Fetal and amniotic fluid iron homeostasis in healthy and complicated murine, macaque, and human pregnancy

Fisher, Allison L.; Sangkhae, Veena; Presicce, Pietro; Chougnet, Claire; Jobe, Alan H.; Kallapur, Suhas G.; Tabbah, Sammy; Buhimschi, Catalin S.; Buhimschi, Irina A.; Ganz, Tomas; Nemeth, Elizabeta

doi:10.1172/jci.insight.135321

Cited by 28 publications

(31 citation statements)

References 46 publications

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“…We recently demonstrated that in a Rhesus macaque model of IUI-induced by LPS, the fetus responded by rapidly upregulating hepcidin and lowering iron in fetal blood, without altering amniotic fluid iron status (45). The present study demonstrates a differential regulation of genes involved in iron homeostasis after live E. coli exposure.…”

Section: Discussionsupporting

confidence: 58%

The intensity of the immune response to LPS andE. coliregulates the induction of preterm labor in Rhesus Macaques

Cappelletti

Presicce

et al. 2021

Preprint

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Intrauterine infection/inflammation (IUI) is a major contributor to preterm labor (PTL). However, IUI does not invariably cause PTL. We hypothesized that quantitative and qualitative differences in immune response exist in subjects with or without PTL. To define the triggers for PTL, we developed Rhesus macaque models of IUI driven by lipopolysaccharyde (LPS) or live E. coli. PTL did not occur in LPS challenged Rhesus macaque while E. coli infected animals frequently delivered preterm. Although LPS and live E. coli both caused immune cell infiltration, E. coli infected animals showed higher levels of inflammatory mediators, particularly IL6 and prostaglandins, in the chorioamnion decidua and amniotic fluid. Neutrophil infiltration in the chorion was a common feature to both LPS and E. coli. However, neutrophilic infiltration and IL6 and PTGS2 expression in the amnion was specifically induced by live E. coli. RNASeq analysis of fetal membranes revealed that specific pathways involved in augmentation of inflammation including type I interferon response, chemotaxis, sumoylation and iron homeostasis were upregulated in the E. coli group compared to the LPS group. Our data suggest that intensity of the host immune response to IUI may determine susceptibility to PTL.

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Section: Discussionsupporting

confidence: 58%

The intensity of the immune response to LPS andE. coliregulates the induction of preterm labor in Rhesus Macaques

Cappelletti

Presicce

et al. 2021

Preprint

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“…Indeed, previous morphologic studies have suggested nonhuman primate renal development closely resembles that of humans. [34][35][36] Nephrogenesis in the rhesus, with material made available to us through ongoing perinatal research collaborative efforts, [37][38][39] begins late in the first trimester, and continues until the middle of the third trimester, providing a potential model for molecular analyses of LBN. [34][35][36] We correlated the morphology of rhesus and human in three-dimensional (3D) renderings of lategestation nephrogenesis, measuring the distance to the last bifurcating branch point and other morphometric criteria to characterize rhesus LBN, and establish it is morphologically similar to late-gestation human archival kidneys.…”

mentioning

confidence: 99%

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

Schuh

Alkhudairy

Potter

et al. 2021

JASN

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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.

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“…Along with traditional markers of erythropoiesis and ferrokinetic disorders, high attention is paid nowadays also to ferroportin, gem iron conveyor, high iron factor, and iron regulatory protein [19]. Conclusive database on the role of proteins in iron metabolism in normal and pathological conditions is being formed [20].…”

Section: Introductionmentioning

confidence: 99%

Diagnostic Relevance of Ferrokinetic Laboratory Markers in Anemic Pregnant Women

Aringazina¹,

Zharmakhanova²,

Курманалина³

et al. 2020

Gynecol Obstet Invest

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Objectives: Different forms of anemia are considered as the most frequent complication of the gestational period. By its etiology, pathogenesis, and clinical hematology, it is not a single disease. Among all forms of anemia occurring during pregnancy, iron deficiency anemia (IDA) is the most common, accounting for 80-95% of all cases. Design: The article describes a theoretical basis for the diagnosis of the anemic syndrome among pregnant women, the determining factors of its development, and the diagnostic methods at different gestational periods. Participants/Materials, Setting, and Methods: Diagnostic and prognostic values of iron balance indicators in the body were established for IDA during pregnancy to improve the outcome of childbirth. A total of 140 anemic patients were examined. The control group consisted of 50 pregnant women without anemia and other significant health problems, 48 IDA pregnant women, and 42 pregnant women with anemia caused by various chronic diseases, including rheumatoid arthritis. All patients of the main and control groups were registered on clinical records at the Family Planning Center in Aktobe city, Kazakhstan. Results: Ferrokinetic indicators were suggested for diagnosing IDA and anemia of chronic diseases. It was established that IDA is characterized by low ferritin levels during gestation, while increased ferritin and C-reactive protein are typical for anemia of chronic diseases. Limitations: Differential diagnostics was applied for pregnant women with IDA and anemia of chronic diseases to observe the dynamics of serum ferritin and C-reactive protein (CRP) levels at different gestational periods. The article presents the results of a study on ferrokinetics in pregnant women with IDA and anemia caused by inflammation or chronic diseases. Other causes of anemia leading to a decrease in hemoglobin (Hb) levels to <90 g/L include hemoglobinopathies, which were not considered in this study. Conclusions: Determination of iron deficiency in pregnant women at different gestational periods will allow for identifying the risk group of anemic patients and deciding on the treatment. IDA (Hb <100 g/L) can be effectively measured by ferritin level <15 ng/mL, iron level of <11.5 μmol/L, and transferrin level >2.6 mg/L at p < 0.001. Anemia due to chronic diseases (Hb <100 g/L) can be effectively diagnosed with ferritin above 15 μg/L and CRP above 10 mg/L at p < 0.001.

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Fetal and amniotic fluid iron homeostasis in healthy and complicated murine, macaque, and human pregnancy

Cited by 28 publications

References 46 publications

The intensity of the immune response to LPS andE. coliregulates the induction of preterm labor in Rhesus Macaques

The intensity of the immune response to LPS andE. coliregulates the induction of preterm labor in Rhesus Macaques

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

Diagnostic Relevance of Ferrokinetic Laboratory Markers in Anemic Pregnant Women

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