Recently we reported that second‐trimester amniotic fluid (AF) is an abundant source of fetal mesenchymal stem cells (MSCs). In this study, we analyze the origin of these MSCs and the presence of MSCs in human‐term AF. In addition, different parts of the human placenta were studied for the presence of either fetal or maternal MSCs. We compared the phenotype and growth characteristics of MSCs derived from AF and placenta. Cells from human second‐trimester (mean gestational age, 19+2 [standard deviation, ± 1+3] weeks, n = 10) and term third‐trimester (mean gestational age, 38+4 [standard deviation, ± 1] weeks, n = 10) AF, amnion, decidua basalis, and decidua parietalis were cultured in M199 medium supplemented with 10% fetal calf serum and endothelial cell growth factor. Cultured cells were immunophenotypically characterized, the adipogenic and osteogenic differentiation capacity was tested, and the growth kinetics were analyzed. The origin of fetal and maternal cells was determined by molecular human leukocyte antigen typing. We successfully isolated MSCs from second‐trimester AF, amnion, and decidua basalis as well as term amnion, decidua parietalis, and decidua basalis. In contrast, MSCs were cultured from only 2 out of 10 term AF samples. The phenotype of MSCs cultured from different fetal and maternal parts of the placenta was comparable. Maternal MSCs from second‐trimester and term decidua basalis and parietalis showed a significantly higher expansion capacity than that of MSCs from adult bone marrow (p < .05). Our results indicate that both fetal and maternal MSCs can be isolated from the human placenta. Amnion is a novel source of fetal MSCs, likely contributing to the presence of MSCs in AF. Decidua basalis and decidua parietalis are sources for maternal MSCs. The expansion potency from both fetal and maternal placenta‐derived MSCs was higher compared with adult bone marrow–derived MSCs.

Objective To compare the effect of induction of labour with a policy of expectant monitoring for intrauterine growth restriction near term.Design Multicentre randomised equivalence trial (the Disproportionate Intrauterine Growth Intervention Trial At Term (DIGITAT)).Setting Eight academic and 44 non-academic hospitals in the Netherlands between November 2004 and November 2008.Participants Pregnant women who had a singleton pregnancy beyond 36+0 weeks’ gestation with suspected intrauterine growth restriction.Interventions Induction of labour or expectant monitoring.Main outcome measures The primary outcome was a composite measure of adverse neonatal outcome, defined as death before hospital discharge, five minute Apgar score of less than 7, umbilical artery pH of less than 7.05, or admission to the intensive care unit. Operative delivery (vaginal instrumental delivery or caesarean section) was a secondary outcome. Analysis was by intention to treat, with confidence intervals calculated for the differences in percentages or means.Results 321 pregnant women were randomly allocated to induction and 329 to expectant monitoring. Induction group infants were delivered 10 days earlier (mean difference −9.9 days, 95% CI −11.3 to −8.6) and weighed 130 g less (mean difference −130 g, 95% CI −188 g to −71 g) than babies in the expectant monitoring group. A total of 17 (5.3%) infants in the induction group experienced the composite adverse neonatal outcome, compared with 20 (6.1%) in the expectant monitoring group (difference −0.8%, 95% CI −4.3% to 3.2%). Caesarean sections were performed on 45 (14.0%) mothers in the induction group and 45 (13.7%) in the expectant monitoring group (difference 0.3%, 95% CI −5.0% to 5.6%).Conclusions In women with suspected intrauterine growth restriction at term, we found no important differences in adverse outcomes between induction of labour and expectant monitoring. Patients who are keen on non-intervention can safely choose expectant management with intensive maternal and fetal monitoring; however, it is rational to choose induction to prevent possible neonatal morbidity and stillbirth.Trial registration International Standard Randomised Controlled Trial number ISRCTN10363217.

During pregnancy, the maternal immune system has to tolerate the persistence of fetal alloantigens. Many mechanisms contribute to the prevention of a destructive immune response mediated by maternal alloreactive lymphocytes directed against the allogeneic fetus. Murine studies suggest that CD4+CD25+ T cells provide mechanisms of specific immune tolerance to fetal alloantigens during pregnancy. Previous studies by our group demonstrate that a significantly higher percentage of activated T cells and CD4+CD25bright T cells are present in decidual tissue in comparison with maternal peripheral blood in human pregnancy. In this study, we examined the phenotypic and functional properties of CD4+CD25bright T cells derived from maternal peripheral blood and decidual tissue. Depletion of CD4+CD25bright T cells from maternal peripheral blood demonstrates regulation to third party umbilical cord blood cells comparable to nonpregnant controls, whereas the suppressive capacity to umbilical cord blood cells of her own child is absent. Furthermore, maternal peripheral blood shows a reduced percentage of CD4+CD25brightFOXP3+ and CD4+CD25brightHLA-DR+ cells compared with peripheral blood of nonpregnant controls. In contrast, decidual lymphocyte isolates contain high percentages of CD4+CD25bright T cells with a regulatory phenotype that is able to down-regulate fetus-specific and fetus-nonspecific immune responses. These data suggest a preferential recruitment of fetus-specific regulatory T cells from maternal peripheral blood to the fetal-maternal interface, where they may contribute to the local regulation of fetus-specific responses.

