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In vitro Modelling of Cardiovascular Damage following Hypertensive Disorders of Pregnancy using Cardiac Spheroids and Patient-derived Plasma

ABSTRACT: Background: Hypertensive disorders of pregnancy (HDP) affect 2-8% of pregnancies and are associated postpartum with ongoing, increased cardiovascular disease (CVD) risk. In this study, we aimed to model HDP-induced CVD and decipher systemic mechanisms, using an advanced 3D in vitro cardiac spheroid model. Methods: Human iPSC-derived cardiomyocytes, cardiac fibroblasts and coronary artery endothelial cells were co-cultured to form cardiac spheroids (CS ) in collagen type-1 hydrogels containing 10% patient plasma collected five years postpartum (n=5 per group: normotensive control, gestational hypertension (GH) and preeclampsia). Plasma-treated CS were assessed for cell viability, contractile function and markers of cardiac damage using immunofluorescence staining and imaging. An untargeted, label-free quantitative proteomic analysis of plasma samples was conducted (controls n=24; GH n=5; preeclampsia n=13). Results: Contraction frequency (CF) was increased in preclampsia-treated CS (CF:45.5 contractions/minute, p<0.001) and GH-treated CS (CF:45.7 contractions/minute, p<0.001), compared to controls (CF=21.8 contractions/minute). Only GH-treated CS presented increased fractional shortening (FS) % (FS%=9.5%, p<0.05), compared to controls (FS%=3.7%); this was in conjunction with a reduction in cell viability by ͠ 20% (p<0.05), and an increase in α-SMA expression (p<0.05). Proteomics analysis identified twenty differentially abundant proteins, with haemoglobin A2 the only protein perturbed in both GH and preeclampsia versus control (p<0.05). Conclusions: GH-induced CVD appears linked to an increase in cell death signaling and cardiac remodeling and preeclampsia-induced CVD to vascular and endothelial cell dysfunction. CS could in future be used to assess early changes in cardiac function and as a precision medicine platform for testing post-HDP CVD prevention therapeutics.

INSTRUMENT(S): Synapt MS

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Plasma

DISEASE(S): Cardiovascular System Disease

SUBMITTER: Matthew Padula

LAB HEAD: Lana McClements

PROVIDER: PXD051288 | Pride | 2024-11-25

REPOSITORIES: Pride

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			Action	DRS
	Plasma_F1.DerivedFromSearch3937fecf-ecc7-43f6-a3f1-048a24aa4405.mgf	Mgf
	Plasma_F1.mzid.gz	Mzid
	Plasma_F2.DerivedFromSearchff9c0520-ba38-4a7b-9d95-740cab5ae7ae.mgf	Mgf
	Plasma_F2.mzid.gz	Mzid
	Plasma_F3.DerivedFromSearch3d7faab1-c42e-4754-a48a-d3ebfd7fc902.mgf	Mgf

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Project description:Background: Platelets may be pivotal mediators of the thrombo-haemorrhagic complications of preeclampsia (PE), linking inflammation and thrombosis with endothelial and vascular dysfunction. While gestational hypertension (GH) falls within the spectrum of hypertensive complications of pregnancy and is a risk factor for preeclampsia, it is unclear what biomarkers distinguish PE from GH. Aim: To identify specific plasma and platelet thrombo-inflammatory biomarkers indicative of preeclampsia and distinguish PE from GH. Methods: We performed multiplex immunoassays, assessed platelet and plasma proteomics and metabolomics data of PE patients, and compared with non-pregnant (NP), healthy pregnant (PC) and GH participants. Results: We report plasma proteins upregulated, enriched plasma metabolites and proteins distinctly overexpressed in platelets of PE and GH compared to NP and PC. Whilst procoagulation in PC may be fibrinogen driven, Inter-Alpha-Trypsin Inhibitors ITIH2 and ITIH3 were enriched in hypertensive complications of pregnancy (PE and GH), and fibronectin and S100A8/9 may be major procoagulant agonists in PE but not GH. In addition, platelet leucine-rich repeat-containing protein 27 and 42 (LRRC27/42) subunits of volume-regulated VRAC anion channels were markedly overexpressed in preeclampsia and may contribute to the heightened glucose sensitivity and the pro-thrombotic tendency of this disorder. Additionally, our multiplex immunoassays confirmed previous reports of increases in preeclampsia plasma cytokines, including SDF-1α, which can directly activate platelets; but also, i-309 and CTACK cytokines, whose effects on platelets we explored using STRING analysis. Conclusion: We identified biomarkers that may be monitored for preeclampsia onset and progression, and distinguish PE from GH. Also, through protein-protein interactions analysis, we generated a new hypothesis for platelets’ contribution to the thrombo-inflammatory states of preeclampsia.

Project description:Molecular characterization of leaf development has not been well studied in soybean. Studies have shown that genomic regions controlling multifoliate leaf morphology in Glycine max also regulates important agronomic characters including yield, seed weight, seed number, shattering, plant growth, and flowering. Two soybean isolines that differed in leaf phenotype were profiled by high throughput RNA and small RNA (sRNA) sequencing. A Clark isoline, homozygous for a dominant mutant allele, Lf1, that specifies a five-foliate compound leaf was compared to wild type Clark that is homozygous for the standard allele that produces trifoliate leaves. Although Lf1 is dominant, it presents variable expressivity as the young plantlets with the Lf1Lf1 genotype initially have trifoliate leaves in the first few weeks, after which they transition to five-foliate leaves. At later developmental stages, they begin to produce four-foliate or trifoliate leaves. In RNA-Seq experiments, a total of 91 and 95 million reads were generated in each lane of Illumina sequencing for the shoot tip of wild type Clark standard (CS) and mutant Clark five-foliate (CF) libraries, respectively. Of these, ~70% million reads aligned to the 78,743 target Glyma models from the reference soybean genome (cv. Williams 82) with maximum of 3 mismatches and up to 25 alignments. Where as in vegetative bud, 56 (CS) to 59 (CF) million reads were produced and of these ~80% aligned to the soybean reference genome. The comparative studies of the transcript profiles of the wild-type versus mutant line revealed a number of differentially expressed genes. A total of 1,296 and 2,083 genes were up-regulated in the shoot tip of CS and CF, respectively that showed ≥2-fold expression difference. On the contrary in the vegetative bud, much smaller number of genes 14 (CS) and 94 (CF) showed increased transcript abundance. In sRNA analysis, a collection of 200,447 and 268,508 unique sRNA sequences isolated from shoot tip tissue of CS and CF were aligned to the soybean reference genome and their target glyma models were predicted using bioinformatics. This sRNA analysis at genome level reveals differences in size distribution of classes in the CS and CF. This study provides insight into the initial understanding of leaf development in soybean by revealing a number of genes and sRNAs differentially expressed between the CS and CF.

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In vitro Modelling of Cardiovascular Damage following Hypertensive Disorders of Pregnancy using Cardiac Spheroids and Patient-derived Plasma

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