scholarly journals The Rhesus Macaque Serves As a Model for Human Lateral Branch Nephrogenesis

2021 ◽  
pp. ASN.2020101459
Author(s):  
Meredith P. Schuh ◽  
Lyan Alkhudairy ◽  
Andrew Potter ◽  
S. Steven Potter ◽  
Kashish Chetal ◽  
...  
Keyword(s):  
Single Cell ◽  
Rhesus Macaque ◽  
Kidney Development ◽  
Rhesus Macaques ◽  
Lateral Branch ◽  
Late Gestation ◽  
Molecular Signature ◽  
Marker Genes ◽  
Third Trimester ◽  
Increased Risk

BackgroundMost nephrons are added in late gestation. Truncated extrauterine nephrogenesis in premature infants results in fewer nephrons and significantly increased risk for CKD in adulthood. To overcome the ethical and technical difficulties associated with studies of late-gestation human fetal kidney development, third-trimester rhesus macaques served as a model to understand lateral branch nephrogenesis (LBN) at the molecular level.MethodsImmunostaining and 3D rendering assessed morphology. Single-cell (sc) and single-nucleus (sn) RNA-Seq were performed on four cortically enriched fetal rhesus kidneys of 129–131 days gestational age (GA). An integrative bioinformatics strategy was applied across single-cell modalities, species, and time. RNAScope validation studies were performed on human archival tissue.ResultsThird-trimester rhesus kidney undergoes human-like LBN. scRNA-Seq of 23,608 cells revealed 37 transcriptionally distinct cell populations, including naïve nephron progenitor cells (NPCs), with the prior noted marker genes CITED1, MEOX1, and EYA1 (c25). These same populations and markers were reflected in snRNA-Seq of 5972 nuclei. Late-gestation rhesus NPC markers resembled late-gestation murine NPC, whereas early second-trimester human NPC markers aligned to midgestation murine NPCs. New, age-specific rhesus NPCs (SHISA8) and ureteric buds (POU3F4 and TWIST) predicted markers were verified in late-gestation human archival samples.ConclusionsRhesus macaque is the first model of bona fide LBN, enabling molecular studies of late gestation, human-like nephrogenesis. These molecular findings support the hypothesis that aging nephron progenitors have a distinct molecular signature and align to their earlier human counterparts, with unique markers highlighting LBN-specific progenitor maturation.

scholarly journals Single-cell immunophenotyping of the fetal immune response to maternal SARS-CoV-2 infection in late gestation

2021 ◽  
Author(s):  
Juan Matute ◽  
Benjamin Finander ◽  
David Pepin ◽  
Xinbin Ai ◽  
Neal Smith ◽  
...  
Keyword(s):  
Immune Response ◽  
Single Cell ◽  
Mononuclear Cells ◽  
Well Being ◽  
Cell Receptor ◽  
Late Gestation ◽  
Third Trimester ◽  
Interferon Stimulated Genes ◽  
Tcr Repertoire ◽  
Transcriptional Changes

Abstract During the COVID-19 pandemic, thousands of pregnant women have been infected with SARS-CoV-2. The implications of maternal SARS-CoV-2 infection on fetal and childhood well-being are unknown. We aimed to characterize the fetal immune response to maternal SARS-CoV-2 infection. We performed single-cell RNA sequencing and T-cell receptor (TCR) sequencing on cord blood mononuclear cells (CBMC) from newborns of mothers infected with SARS-CoV-2 in the third-trimester (cases) or without SARS-CoV-2 infection. We identified widespread gene expression changes in CBMC from cases, including upregulation of interferon-stimulated genes and Major Histocompatibility Complex genes in CD14 + monocytes; transcriptional changes suggestive of activation of plasmacytoid dendritic cells, and activation and exhaustion of NK cells and CD8 + T-cells. Lastly, we observed fetal TCR repertoire expansion in cases. As none of the infants were infected with SARS-CoV-2, our results suggest that SARS-CoV-2 maternal infection might modulate the fetal immune system in the absence of vertical transmission.

scholarly journals Perinatal Adverse Effects in Newborns with Estimated Loss of Weight Percentile between the Third Trimester Ultrasound and Delivery. The GROWIN Study

2021 ◽  
Vol 10 (20) ◽  
pp. 4643
Author(s):  
María Sonsoles Galán Arévalo ◽  
Ignacio Mahillo-Fernández ◽  
Luis Mariano Esteban ◽  
Mercedes Andeyro-García ◽  
Roi Piñeiro Pérez ◽  
...  
Keyword(s):  
Fetal Growth ◽  
Gestational Age ◽  
Perinatal Outcomes ◽  
Late Gestation ◽  
Third Trimester ◽  
Loss Of Weight ◽  
Increased Risk ◽  
Appropriate For Gestational Age ◽  
Adverse Perinatal Outcomes ◽  
Weight Percentile

