Placental Research Articles

Hallmarks of uterine receptivity predate placental mammals.

Embryo implantation requires tightly coordinated signaling between the blastocyst and the endometrium, and is crucial for the establishment of a uteroplacental unit that persists until term in eutherian mammals. In contrast, marsupials, with a unique life cycle and short gestation, make only brief fetal-maternal contact and lack implantation. To better understand the evolutionary link between eutherian implantation and its ancestral equivalent in marsupials, we compare single-cell transcriptomes from the receptive and non-receptive endometrium of the mouse and guinea pig with that of the opossum, a marsupial. We identify substantial differences between rodent peri-implantation endometrium and opossum placental attachment, including differences in the diversity and abundance of stromal and epithelial cells which parallel the difference between histotrophic and hemotrophic provisioning strategies. We also identify a window of conserved epithelial gene expression between the opossum shelled blastocyst stage and rodent peri-implantation, including IHH and LIF . We find strong conservation of blastocyst proteases, steroid synthetases, Wnt and BMP signals between eutherians and the opossum despite its lack of implantation. Finally, we show that the signaling repertoire of the maternal uterine epithelium during implantation displays substantial overlap with that of the post-implantation placental trophoblast, suggesting that the fetal trophoblast can compensate for the loss of endometrial epithelium in eutherian invasive placentation. Together, our results suggest that eutherian implantation primarily involved the re-wiring of maternal signaling networks, some of which were already present in the therian ancestor, and points towards an essential role of maternal innovations in the evolution of invasive placentation.

Comparative transcriptomic insights into the evolutionary origin of the tetrapod double cone.

The tetrapod double cone is a pair of tightly associated cones called the "principal" and the "accessory" member. It is found in amphibians, reptiles, and birds, as well as monotreme and marsupial mammals but is absent in fish and eutherian mammals. To explore the potential evolutionary origins of the double cone, we analyzed single-cell and -nucleus transcriptomic atlases of photoreceptors from six vertebrate species: zebrafish, chicken, lizard, opossum, ground squirrel, and human. Computational analyses separated the principal and accessory members in chicken and lizard, identifying molecular signatures distinguishing either member from single cones and rods in the same species. Comparative transcriptomic analyses suggest that both the principal and accessory originated from ancestral red cones. Furthermore, the gene expression variation among cone subtypes mirrors their spectral order (red → green → blue → UV), suggesting a constraint in their order of emergence during evolution. Finally, we find that rods are equally dissimilar to all cone types, suggesting that they emerged before the spectral diversification of cones.

Calcitriol prevents SARS-CoV spike-induced inflammation in human trophoblasts through downregulating ACE2 and TMPRSS2 expression

SARS-CoV-2, the causative virus of COVID-19, increases the risk of pregnancy complications including hypertensive disorders and placental inflammation. The spike glycoprotein mediates viral cell entry by interacting with the angiotensin-converting enzyme (ACE)2 in conjunction with the transmembrane serine protease 2 (TMPRSS2). ACE1, ACE2 and renin are components of the renin-angiotensin system (RAS), which regulates blood pressure. As the placenta expresses all these proteins, it is a target for SARS-CoV-2 and a source of blood pressure modulators. Noteworthy, an ACE1/ACE2 ratio imbalance can lead to RAS dysregulation and a bad prognosis in COVID-19 patients. Calcitriol, the most active vitamin D metabolite, negatively regulates RAS, reduces inflammation, and enhances antiviral immunity, thereby protecting against COVID-19 severity. However, contrasting information exists on the regulatory role of calcitriol upon RAS components and SARS-CoV-2 receptors; while the impact of calcitriol on spike-induced inflammation in placental cells has not been explored. Thus, we studied the effects of calcitriol on these parameters using the trophoblast cell line HTR-8/SVneo and primary syncytiotrophoblasts. By RT-qPCR, ELISA, and immunocytochemistry, we found that the spike enhanced proinflammatory cytokines expression and secretion, while calcitriol significantly downregulated this effect. Calcitriol also diminished ACE1, ACE2, TMPRSS2, and renin gene expression, as well as ACE1/ACE2 mRNA ratio. ConclusionsIn the human placenta, calcitriol reduced the gene expression of main RAS components and TMPRSS2, resulting in the inhibition of spike-induced inflammation. This outcome suggest that vitamin D participates in restricting SARS-CoV-2 placental infection by rendering trophoblasts less permissive to infection while helping to regulate maternal blood pressure and decreasing inflammation.

