual of the human a process through culture In a capacity for in with the ability to [22]. their expression of and receptors we that to and decidualization the of the from MD-MSCs to decidual cells, we in cell and the of specific a with or MD-MSCs significant from a to a as in Fig. these observed in we and to the induction, of MD-MSCs a in (Supplementary Fig. investigate the with decidualization in we an to explore potential decidual cell our with previously to that as for decidual cells. This in the of the expression of which were in as in Fig. and Supplementary 1. are as potential decidual cell markers through with the (Supplementary the results obtained from we on these including growth factor binding protein 1 and receptor class A type 5 as potential for decidual cells. IGFBP1 at both the as by and the protein by its expression in the This is due to the in the conditions can especially when expression is (Supplementary Fig. a that are in the the potential decidual cell markers were on a observed in both and to the of through studies have shown that from or tissue decidualization through However, to that the cAMP can the ER and and address this we of to the decidualization potential of MD-MSCs. the expression of and were in with marrow-derived and (Supplementary Fig. the protein expression of these decidual cell markers by were defects in PA-MSCs have observed in the MD-MSC-based decidualization system previous for the decidualization potential of we to into the mechanisms underlying a condition with decidualization defects we to the mechanisms of this through the decidualization system. that PA-MSCs exhibit an of to trophoblast as the we observed that PA-MSCs to MD-MSCs that PA-MSCs their a as by their and Additionally, we the and protein expression of decidual cell in shown in the the expression of and were significantly in PA-MSCs to were significant in protein between and by of placental tissues significantly expression of PRL and IGFBP1 proteins in PAS to These findings that the of and at the is at the protein in placental supporting a and the expression of were in in protein The between SCARA5 and protein expression is to and which can protein of these a in expression between PA-MSCs and a decidualization process in during decidualization were in as shown in Supplementary Fig. explore the potential of this we the expression of ER and Therefore, we the expression of ER and we that ER was in PA-MSCs in as by (Supplementary Fig. This was by on PAS and placenta (Supplementary Fig. The severe PAS is by of the decidual Therefore, we obtained PAS which is by the of as observed in and Supplementary Fig. defects the cause of in trophoblast thereby to PAS. the between PAS and decidual cells trophoblast we established a co-culture system to the interaction between PA-MSCs and The trophoblast invasion is in Fig. In this we a as in Fig. that MD-MSCs with trophoblast and MD-MSCs enhanced trophoblast This that MD-MSCs and can regulate trophoblast with the proposed in clinical that cells as a natural to excessive trophoblast This highlights the intricate interactions between decidual cells and trophoblasts and insights into the regulation of trophoblast invasion during a significant in the regulation of trophoblast invasion to the as In MD-MSCs a significant in trophoblast invasion between and conditions These results suggest that PA-MSCs regulate trophoblast invasion However, was significant in the regulation of trophoblast invasion between and MD-MSCs This the that decidualization is one of the of PAS. we potential and in trophoblast invasion The expression of with the regulation of trophoblast invasion are through our the trophoblast in were in MD-MSCs treatment and Supplementary Additionally, when to we observed lower expression of and was and by forming a complex with and at the cell this trophoblast invasion In and were significantly in the treatment The interactions were by for these by these and a of interactions in trophoblast tissue inhibitors of and exhibit a of of known interactions These suggest that the mechanisms governing trophoblast invasion through decidualization in PA-MSCs from observed in MD-MSCs. However, the of these were to for the abnormal trophoblast is necessary to the underlying mechanisms contributing to PAS. to dNK cells due to their role in pregnancy through their interactions with decidual cells and trophoblasts within the physiological The of dNK-like cells from pNK cells is potentially through an MD-MSC-based co-culture system. is from decidual cells, dNK cells play a crucial role in blastocyst and placental to limitations in dNK cells, we to the in vitro of dNK cells from pNK cells through with MD-MSCs or The of the successful of dNK cells is the of dNK cells. The of the dNK-like cell and the are in Fig. the results after with MD-MSCs or the of cells on trophoblasts at of cells and cells with pNK cells in the dNK cell and cells, the cytolytic ability was by with pNK cells at the cell of the that the in cell is to we the expression of KIR2DL4, on dNK cell to with HLA-G on trophoblast and the contributing to to trophoblasts from we the of HLA-G on trophoblasts to its (Supplementary Fig. expression was particularly on dNK cell and cells, with and to the The with pNK cells, a in the expression of after with trophoblasts and Supplementary Fig. The expression of was with the from the receptor the and with by decidual cells are in the including and and Supplementary The interactions