Fetal growth restriction has been associated with an increased risk of adverse perinatal outcomes (APOs). We determined the importance of fetal growth detention (FGD) in late gestation for the occurrence of APOs in small-for-gestational-age (SGA) and appropriate-for-gestational-age (AGA) newborns. For this purpose, we analyzed a retrospective cohort study of 1067 singleton pregnancies. The newborns with higher APOs were SGA non-FGD and SGA FGD in 40.9% and 31.5% of cases, respectively, and we found an association between SGA non-FGD and any APO (OR 2.61; 95% CI: 1.35–4.99; p = 0.004). We did not find an increased APO risk in AGA FGD newborns (OR: 1.13, 95% CI: 0.80, 1.59; p = 0.483), except for cesarean delivery for non-reassuring fetal status (NRFS) with a decrease in percentile cutoff greater than 40 (RR: 2.41, 95% CI: 1.11–5.21) and 50 (RR: 2.93, 95% CI: 1.14–7.54). Conclusions: Newborns with the highest probability of APOs are SGA non-FGDs. AGA FGD newborns do not have a higher incidence of APOs than AGA non-FGDs, although with falls in percentile cutoff over 40, they have an increased risk of cesarean section due to NRFS. Further studies are warranted to detect these newborns who would benefit from close surveillance in late gestation and at delivery.

scholarly journals DevKidCC allows for robust classification and direct comparisons of kidney organoid datasets

2021 ◽  
Author(s):  
Sean B. Wilson ◽  
Sara E. Howden ◽  
Jessica M. Vanslambrouck ◽  
Aude Dorison ◽  
Jose Alquicira-Hernandez ◽  
...  
Keyword(s):  
Single Cell ◽  
Kidney Development ◽  
Sequence Data ◽  
Clustering Algorithms ◽  
Marker Genes ◽  
Disease Clustering ◽  
Machine Learning Model ◽  
Cellular Identity ◽  
Kidney Organoids ◽  
Comprehensive Reference

AbstractKidney organoids provide a valuable resource to understand kidney development and disease. Clustering algorithms and marker genes fail to accurately and robustly classify cellular identity between human pluripotent stem cell (hPSC)-derived organoid datasets. Here we present a new method able to accurately classify kidney cell subtypes, a hierarchical machine learning model trained using comprehensive reference data from single cell RNA-sequencing of human fetal kidney (HFK). We demonstrate the tool’s (DevKidCC) performance by application to all published kidney organoid datasets and a novel dataset. DevKidCC is available on Github and can be used on any kidney single cell RNA-sequence data.

scholarly journals Transcriptomic Profiling of Human Placenta in Gestational Diabetes Mellitus at the Single-Cell Level

2021 ◽  
Vol 12 ◽  
Author(s):  
Yuqi Yang ◽  
Fang Guo ◽  
Yue Peng ◽  
Rong Chen ◽  
Wenbo Zhou ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Gestational Diabetes ◽  
Gestational Diabetes Mellitus ◽  
Single Cell ◽  
Human Placenta ◽  
Molecular Mechanisms ◽  
Marker Genes ◽  
Specific Marker ◽  
Increased Risk ◽  
Adverse Pregnancy

Gestational diabetes mellitus (GDM) is associated with an increased risk of adverse pregnancy outcomes. Increasing evidence shows that placentation defects may play important roles in GDM. However, our understanding of the human placenta remains limited. In this study, we generated a comprehensive transcriptomic profile of cellular signatures and transcriptomes in the human placenta in GDM using single-cell RNA sequencing (scRNA-seq), constructed a comprehensive cell atlas, and identified cell subtypes and subtype-specific marker genes. In addition, we investigated the placental cellular function and intercellular interactions in GDM. These findings help to elucidate the molecular mechanisms of GDM, and may facilitate the development of new approaches to GDM treatment and prevention.

scholarly journals From Oncogenic Signaling Pathways to Single-Cell Sequencing of Immune Cells: Changing the Landscape of Cancer Immunotherapy

Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2278
Author(s):  
Afshin Derakhshani ◽  
Zeinab Rostami ◽  
Hossein Safarpour ◽  
Mahdi Abdoli Shadbad ◽  
Niloufar Sadat Nourbakhsh ◽  
...  
Keyword(s):  
Single Cell ◽  
Signaling Pathways ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Cancer Development ◽  
Immune Checkpoints ◽  
Single Cell Sequencing ◽  
Increased Risk