CD4+ but not CD8+ T cells are required for protection against severe guinea pig cytomegalovirus infections.

Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus and the leading cause of infectious disease related birth defects worldwide. How the immune response modulates the risk of intrauterine transmission of HCMV after maternal infection remains poorly understood. Maternal T cells likely play a critical role in preventing infection at the maternal-fetal interface and limiting spread across the placenta, but concerns exist that immune responses to infection may also cause placental dysfunction and adverse pregnancy outcomes. This study investigated the role of CD4+ and CD8+ T cells in a guinea pig model of primary cytomegalovirus infection. Monoclonal antibodies specific to guinea pig CD4 and CD8 were used to deplete T cells in non-pregnant and in pregnant guinea pigs after mid-gestation. CD4+ T cell depletion increased the severity of illness, caused significantly elevated viral loads, and increased the rate of congenital guinea pig cytomegalovirus (GPCMV) infection relative to animals treated with control antibody. CD8+ T cell depletion was comparably well tolerated and did not significantly affect the weight of infected guinea pigs or viral loads in their blood or tissue. However, significantly more viral genomes and transcripts were detected in the placenta and decidua of CD8+ T cell depleted dams post-infection. This study corroborates earlier findings made in nonhuman primates that maternal CD4+ T cells play a critical role in limiting the severity of primary CMV infection during pregnancy while also revealing that other innate and adaptive immune responses can compensate for an absent CD8+ T cell response in α-CD8-treated guinea pigs.

Discovery of a multipotent cell type from the term human placenta.

We report a population of multipotent cells isolated from term human placentas, for the first time, that differentiates into cardiomyocytes and vascular cells with clonal ability, migratory ability, and trancriptomic evidence of immune privilege. Caudal-type homeobox-2 (CDX2) is a conserved factor that regulates trophectoderm formation and placentation during early embryonic development but has not previously been implicated in developmentally conserved regenerative mechanisms. We earlier reported that murine Cdx2 cells restored cardiac function after intravenous delivery in male mice with experimental myocardial infarction (MI). Here we demonstrate that CDX2 cells found in human chorion are poised for cardiovascular differentiation. We isolated CDX2 cells from term placentas of 150 healthy patients and showed that they spontaneously differentiate into cardiomyocytes, functional vascular cells, and retain homing ability in vitro with a transcriptome that supports enhanced cardiogenesis, vasculogenesis, immune modulation, and chemotaxis gene signatures. They restore cardiac function when administered to NOD/SCID mice subjected to MI. CDX2 cells can be clonally propagated in culture with retention of cardiovascular differentiation. Our data compels further use of this ethically feasible cell source in the design of therapeutic strategies for cardiovascular disease.

The Scutulum and the Pre-Auricular Aponeurosis in Bats.

The external ear in eutherian mammals is composed of the annular, auricular (pinna), and scutellar cartilages. The latter extends between the pinnae, across the top of the head, and lies at the intersection of numerous auricular muscles and is thought to be a sesamoid element. In bats, this scutulum consists of two distinct regions, (1) a thin squama that is in contact with the underlying temporalis fascia and (2) a lateral bossed portion that is lightly tethered to the medial surface of the pinna. The planar size, shape, and proportions of the squama vary by taxa, as does the relative size and thickness of the boss. The origins, insertions, and relative functions of the auricular muscles are complicated. Here, 30 muscles were tallied as to their primary attachment to the pinnae, scutula, or a pre-auricular musculo-aponeurotic plate that is derived from the epicranius. In contrast to Yangochiroptera, the origins and insertions of many auricular muscles have shifted from the scutulum to this aponeurotic plate, in both the Rhinolophidae and Hipposideridae. We propose that this functional shift is a derived character related primarily to the rapid translations and rotations of the pinna in high-duty-cycle rhinolophid and hipposiderid bats.

Galectin-1 Elicits a Tissue-Specific Anti-Inflammatory and Anti-Degradative Effect Upon LPS-Induced Response in an Ex Vivo Model of Human Fetal Membranes Modeling an Intraamniotic Inflammation.