Amniotic fluid as a novel source of mesenchymal stem cells for therapeutic transplantationHuman mesenchymal stem cells (MSCs) are multipotent stem cells, able to differentiate into multiple mesenchymal lineages. [1][2][3] Previously, we have shown that human fetal lung-derived MSCs enhance the engraftment of human umbilical cord blood (UCB)-derived CD34 ϩ hematopoietic cells in nonobese diabetic-severe combined immunodeficiency mice. 1 Here we show that secondtrimester amniotic fluid is an abundant source of fetal MSCs that exhibit a phenotype and multilineage differentiation potential similar to that of postnatal bone marrow (BM)-derived MSCs. We suggest that amniotic fluid is an attractive source of MSCs for cotransplantation in conjunction with UCB-derived hematopoietic stem cells.Amniotic fluid was collected transcervically from 6 secondtrimester legal terminations of pregnancy (mean gestational age, 19 weeks [range, 17-22 weeks]) according to a protocol approved by the medical ethical review board of our hospital. Amniotic fluid samples, without visible contamination with blood, were centrifuged for 10 minutes at 1283 rpm. Pellets were resuspended and cultured as described previously. 1 Adherent cells were detached with trypsin/EDTA (ethylenediaminetetraacetic acid) and phenotypically characterized by flow cytometry using fluorescein isothiocyanate-or phycoerythrin-conjugated antibodies. The adipogenic and osteogenic differentiation capacity of culture-expanded MSCs was determined as previously reported. 1 To confirm the fetal origin of cultured cells, a molecular HLA typing was performed on DNA obtained from expanded MSCs, and fetal and maternal blood cells by polymerase chain reaction/sequence-specific oligonucleotide using a reverse dot blot method. 4 MSCs were cultured from all 6 consecutive samples of second-trimester amniotic fluid. A quantity of 2 mL amniotic fluid was sufficient to culture these cells. The expansion potential of amniotic fluid-derived MSCs exceeded that of BM-derived MSCs. As a result, we were able to expand amniotic fluid MSCs to about 180 ϫ 10 6 cells within 4 weeks (3 passages). The phenotype of the culture-expanded amniotic fluid-derived cells was similar to that reported for MSCs derived from secondtrimester fetal tissues and adult BM 1,2 (Table 1). Amniotic fluidderived MSCs showed multilineage differentiation potential into fibroblasts, adipocytes, and osteocytes. Molecular HLA typing of fetal and maternal cells confirmed that the cultured cells were of fetal origin, without detectable contamination of maternal cells (Figure 1).Following allogeneic transplantation, most studies indicate that MSCs remain of host origin, 5 possibly as a result of the low frequency of these cells in stem cell grafts. The frequency of MSCs in UCB is particularly low, and most laboratories have been unable to grow MSCs from UCB. 6,7 Supplementing stem cell grafts with MSCs to promote engraftment has been proposed. Studies in mice and sheep show that engraftment can be promoted by the addition of t...

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The most important function of the placenta is the exchange of nutrients and oxygen between a mother and her fetus. To establish a healthy functioning placenta, placentation needs to occur with adequate remodelling of spiral arteries by extravillous trophoblasts. When this process is impaired, the resulting suboptimal and inadequate placenta function results in the manifestation of pregnancy complications. Impaired placenta function can cause preeclampsia and leads to fetal growth restriction due to hypoxia. Presence of hypoxia leads to oxidative stress due to an imbalance between reactive oxygen species and antioxidants, thereby causing damage to proteins, lipids and DNA. In the placenta, signs of morphological adaptation in response to hypoxia can be found. Different placental lesions like maternal or fetal vascular malperfusion or chronic villitis lead to a decreased exchange of oxygen between the mother and the fetus. Clinically, several biomarkers indicative for oxidative stress, e.g. malondialdehyde and reduced levels of free thiols are found. This review aims to give an overview of the causes and (potential) role of placental oxidative stress in the development of placental parenchymal pathology and its clinical consequences. Also, therapeutic options aiming at prevention or treatment of hypoxia of the placenta and fetus are described.

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