Preeclampsia in mice carrying fetuses with APOL1 risk variants
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Abstract
African-American women have a maternal mortality rate approximately three times higher than European-American women. This is partially due to hypertensive disorders of pregnancy, including preeclampsia. Fetal APOL1 high-risk genotype increases preeclampsia risk, although mechanisms remain elusive. We characterized two mouse models to investigate whether fetal-origin APOL1 induces preeclampsia and which cell types contribute. We in vitro fertilized mice with sperm from two transgenic mouse lines: APOL1 transgenic mice carrying human genomic locus constructs from bacterial artificial chromosomes (BAC) containing the APOL1 gene, mimicking expression and function of human APOL1 (BAC/APOL1 mice) and albumin promoter APOL1 transgenic mice expressing APOL1 in liver and plasma (Alb/APOL1 mice). Dams carrying either BAC/APOL1-G1 or Alb/APOL1-G1 fetuses had elevated systolic blood pressure, while dams carrying BAC/APOL1-G0 or Alb/APOL1-G0 fetuses did not. BAC/APOL1-G1 and Alb/APOL1-G1 fetuses weighed less than littermates, indicating intrauterine growth restriction. Single-nucleus RNA-seq of APOL1-G1 placentas showed increased expression of osteopontin/Spp1, most prominently in vascular endothelial cells with robust APOL1 expression. Cell-cell interaction analysis indicated pro-inflammatory signaling between placental cells and maternal monocytes. These models show that fetal origin APOL1-G1 causes preeclampsia, inducing pro-inflammatory response in placenta and maternal monocytes. The APOL1-G1 variant poses a multi-generational problem, causing effects in mothers and offspring.
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Mice were anesthetized mice
Typo? Do you mean "Mice were anesthetized with..." ?
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in in vitro
Typo? Do you mean "Osteopontin activates trophoblast invasion in vitro." ?
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endothelial cells. induced endothelial
Typo? Do you mean "...endothelial cells, induced endothelial..." ?
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change in the of
Typo? Do you mean "...change in the sFlt-1/PIGF-2 ratio" ?
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It is also worth noting thatAlb/APOL1-G1 model showed similar level of phenotypes compared with BAC/APOL1-G1model, except for change in the of sFlt-1/PlGF-2 ratio
Considering the importance of using the sFlt-1/PIGF ratio as a marker for preeclampsia (the only FDA-approved immunoassay to assess preeclampsia risk is based on the sFlt-1/PIGF ratio), do you believe the BAC/APOL-G1 model is a better model for preeclampsia?
Given the results of your work, is there a reason where one would prefer to use the Alb/APOL-G1 model?
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micel
Typo? "mice" ?
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though
Typo? Do you mean "...cell types through Cd44..." ?
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Dams carrying offspring with BAC/APOL1-G1 andAlb/APOL1-G1 had higher systolic blood pressure (158.4 mmHg [141.3-163.4], P=0.005 and159.0 [137.3-164.8], P=0.0002), compared to dams carrying BAC/APOL1-G0 and Alb/APOL1-G0 mice did not (115.9 [114.5-130.8] and 109.5 [96.3-133.3]) (Figure 1B).
This sentence is a bit confusing. I’d re-word this to “Dams carrying offspring with BAC/APOL1-G1 and Alb/APOL1-G1 had higher systolic blood pressure (158.4 mm Hg [141.3-163.4], P=0.005 and 159.0 [137.3-164.8], P=0.002) compared to dams carrying BAC/APOL1-G0 and Alb/APOL1-G0 mice (115.9 [114.5-130.8] and 109.5 [96.3-133.3]) (Figure 1B).
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The first set of transgenic mice (BAC/APOL1 mice) contained human genomicconstructs from bacterial artificial chromosomes (BAC) containing APOL1-G0 or APOL1-G1.The second set of transgenic mice (Alb/APOL1 mice) had the mouse albumin promotorregulated expression of cDNAs encoding human APOL-G0 or APOL1-G1.
You mention this later in the discussion but I would include a sentence conveying why you didn’t test APOL1-G2 variants since your introduction refers to both APOL1 high-risk variants (G1 and G2) and to evidence of preeclampsia development in APOL1-G2 transgenic mice (citation 16). E.g. “We did not study APOL1-G2 variants because we did not observe physical preeclampsia phenotypes in these transgenic lines.”
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isreported
Suggestion: "...has been reported."
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In an attempt to better understand the cell types and molecular mechanisms implicated in preeclampsia, Yoshida et al. analyzed pregnant female mice carrying BAC/APOL-G1 and Alb/APOL-G1 fetuses – novel IVF-derived preeclampsia mouse models – for physical biomarkers of preeclampsia and performed single-nucleus RNA-seq to identify differentially expressed genes and impacted cell-cell interactions.
When testing physical biomarkers of preeclampsia, the authors found that female mice carrying BAC/APOL-G1 and Alb/APOL-G1 fetuses had higher systolic blood pressure and smaller body weight, while just the female mice carrying BAC/APOL-G1 fetuses had a higher sFlt-1/PIGF-2 ratio. Elevated blood pressure and sFlt-1 levels and lower PIGF levels are phenotypes/markers clinically associated with preeclampsia.
Single-nucleus RNA-sequencing of placenta …
In an attempt to better understand the cell types and molecular mechanisms implicated in preeclampsia, Yoshida et al. analyzed pregnant female mice carrying BAC/APOL-G1 and Alb/APOL-G1 fetuses – novel IVF-derived preeclampsia mouse models – for physical biomarkers of preeclampsia and performed single-nucleus RNA-seq to identify differentially expressed genes and impacted cell-cell interactions.
When testing physical biomarkers of preeclampsia, the authors found that female mice carrying BAC/APOL-G1 and Alb/APOL-G1 fetuses had higher systolic blood pressure and smaller body weight, while just the female mice carrying BAC/APOL-G1 fetuses had a higher sFlt-1/PIGF-2 ratio. Elevated blood pressure and sFlt-1 levels and lower PIGF levels are phenotypes/markers clinically associated with preeclampsia.
Single-nucleus RNA-sequencing of placenta was conducted and differentially expressed genes were identified between APOL1-G1 and APOL1-G0 or APOL1-G1 and wild type mice. Inflammatory pathways and autoimmune disease pathways that were identified when comparing human preeclampsia RNA-seq data and a normal control were also implicated in the BAC/APOL1-G1 vs. BAC/APOL1-G0 DEG analysis results (e.g. pathogen induced cytokine storm signaling pathway and HIFI⍺ pathway).
The authors then performed cell-cell interaction analyses (Seurat) and found 31 shared activated and 4 shared deactivated pathways in BAC/APOL1-G1 placentas compared to BAC/APOL-G0 and wild type placentas. One of the identified shared activated pathways was the osteopontin/Spp1 signaling pathway which was found to be most upregulated in vascular endothelia – the cell type with the highest APOL1 expression.
Lastly, the authors attempted to determine the impact of maternal monocytes and decidual cells by APOL-G1 placentas and found upregulated signals to monocytes associated with the Cd44 receptor and upregulated expression of Ccl2 – supporting their hypothesis that APOL1-G1 induced preeclampsia in female mice activates maternal monocytes.
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