Intrauterine infection is one of the most jeopardizing conditions associated with adverse outcomes, including preterm birth; however, multiple tolerance mechanisms operate at the maternal-fetal interface to avoid the rejection of the fetus. Among the factors that maintain the uterus as an immunoprivileged site, Galectin-1 (Gal-1), an immunomodulatory glycan-binding protein secreted by the maternal-fetal unit, is pivotal in promoting immune cell homeostasis. This work aimed to evaluate the role of Gal-1 during a lipopolysaccharide(LPS)-induced-inflammatory milieu. Using an ex vivo culture with two independent compartments, human fetal membranes at term were pretreated with 40 and 80ng/mL of Gal-1, then to reproduce an intraamniotic inflammation, the fetal side of membranes was stimulated with 500ng/mL of LPS for 24h. The concentrations of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, monocyte chemoattractant protein (MCP1), macrophage inflammatory protein (MIP1) α, regulated upon activation normal T cell expressed and secreted (RANTES), and matrix metalloproteinase (MMP)-9 were measured in both amnion and choriodecidua compartments. In a tissue-specific fashion profile, pretreatment with the physiologic concentration of Gal-1 significantly diminished the LPS-dependent secretion of TNF-α, IL-1β, Il-6, MCP1, MIP1α, RANTES, and MMP-9. Gal-1 elicits an anti-inflammatory effect on the human fetal membranes stimulated with LPS, which supports the hypothesis that Gal-1 is part of the immunomodulatory mechanisms intended to stop the harmful effect of inflammation of the maternal-fetal interface.

Evolutionary innovations in germline biology of placental mammals identified by transcriptomics of first-wave spermatogenesis in opossum.

Mammalian spermatogenesis is a highly stereotyped and conserved developmental process that is essential for fitness. At the same time, gene expression in spermatogenic cells is rapidly evolving. This combination of features has been suggested to drive rapid fixation of new gene expression patterns. Using a high-resolution dataset comprising bulk and single-cell data from juvenile and adult testes of the opossum Monodelphis domestica, a model marsupial, we define the developmental timing of the spermatogenic first wave in opossum and delineate conserved and divergent gene expression programs across the placental-marsupial split by comparison to equivalent data from mouse, a model placental mammal. Epigenomic data confirmed divergent regulation at the level of transcription, and comparison to data from four additional amniote species identified hundreds of genes with evidence of rapid fixation of expression. This gene set encompasses known and previously undescribed regulators of spermatogenic development.

Definite Treatment Delay With Neoadjuvant Chemotherapy and Longitudinal Monitoring by Circulating Tumor DNA for Advanced Cervical Cancer During Pregnancy: A Case Series and Literature Review.

Previous studies mainly concentrate on neoadjuvant chemotherapy (NACT) for delivery delay in FIGO Stage IB1-IIIB cervical cancer during pregnancy to prevent early preterm delivery while not affecting maternal outcome. Here, we described two pregnant patients with FIGO Stage IIIC cervical cancer about their diagnosis, treatment, and outcome. Both patients underwent cesarean delivery, left enlarged lymph node dissection, and longitudinal monitoring by circulating tumor DNA. Our study suggested that pregnant patient was completely response to NACT, which was confirmed by ctDNA monitoring, followed by left pelvic enlarged lymph node dissection during cesarean section and adjuvant chemoradiotherapy postpartum. The infant grew normally, without any evidence of chemotherapy-related side effects after delivery. In pregnant women with advanced cervical cancer, longitudinal ctDNA monitoring might be able to evaluate maternal response to NACT and confirm if delivery delay to optimize fetal outcome would compacting the maternal outcomes or not. Cervical cancer may not transmit across the placental barrier and so it is safe for delayed delivery until fetal maturity in utero during pregnancy.

PM2.5 Induces Developmental Neurotoxicity in Cortical Organoids

There is mounting evidence implicating the potential neurotoxic effects of PM2.5 during brain development, as it has been observed to traverse both the placental barrier and the fetal blood-brain barrier. However, the current utilization of 2D cell culture and animal models falls short in providing an accurate representation of human brain development. Consequently, the precise mechanisms underlying PM2.5-induced developmental neurotoxicity in humans remain obscure. To address this research gap, we constructed three-dimensional (3D) cortical organoids that faithfully recapitulate the initial stages of human cerebral cortex development. Our goal is to investigate the mechanisms of PM2.5-induced neurotoxicity using 3D brain organoids that express cortical layer proteins. Our findings demonstrate that exposure to PM2.5 concentrations of 5μg/mL and 50μg/mL induces neuronal apoptosis and disrupts normal neural differentiation, thereby suggesting a detrimental impact on neurodevelopment. Furthermore, transcriptomic analysis revealed PM2.5 exposure induced aberrations in mitochondrial complex I functionality, which is reminiscent of Parkinson's syndrome, potentially mediated by misguided axon guidance and compromised synaptic maintenance. This study is a pioneering assessment of the neurotoxicity of PM2.5 pollution on human brain tissues based on 3D cortical organoids, and the results are of great significance in guiding the formulation of the next air pollution prevention and control policies in China to achieve the sustainable improvement of air quality and to formulate pollution abatement strategies that can maximize the benefits to public health.