Over the past decade, there have been remarkable advances in understanding the signaling pathways involved in cancer development. It is well-established that cancer is caused by the dysregulation of cellular pathways involved in proliferation, cell cycle, apoptosis, cell metabolism, migration, cell polarity, and differentiation. Besides, growing evidence indicates that extracellular matrix signaling, cell surface proteoglycans, and angiogenesis can contribute to cancer development. Given the genetic instability and vast intra-tumoral heterogeneity revealed by the single-cell sequencing of tumoral cells, the current approaches cannot eliminate the mutating cancer cells. Besides, the polyclonal expansion of tumor-infiltrated lymphocytes in response to tumoral neoantigens cannot elicit anti-tumoral immune responses due to the immunosuppressive tumor microenvironment. Nevertheless, the data from the single-cell sequencing of immune cells can provide valuable insights regarding the expression of inhibitory immune checkpoints/related signaling factors in immune cells, which can be used to select immune checkpoint inhibitors and adjust their dosage. Indeed, the integration of the data obtained from the single-cell sequencing of immune cells with immune checkpoint inhibitors can increase the response rate of immune checkpoint inhibitors, decrease the immune-related adverse events, and facilitate tumoral cell elimination. This study aims to review key pathways involved in tumor development and shed light on single-cell sequencing. It also intends to address the shortcomings of immune checkpoint inhibitors, i.e., their varied response rates among cancer patients and increased risk of autoimmunity development, via applying the data from the single-cell sequencing of immune cells.

scholarly journals Increased risk of preeclampsia after use of paracetamol during pregnancy – causal or coincidence?

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Hetti von Hellens ◽  
Leea Keski-Nisula ◽  
Heidi Sahlman
Keyword(s):  
Third Trimester ◽  
Retrospective Case ◽  
Reverse Causation ◽  
Gestational Period ◽  
The Third ◽  
Precise Data ◽  
Increased Risk ◽  
Study Population ◽  
The Difference ◽  
Risk Of Preeclampsia

Abstract Background The maternal use of paracetamol during pregnancy has been associated with the development of preeclampsia. This study aims to clarify whether the connection is causal or whether it is due to reverse causation. Methods This study is a continuation of the retrospective case cohort study examining 2,508 pregnant women using a variety of drugs and the development of preeclampsia (1,252 women with preeclampsia and 1,256 controls). For the purposes of this study, more precise data was collected from several hospital databases of the women among this cohort who had reported taking paracetamol during pregnancy (indications, gestational period etc.); this was evaluated in association with the development of preeclampsia. Results 5.5% (100 cases and 37 controls) of all the study population (2,508) had clearly reported paracetamol use. Women with preeclampsia had used significantly more often paracetamol during pregnancy compared to controls (cases 8.0%, controls 2.9%, p < 0.001). The difference was most evident in the third trimester (after the 29th GW) and the use of paracetamol was associated with both mild and severe preeclampsia. Headache and “general pain” were the most common indications for medication among all paracetamol users. Conclusions The use of paracetamol in the third trimester of pregnancy was associated with preeclampsia. This observation indicates that association between paracetamol use and preeclampsia is probably due to reverse causation, i.e. women with preeclampsia experience more headaches due to preeclampsia symptoms since this association was not detected with the use of paracetamol in earlier stages of pregnancy.

Epigenetic mechanisms involved in intrauterine growth restriction and aberrant kidney development and function

2020 ◽  
pp. 1-11
Author(s):  
Thu N. A. Doan ◽  
Jessica F. Briffa ◽  
Aaron L. Phillips ◽  
Shalem Y. Leemaqz ◽  
Rachel A. Burton ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Intrauterine Growth Restriction ◽  
Kidney Development ◽  
Dna Methyltransferases ◽  
Growth Restriction ◽  
Epigenetic Mechanisms ◽  
Specific Expression ◽  
Maternal Line ◽  
Intrauterine Growth ◽  
Increased Risk

Abstract Intrauterine growth restriction (IUGR) due to uteroplacental insufficiency results in a placenta that is unable to provide adequate nutrients and oxygen to the fetus. These growth-restricted babies have an increased risk of hypertension and chronic kidney disease later in life. In rats, both male and female growth-restricted offspring have nephron deficits but only males develop kidney dysfunction and high blood pressure. In addition, there is transgenerational transmission of nephron deficits and hypertension risk. Therefore, epigenetic mechanisms may explain the sex-specific programming and multigenerational transmission of IUGR-related phenotypes. Expression of DNA methyltransferases (Dnmt1and Dnmt3a) and imprinted genes (Peg3, Snrpn, Kcnq1, and Cdkn1c) were investigated in kidney tissues of sham and IUGR rats in F1 (embryonic day 20 (E20) and postnatal day 1 (PN1)) and F2 (6 and 12 months of age, paternal and maternal lines) generations (n = 6–13/group). In comparison to sham offspring, F1 IUGR rats had a 19% decrease in Dnmt3a expression at E20 (P < 0.05), with decreased Cdkn1c (19%, P < 0.05) and increased Kcnq1 (1.6-fold, P < 0.01) at PN1. There was a sex-specific difference in Cdkn1c and Snrpn expression at E20, with 29% and 34% higher expression in IUGR males compared to females, respectively (P < 0.05). Peg3 sex-specific expression was lost in the F2 IUGR offspring, only in the maternal line. These findings suggest that epigenetic mechanisms may be altered in renal embryonic and/or fetal development in growth-restricted offspring, which could alter kidney function, predisposing these offspring to kidney disease later in life.

scholarly journals Molecular characteristics and spatial distribution of adult human corneal cell subtypes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ann J. Ligocki ◽  
Wen Fury ◽  
Christian Gutierrez ◽  
Christina Adler ◽  
Tao Yang ◽  
...  
Keyword(s):  
Single Cell ◽  
Rna Sequencing ◽  
Cross Sections ◽  
Cell Types ◽  
Marker Genes ◽  
Molecular Characteristics ◽  
Transcriptional Level ◽  
Human Cornea ◽  
Adult Human ◽  
And Migration

AbstractBulk RNA sequencing of a tissue captures the gene expression profile from all cell types combined. Single-cell RNA sequencing identifies discrete cell-signatures based on transcriptomic identities. Six adult human corneas were processed for single-cell RNAseq and 16 cell clusters were bioinformatically identified. Based on their transcriptomic signatures and RNAscope results using representative cluster marker genes on human cornea cross-sections, these clusters were confirmed to be stromal keratocytes, endothelium, several subtypes of corneal epithelium, conjunctival epithelium, and supportive cells in the limbal stem cell niche. The complexity of the epithelial cell layer was captured by eight distinct corneal clusters and three conjunctival clusters. These were further characterized by enriched biological pathways and molecular characteristics which revealed novel groupings related to development, function, and location within the epithelial layer. Moreover, epithelial subtypes were found to reflect their initial generation in the limbal region, differentiation, and migration through to mature epithelial cells. The single-cell map of the human cornea deepens the knowledge of the cellular subsets of the cornea on a whole genome transcriptional level. This information can be applied to better understand normal corneal biology, serve as a reference to understand corneal disease pathology, and provide potential insights into therapeutic approaches.

scholarly journals Programming of growth, insulin resistance and vascular dysfunction in offspring of late gestation diabetic rats

2009 ◽  
Vol 117 (3) ◽  
pp. 129-138 ◽  
Author(s):  
Emily M. Segar ◽  
Andrew W. Norris ◽  
Jian-Rong Yao ◽  
Shanming Hu ◽  
Stacia L. Koppenhafer ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Diabetic Rats ◽  
Late Gestation ◽  
Group Differences ◽  
Pregnant Rats ◽  
Increased Risk ◽  
Specific Insulin ◽  
Diabetic Mothers

ODM (offspring of diabetic mothers) have an increased risk of developing metabolic and cardiovascular dysfunction; however, few studies have focused on the susceptibility to disease in offspring of mothers developing diabetes during pregnancy. We developed an animal model of late gestation diabetic pregnancy and characterized metabolic and vascular function in the offspring. Diabetes was induced by streptozotocin (50 mg/kg of body weight, intraperitoneally) in pregnant rats on gestational day 13 and was partially controlled by twice-daily injections of insulin. At 2 months of age, ODM had slightly better glucose tolerance than controls (P<0.05); however, by 6 months of age this trend had reversed. A euglycaemic–hyperinsulinamic clamp revealed insulin resistance in male ODM (P<0.05). In 6–8-month-old female ODM, aortas had significantly enhanced contractility in response to KCl, ET-1 (endothelin-1) and NA (noradrenaline). No differences in responses to ET-1 and NA were apparent with co-administration of L-NNA (NG-nitro-L-arginine). Relaxation in response to ACh (acetylcholine), but not SNP (sodium nitroprusside), was significantly impaired in female ODM. In contrast, males had no between-group differences in response to vasoconstrictors, whereas relaxation to SNP and ACh was greater in ODM compared with control animals. Thus the development of diabetes during pregnancy programmes gender-specific insulin resistance and vascular dysfunction in adult offspring.

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