by for these proteins exhibit interactions in immune tolerance for dNK cells. is the interaction between and which is by from These results suggest that MD-MSCs can potentially convert pNK cells into dNK-like cells and potentially the on trophoblasts in Moreover, we cells and to pNK cells and markers shown in Supplementary Fig. cells exhibit a differentiation by in to pNK cells. of dNK-like cells in PA-MSCs the successful of dNK-like cells in we a to the of MD-MSCs and PA-MSCs on dNK-like cells in an to the potential of PAS. we cell co-culture conditions with MD-MSCs or PA-MSCs decidualization The with to the dNK-like cell In the cell we an PA-MSCs a greater capacity to cell to particularly in the The clearly a in cell after co-culture with PA-MSCs to MD-MSCs on This to explore the between cell and trophoblast invasion Additionally, our identified known as of cell which were in the PA-MSCs potentially cell in were including and and Supplementary with the interactions of these proteins shown in Fig. was in the interaction due to the of in the These findings a potential between abnormal cell and the development of PAS. Moreover, the increased of dNK cells in the placenta of PAS patients is through for and markers Consequently, we the that dNK cell a significant contributing factor to the of PAS. dNK cell numbers one of the factors contributing to PAS. the that PAS to trophoblast we the previously established co-culture system to investigate the of the dNK cell cell numbers on trophoblast The for this study is in Fig. the complex among the cells we the co-culture system by a that cells exhibit an enhanced capacity to promote trophoblast invasion with a cells by PA-MSCs a greater capacity to trophoblast invasion to by MD-MSCs was by the results with the trophoblast This that increased dNK cell a factor in abnormal trophoblast potentially contributing to PAS as in Fig. The novel on the mechanisms underlying PAS and the for the development of for this studies have the critical role that trophoblast invasion in a successful of trophoblast invasion can to maternal like the severe PAS. PAS is with interactions among decidual cells, and dNK cells. The potential mechanisms of the PAS have due to the limitations of the cell In the and even decidual cells were obtained from or endometrial including and of pregnancy However, these of have limitations cell and and procedures that cause to the specimens from women has particularly due to In this study, we have identified a cell type among from placenta by its potential for decidualization and capacity for in vitro the decidualization process of with to decidual cell markers as and Our study observed a unique of in which has to play a role in crucial cellular functions during Studies that SCARA5 is in decidual cells, its potential therapeutic in is to the mechanisms underlying the of SCARA5 in decidualization and its for their unique in vitro decidualization potential and their ability to MD-MSCs as a potentially for the study of placental development and diseases. In the trophoblast invasion the EVT cell was in this that MD-MSCs with regulate trophoblast in to which trophoblast The regulation of trophoblast invasion intricate interactions and of from decidual cells can promote or trophoblast trophoblast invasion expression that with trophoblast invasion are with trophoblast invasion are in with their on trophoblasts In treatment or expression to an environment that trophoblast is the of which to both the and of a mechanism These findings the to trophoblast and decidual that we observed that the decidual was in PAS this the of the of the decidual Beyond the of the decidual decidualization and decidual cells play critical roles in the development of PAS Consequently, we to investigate the underlying mechanisms by pathological on the of the decidual observed and expression of PRL and both at and protein in vitro and in Additionally, these decidual decidualization were to This due to ER which has with decidualization defects and expression and in promote growth by and invasion through trophoblast on trophoblast invasion were observed between and However, expression of in trophoblast invasion regulation in and and and which promote trophoblast on these we is that the of is to the decidualization in abnormal trophoblast invasion to the of decidual cells. investigate the on trophoblast dNK cells were in the co-culture system to explore their interactions with decidual cells and the maternal-fetal interface, dNK cells play a crucial role in immune tolerance through specific interactions between KIRs on dNK cells and HLA on trophoblasts on maternal dNK cells can interact with HLA-G from fetal trophoblast cells, potentially immune responses and tolerance to the during pregnancy This interaction is in maternal immune responses and maintaining the of the maternal-fetal However, due to the in dNK cells, we for in vitro to address this of and we decidual cell to the physiological the ability to induce dNK-like cells from pNK cells. these dNK-like cells exhibit expression of dNK cell by their potentially enhanced conditions the expression of expression was significantly in dNK-like cells when co-cultured with with or The observed in immune to by decidual cells, including and as by we a novel the abnormal interaction between PA-MSCs and dNK-like cells. PA-MSCs a significant capacity to dNK-like cell as by the increased dNK cells in PAS placenta from However, the underlying mechanisms