Between Living and Non-living: Materiality of the Placentain Ming China.

This study explores materiality and material cultures of human placenta in Ming China (1368-1644), for it perfectly displays Chinese ambiguous attitudes towards the human body parts between living and non-living. For a long time, the Chinese had widely applied human body parts in medical treatments and ritual healings. Numerous evidences in relation to their collection, production, efficacy and application are widely recorded in medical works, in particular those found in materia medica. In the sixteenth century, the Bencao gangmu (Systemic Materia Medica, 1596) illustrates thirty-five "human body drugs." Of those, the placenta was believed effective for curing illnesses, nourishing the body and prolonging life. The questions to be answered include: how is the placenta perceived in medical and religious discourses? What is its "materiality" and "efficacy" when it becomes a drug? What ethical issues and moral concerns are involved with eating the placenta? Last but not least, how was the placenta ritually buried after childbirth in premodern China? In so doing, this essay aims to provide a better understanding of the placenta situated in both material and cosmological worlds. It helps us rethink the multiple relations of human body part to part, part to whole, and body to body.

Translation Prospects of a Novel ECM‐Silk Fibroin/Alginate 3D‐Printed Scaffold for Treatment of Full‐Thickness Skin Wounds: An In Vitro and In Vivo Study

ABSTRACTThe development of bioinks incorporating extracellular matrix (ECM) has attracted significant interest for creating three‐dimensional (3D)‐printed structures that simulate natural skin, aiming to facilitate profound wound healing. In our study, we utilized the potential of human placenta, renowned for its abundant structural proteins and growth factors essential for wound recovery, as a basis for an ECM‐based bioink. Different concentrations (1.5%, 3% and 5% w/v) of decellularized/solubilized placental ECM were integrated into silk fibroin/alginate to generate a printable bioink. The biocompatibility of the printed hydrogels was studied in vitro. Our refined ECM‐based bioink at a 5% w/v concentration was administered to full‐thickness wounds in a mouse model. The ECM‐based frameworks, due to their distinct structure, created a non‐cytotoxic environment conducive to in vitro cell adhesion, infiltration, and proliferation. Crucially, they did not provoke an adverse immune reaction in the host. Implanting the 3D‐printed ECM scaffold into deep wounds resulted in increased formation of granulation tissue, angiogenesis, and re‐epithelialization compared to scaffolds lacking ECM and untreated wounds. Our findings decisively demonstrate that the 5% ECM 3D scaffold promotes regeneration of deep wounds in vivo, creating a skin substitute with cellular organization closely resembling normal skin. This advancement sets the stage for future clinical exploration and holds tremendous promise for advancing wound healing therapies.

Long-Term Implicit Epigenetic Stress Information in the Enteric Nervous System and its Contribution to Developing and Perpetuating IBS.

Psychiatric and mood disorders may play an important role in the development and persistence of irritable bowel syndrome (IBS). Previously, we hypothesized that stress-induced implicit memories may persist throughout life via epigenetic processes in the enteric nervous system (ENS), independent of the central nervous system (CNS). These epigenetic memories in the ENS may contribute to developing and perpetuating IBS. Here, we further elaborate on our earlier hypothesis. That is, during pregnancy, maternal prenatal stresses perturb the HPA axis and increase circulating cortisol levels, which can affect the maternal gut microbiota. Maternal cortisol can cross the placental barrier and increase cortisol-circulating levels in the fetus. This leads to dysregulation of the HPA axis, affecting the gut microbiota, microbial metabolites, and intestinal permeability in the fetus. Microbial metabolites, such as short-chain fatty acids (which also regulate the development of fetal ENS), can modulate a range of diseases by inducing epigenetic changes. These mentioned processes suggest that stress-related, implicit, long-term epigenetic memories may be programmed into the fetal ENS during pregnancy. Subsequently, this implicit epigenetic stress information from the fetal ENS could be conveyed to the CNS through the bidirectional microbiota-gut-brain axis (MGBA), leading to perturbed functional connectivity among various brain networks and the dysregulation of affective and pain processes.

A Mini Review of the Literature with a Special Focus on India on the Prevalence of Indian Traditional Medicine (ITM) use During Pregnancy

Background: Although pregnancy has been an integral part of women’s lives for millennia, not all women have found the process comfortable. About 65 percent of women in India consume Indian traditional herbs during pregnancy. Herbal medicines are used nowadays by up to half of the world's population. Phytomedicines isolated from plants contain a wide variety of bioactive components that can have both negative and positive effects. Many herbal plants, such as Sage (Salvia fruticosa), golden cotula (Matricaria aurea), anise (P. anisum), peppermint (Mentha aquatica), and cumin (Cuminum cyminum), etc., are used in pregnancy. To minimize the adverse effects, the use of Indian traditional medicine can be the best possible alternative. Objective: Regarding the usage of herbal medicines in India, there are large research gaps and a lack of a regulatory framework. This article aims to highlight the most common traditional Indian remedies used by pregnant women, along with their uses and any possible interactions between herbal remedies and prescription drugs. Method: Several databases, including the WHO guidelines, PubMed, Bentham Science, Elsevier, Springer Nature, Wiley, and Research Gate, were used to compile the data for the article following a thorough analysis of the various research findings connected to pregnancy and herbs for pregnancy care. Result: An overview of the use of herbal medicine is given in this review, along with information on its limitations and general safety. The prevalence of herbal medicine use during pregnancy in India is then discussed, along with the uses, adverse effects, side effects, and efficacy of the most popular herbal medications. Conclusion: The use of herbal medicine during pregnancy is a common phenomenon. The outcomes of this study showed Indian Traditional medicines are known to have numerous advantages that can be helpful during or after pregnancy, including raising milk production, reducing nausea, easing labor pains, reducing morning sickness, or reducing flatulence, however, some herbal remedies have the potential to be teratogenic, poisonous, and abortive, especially during the first trimester of pregnancy because the active components of some medicinal plants can cross the placental barrier and get to the foetus. To determine the safety of taking herbal medications, studies, especially clinical trial trials, must be conducted.

Analysis of the relationship between neonatal birth weight and meconium metabolites based on birth cohort metabolomics

Neonatal birth weight is a crucial indicator of intrauterine growth and development with important implications for child development and adult health. The birth weight of a newborn is closely linked to the nutrition and health of the mother during pregnancy as well as genetic factors. Therefore, assessing the metabolic status of the fetus in utero is greatly significant for understanding the mechanisms responsible for abnormal birth weight. While previous studies often analyzed the impact of maternal metabolism on fetal development using umbilical cord blood from pregnant women, such blood may not accurately reflect the actual intrauterine environment owing to the barrier function of the placenta; moreover, obtaining biological samples during the fetal period is challenging. Meconium, the first feces excreted by a newborn, provides ideal biological material for studying maternal and infant health. Metabolomics can reveal metabolic changes in living organisms by analyzing small molecules in biological samples; hence studying meconium samples using metabolomics technology is expected to reveal fetal metabolic changes during pregnancy, thereby providing new insights into fetal nutritional intake, growth, and development, as well as metabolic pathways related to birth weight. To gain a deeper understanding of the metabolic changes associated with birth weight, this study collected metabolomic data from the meconium of 484 newborns in the established Xiaogan birth cohort using an untargeted metabolomics technique based on liquid chromatography-high resolution mass spectrometry (LC-HRMS) and analyzed the association between meconium metabolites and birth weight. This cohort exhibited incidence rates of low birth weight (<2500 g) and macrosomia (>4000 g) of 3.3% and 7.2%, respectively, which were roughly equivalent to the national average. Orthogonal partial least squares discriminant analysis revealed significant differences between the meconium metabolomes of the low birth weight and macrosomic groups when compared to the normal weight group. We discovered significant distinctions between the differential metabolites of newborns of low birth weight and those of normal weight, as well as between macrosomic and normal weight newborns that point to disparate biological pathways. Newborns with low birth weight exhibited significantly lower levels of critical amino acids, such as glutamate and proline, compared to the normal weight group, which may be associated with placental dysfunction and maternal nutritional deficiencies. Conversely, the meconium of macrosomic newborns contained significantly elevated levels of hormone metabolites such as estrone that reflected the pathophysiological state associated with maternal metabolic diseases or excessive placental hormone levels. Our study suggests that the metabolomic profile of the meconium reflects the metabolic pathways and regulatory mechanisms at play during fetal growth and development, and offers potential metabolic biomarkers and directions for future in-depth research into diseases related to fetal development. However, this study was based solely on the Xiaogan birth cohort, which was limited to specific regions and populations. A multicenter, multiethnic, and multiregional study is expected to help validate the universality of our research findings.

COVID-19 and Its Potential Impact on Children Born to Mothers Infected During Pregnancy: A Comprehensive Review.

Pregnancy is a vulnerable period of time during which pregnant people are prone to infections like COVID-19, which can increase risks for both the mother and fetus. These infections may lead to complications such as preterm birth, developmental delays, and congenital abnormalities. While COVID-19 poses additional risks like placental dysfunction and neonatal infections, studies on long-term effects remain limited. Ongoing research and monitoring are essential to understand and mitigate potential cognitive and developmental challenges in children born to mothers infected with COVID-19. This review aims to guide clinicians in managing these risks throughout childhood. Maternal COVID-19 infection during pregnancy can have significant implications for fetal development, even if the newborn is not infected at birth. The release of inflammatory cytokines may cross the placental barrier, potentially disrupting fetal brain development and increasing the risk of long-term cognitive and behavioral issues, such as ADHD or autism. Placental dysfunction, caused by inflammation or thrombosis, can lead to intrauterine growth restriction (IUGR), preterm birth, or hypoxia, affecting both neurological and respiratory health in newborns. Furthermore, a compromised fetal immune system can increase susceptibility to autoimmune conditions and infections. The early diagnosis and management of infections during pregnancy are crucial in mitigating risks to both the mother and fetus. Swift intervention can prevent complications like preterm birth and long-term developmental challenges, ensuring better health outcomes for both the mother and child. Long-term monitoring of children born to mothers infected with COVID-19 is necessary to understand the full extent of the virus's impact. This review evaluates the long-term systemic effects of maternal COVID-19 infection during pregnancy on fetuses, newborns, and children, focusing beyond vertical transmission. It highlights the broader impacts on fetal development, offering insights to help clinicians manage potential issues that may arise later in life.

Optimization of an Affordable and Efficient Skin Allograft Composite with Excellent Biomechanical and Biological Properties Suitable for the Regeneration of Deep Skin Wounds: A Preclinical Study.

Deep skin wounds require grafting with a skin substitute for treatment. Despite many attempts in the development of an affordable and efficient skin substitute, the repair of deep skin wounds still remains challenging. In the current study, we present a 3D sponge composite made from human placenta (a disposable organ) and sodium alginate with exceptional properties for skin tissue engineering applications. Toward this goal, different proportions of alginate (Alg) and decellularized placenta scaffold (DPS) were composited and freeze-dried to generate a 3D sponge with the desired biomechanical and biological features. Comprehensive in vitro, in ovo, and in vivo characterizations were performed to assess the morphology, physical structure, mechanical behaviors, angiogenic potential, and wound healing properties of the composites. Through these analyses, the scaffold with optimal proportions of Alg (50%) and DPS (50%) was found to have superior properties. The optimized scaffold (Alg50/DPS50) was applied to the full-thickness wounds created in rats. Our data revealed that the addition of DPS to the Alg solution caused a significant improvement in the mechanical characteristics of the scaffold. Remarkably, the fabricated composite scaffold exhibited mechanical properties similar to those of native skin tissue. When implanted into the full-thickness wounds, the Alg50/DPS50 composite scaffold promoted angiogenesis, re-epithelialization, and granulation tissue formation, as compared to the group without a scaffold. Overall, our findings underscore the potential value of this hybrid scaffold for enhancing skin wound healing and suggest an Alg50/DPS50 composite for clinical investigations.

An unexpected late paroxyclaenid (Mammalia, Cimolesta) out of Europe: dental evidence from the Oligocene of the Bugti Hills, Pakistan

AbstractEight isolated mammal molars were discovered in lower Oligocene deposits of the Bugti Hills, Pakistan (Paali Nala, DB‐C2; lower Chitarwata Formation). Because of their unusual morphology, these molars have long remained enigmatic. Extensive comparisons with fossil eutherian and metatherian mammals and the recent description of new paroxyclaenids (Mammalia, Cimolesta) from the lower Eocene (Ypresian) of Europe have highlighted the plausible affinities of these teeth from the Oligocene of Pakistan and suggest a referral to Paroxyclaenidae. The dental morphology of this taxon is singular among Paroxyclaenidae, and as such it allows us to propose here a new species and a new genus: Welcommoides gurki. The occurrence of a paroxyclaenid in the Oligocene of Pakistan remains somewhat unexpected inasmuch as these mammals have so far been known only from the Eocene of Europe. At c. 4.2 kg, W. gurki is the largest paroxyclaenid ever discovered, and is assigned to the subfamily Merialinae, which became extinct in Europe around the Ypresian–Lutetian transition, long before the occurrence of this new taxon from Pakistan. Welcommoides has a suite of unusual characters compared with merialines, suggesting that this South Asian lineage had diverged for some time from its European Ypresian counterparts. Such a hypothesis is supported by the faunal similarities between European and Indian subcontinent faunas during the Ypresian. Moreover, our discovery strengthens support for the hypothesis that low latitudes of South Asia were a tropical refugium, at least during the first steps of the global climatic deterioration started at the Eocene–Oligocene transition.

Effects of oxycodone on placental lineages: Evidence from the transcriptome profile of mouse trophoblast giant cells

Pregnant women are often prescribed or abuse opioid drugs. The placenta is likely the key to understanding how opioids cause adverse pregnancy outcomes. Maternal oxycodone (OXY) exposure of pregnant mice leads to disturbances in the layer of invasive parietal trophoblast giant cells (pTGC) that forms the interface between the placenta and uterus. These cells are analogous to extravillous trophoblasts of the human placenta. They are crucial to coordinating the metabolic needs of the conceptus with those of the mother and are primary participants in the placenta-brain axis. Their large nuclear size, however, has precluded both single-cell (sc) and single-nucleus (sn) RNA-seq analyses beyond embryonic day (E) 8.5. Here, we compared the transcriptomes of placentas from pregnant mice exposed to OXY with unexposed controls at E12.5, with particular emphasis on the pTGC. The nonfluidic Parse snRNA-seq approach permitted characterization of the nuclear transcriptomes of all the major placental cell lineages and their presumed progenitors at E12.5. OXY exposure had a negligible effect on components of the placental labyrinth, including the two syncytial cell layers, but caused transcriptomic changes consistent with metabolic stress throughout the spongiotrophoblast. Most notably, there was loss of the majority of pTGC, whose normal gene expression is consistent with elevated energy demand relating to biosynthesis of multiple secretory products, especially hormones, and endoduplication of DNA. This unusual sensitivity of pTGC presumably puts the pregnancy and future health of the offspring at particular risk to OXY exposure.

Human decidua basalis mesenchymal stem/stromal cells enhance anticancer properties of human natural killer cells, in vitro.

Mesenchymal stem cells/stromal cells from the Decidua Basalis of the human placenta (DBMSCs) express wide range of effector molecules that modulate the functions of their target cells. These properties make them potential candidate for use in cellular therapy. In this study, we have investigated the consequences of interaction between DBMSCs and natural killer (NK) cells for both cell types. DBMSCs were cultured with IL-2-activated and resting non-activated NK cells isolated from healthy human peripheral blood and various functional assays were performed including, NK cell proliferation and cytolytic activities. Flow cytometry and microscopic studies were performed to examine the expression of NK cell receptors that mediate these cytolytic activities against DBMSCs. Moreover, the mechanism underlying these effects was also investigated. Our findings revealed that, co-culture of DBMSCs and NK cells resulted in inhibition of proliferation of resting NK cells, while proliferation of IL-2 activated NK cells was increased. Contrarily, treatment of DBMSC's with comparatively high numbers of IL-2 activated NK cells, resulted in their lysis, whereas treatment with low numbers resulted in reduction in their proliferation. Cytolytic activity of NK cells against DBMSCs was mediated by several activating NK cell receptors. In spite of the expression of HLA class I molecules by DBMSCs, they were still lysed by NK cells, excluding their involvement in cytolytic activity. In addition, preconditioning NK cells by DBMSCs, enhanced their ability to suppress tumor cell proliferation and in severe cases resulted in their partial lysis. Lysis and decrease of tumor cell proliferation is associated with increased expression of important molecules involved in anticancer activities. We conclude that DBMSCs exhibit dualfunctions on NK cells that enhance their anticancer therapeutic potential.