this abnormal of dNK cells in PAS have to a studies proposed that the of dNK cells one of the contributing factors to PAS Thus, is to the between dNK cell and PAS. on the observed decidualization and the dNK-like cells by proteins in dNK cell and with trophoblast invasion are to and in from PA-MSCs to MD-MSCs. by decidual cells can to receptors on dNK cells or or trophoblast and which through and (Supplementary Fig. (Supplementary In has to the and and is essential for trophoblast invasion and placental development by the immune environment (Supplementary Fig. which has in to cell is in a in that excessive trophoblast the is at the by of which or (Supplementary Fig. and by both decidual cells and dNK cells, trophoblast invasion promote and potentially to significant bleeding in PAS In our study, the and suggest a among dNK cell trophoblast and that derived from by has a greater capacity to trophoblast invasion in a to dNK-like cells by These findings new insights into the underlying mechanisms of PAS through the decidualization and subsequent abnormal interactions among decidual, dNK, and trophoblast cells. MD-MSCs have the potential to the limitations of in vitro studies to complex placental and significantly to in human However, the co-culture for studying placental that to The physiological of MD-MSCs in the endometrium to their with decidualization and their role in placental thereby the of this cell to a clinical our results to findings through both in vitro cell and in The MD-MSC-based co-culture system to by with cell to the complex Additionally, and to the trophoblast this study on invasion the expression of differentiation markers a critical role in trophoblast and specific to the mechanisms underlying complex PAS in This study highlights the development of an MD-MSC-based system for in vitro of the intricate interactions among decidual, dNK, and trophoblast cell and their for PAS. the MD-MSC-based co-culture decidualization defects by and expression of decidual markers were observed in the decidual of Additionally, MD-MSCs the capacity to induce the differentiation of pNK cells into dNK-like cells, as by on trophoblasts and increased expression of PA-MSCs a capacity to induce dNK-like cell trophoblast invasion and through and These findings new insights and the for the complex of PAS through the novel MD-MSC cell Figure Figure 1 of MD-MSCs for decidualization potential through and of decidual cell of the for MD-MSCs and culture for subsequent of MD-MSCs with and of in and in MD-MSCs decidualization in both and treatment A of was with to potential decidual cell are from the in decidual cells within the the expression of the during decidualization in MD-MSCs and are as which have to the expression The the of for potential as decidual cell of through and are identified as potential for are to The protein expression of and SCARA5 of MD-MSCs and decidualization are as and Insulin-like growth factor binding protein Scavenger receptor class A type Figure PA-MSCs demonstrate decidualization defects with and decidual cell expression and of and in PA-MSCs with and with MD-MSCs. The expression of potential decidual cell and in PA-MSCs with MD-MSCs. The protein expression of potential decidual cell and in PA-MSCs with MD-MSCs. the expression of and SCARA5 in decidual cells between and PAS are as Insulin-like growth factor protein Scavenger receptor class A type Figure PA-MSCs and MD-MSCs have on trophoblast invasion through an MD-MSC-based co-culture system. of the co-culture system and for the assessment of trophoblast The of MD-MSCs and PA-MSCs decidualization were to their on trophoblast are as and The the potential that are in the regulation of trophoblast through the that regulate trophoblast invasion were in are as which have to the expression of interaction among proteins through The between the interaction between with the the of Figure 4 MD-MSCs can potentially convert dNK-like cells from pNK cells. A and the assessment of immune in dNK-like cells a co-culture system. of dNK-like cells with and expression on of cells after co-culture with trophoblasts for as the for are to the and as are as and with the pNK cell The potential proteins that regulate the of pNK cells into dNK-like cells. are as which have to the expression of interaction among proteins through The between the interaction between with the of the the for pNK dNK-like dNK-like dNK-like cells. Figure 5 PA-MSCs demonstrate a greater capacity to dNK-like cell MD-MSCs. A of the co-culture system for the dNK-like cell MD-MSCs and The of dNK-like cells was at specific and including co-culture with and their decidual The of and their decidual on dNK-like cell were at are as and The the expression of proteins for dNK-like cell are as which have to the expression of interaction among proteins through The between the interaction between with the of the the of The of the is the of the of dNK cells in a placenta and a PAS The sections the decidual dNK cells are with and pNK dNK-like dNK-like dNK-like cells. Figure trophoblast invasion was observed dNK-like cells with a A and the assessment of trophoblast invasion MD-MSC or in of cells. are as are as and with the pNK cell pNK dNK-like cells. Figure of the underlying mechanisms of PAS. The of dNK cells by decidual cells trophoblast to PAS. endometrial stromal decidual extravillous decidual natural killer
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W4416122824
Cites:
Cited by:
Related to: