Biology subjects

Dominguez, E. M.

Publications and source records attributed to Dominguez, E. M..

7 recordsLinked to original sources

bioRxiv2026

Targeting pathogenic VWF/ADAMTS13 dysregulation attenuates CTEPH progression

Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening pulmonary vascular disease, characterized by persistent thrombotic obstruction and progressive pulmonary vascular remodeling, yet the molecular mechanisms linking persistent thrombosis to vascular remodeling remain incompletely understood. Clinical studies have reported elevated plasma von Willebrand factor (VWF) levels and reduced ADAMTS13 in patients with CTEPH, but whether VWF/ADAMTS13 dysregulation contributes directly to disease pathogenesis remains unclear. Here, using newly established rat models of CTEPH, we identify a causative role for dysregulation of the VWF-ADAMTS13 axis in chronic thromboembolic progression. CTEPH rats developed persistent, unresolved VWF- and fibrin-rich thrombi accompanied by markedly increased endothelial VWF deposition. In contrast, ADAMTS13 expression and activity were significantly reduced in CTEPH rats. Consistent with these findings, genetic Adamts13 deficiency further exacerbates pulmonary microvascular thrombosis and accelerated early mortality following disease induction. Mechanistically, ultra-large (UL)-VWF accumulated on the pulmonary endothelial surface, promoting robust platelet recruitment under shear. This platelet-VWF interaction stimulated the release of platelet-derived pro-remodeling mediators, including TGF-{beta}1 and PDGF-BB. Genetic ablation of Vwf markedly reduced in situ microvascular thrombosis within pulmonary arterioles, attenuated pulmonary arterial remodeling, and improved pulmonary hemodynamics. Moreover, treatment with recombinant ADAMTS13 reduced endothelial UL-VWF accumulation, suppressed platelet activation, and effectively prevented thrombosis and platelet-driven pro-remodeling signaling in CTEPH rats. Collectively, these findings identify dysregulation of the VWF-ADAMTS13 axis as a key driver of pulmonary thrombosis and vascular remodeling in CTEPH and support therapeutic targeting of this pathway as a potential disease-modifying strategy. Key PointsO_LIVWF-ADAMTS13 dysregulation promotes persistent pulmonary thrombosis and platelet-driven arterial remodeling within pulmonary arterioles. C_LIO_LIRecombinant ADAMTS13 treatment or VWF ablation abrogates pulmonary arterial thrombosis and halts vascular remodeling in CTEPH. C_LI

pathology↗

bioRxiv2025

SARS-CoV-2 Variant-Dependent Alterations in Nasopharyngeal Microbiota and Host Inflammatory Response

The SARS-CoV-2 pandemic saw multiple outbreaks occur over short periods. This was linked to the viruss high infectivity and rapid mutation rate, which hindered the development of effective treatments and a comprehensive understanding of COVID-19 pathophysiology. The nasopharyngeal tract, the main entry site of SARS-CoV-2, interacts with angiotensin-converting enzyme 2 (ACE2) receptors via the viral spike glycoprotein, triggering pro-inflammatory responses that affect both tissue integrity and the resident microbiota. Viral infection induces dysbiosis by modulating microbiome diversity. Although distinct variants produce independent symptoms and viral loads, their impact on the nasopharyngeal microbiota and host inflammatory profile remains poorly understood. To address this, we analyzed nasopharyngeal samples from Chilean individuals collected during different phases of the pandemic. The microbiota was characterized by 16S rRNA gene sequencing (V3-V4 region), and cytokine expression was quantified by RT-qPCR. Finally, applied rigorous data processing and machine-learning models Random Forest and K-Nearest Neighbors to identify associations between SARS-CoV-2 variants, inflammatory markers, and opportunistic bacterial genera. Our results reveal that SARS-CoV-2 infection promotes distinct immunomicrobial signatures marked by TNF--driven inflammation and the expansion of opportunistic taxa. These variant-dependent alterations indicate that host inflammatory responses and microbial dysbiosis are closely intertwined in the nasopharyngeal environment. This study provides a comprehensive framework integrating microbial and host factors to better understand the mechanisms underlying COVID-19 pathogenesis and highlights the potential of combining microbiome and cytokine profiling with machine-learning approaches to differentiate infection outcomes across viral variants. ImportanceUnderstanding how SARS-CoV-2 infection alters the upper respiratory microbiota and host immune responses is essential to uncover the mechanisms underlying COVID-19 severity. In this study, we integrate bacterial 16S rRNA sequencing, inflammatory markers, and machine learning to identify key descriptors of infection such as TNF-, Acinetobacter, Prevotella, and Staphylococcus. These markers define a conserved immunomicrobial signature across viral variants, linking inflammatory activation with microbial dysbiosis in the nasopharyngeal environment. Our findings highlight the value of the correct and robust application of machine learning models and nested cross-validation strategies in high-dimensional (wide) datasets to improve variant discrimination, reveal host-microbe interactions, and support the development of therapeutic strategies for respiratory viral infections.

microbiology↗

bioRxiv2025

PPARG directs trophoblast cell fate and establishment of the uterine-placental interface

The expansion and differentiation of trophoblast stem (TS) cells are critical for defining fundamental properties of the placenta. Specialized trophoblast cells exit the placenta and enter and transform the uterus, including restructuring uterine spiral arteries. In the human these cells are named extravillous trophoblast (EVT) cells, whereas in the rat they are termed invasive trophoblast cells. Mechanisms governing invasive trophoblast cell differentiation remain poorly understood. We investigated peroxisome proliferator-activated receptor gamma (PPARG) as a potential regulator of EVT/invasive trophoblast cell development. In first trimester human placentas, PPARG was expressed in the EVT cell column and increased in amount as human TS cells differentiated into EVT cells. PPARG disruption impaired EVT cell differentiation. Rat invasive trophoblast cells similarly expressed PPARG. Conditional inactivation of PPARG within rat invasive trophoblast cells was used to assess the in vivo role of PPARG on the uterine-placental interface. PPARG was established as an essential cell-autonomous regulator of the invasive trophoblast cells. In conclusion, PPARG is a conserved regulator of placentation and is essential for directing trophoblast cell-guided uterine transformation.

developmental biology↗

bioRxiv2024

TFAP2C is a key regulator of intrauterine trophoblast cell invasion and deep hemochorial placentation

Transcription factor AP-2 gamma (TFAP2C) has been identified as a key regulator of the trophoblast cell lineage and hemochorial placentation. The rat possesses deep placentation characterized by extensive intrauterine trophoblast cell invasion, which resembles human placentation. Tfap2c is expressed in multiple trophoblast cell lineages, including invasive trophoblast cells situated within the uterine-placental interface of the rat placentation site. Global genome-editing was used to explore the biology of Tfap2c in rat placenta development. Homozygous global disruption of Tfap2c resulted in prenatal lethality. Heterozygous global disruption of Tfap2c was associated with diminished invasive trophoblast cell infiltration into the uterus. The role of TFAP2C in the invasive trophoblast cell lineage was explored using Cre-lox conditional mutagenesis. Invasive trophoblast cell-specific disruption of Tfap2c resulted in inhibition of intrauterine trophoblast cell invasion and intrauterine and postnatal growth restriction. The invasive trophoblast cell lineage was not impaired following conditional monoallelic disruption of Tfap2c. In summary, TFAP2C contributes to the progression of distinct stages of placental development. TFAP2C is a driver of early events in trophoblast cell development and reappears later in gestation as an essential regulator of the invasive trophoblast cell lineage. A subset of TFAP2C actions on trophoblast cells are dependent on gene dosage.

developmental biology↗

bioRxiv2023

TAF7L REGULATES EARLY STAGES OF MALE GERM CELL DEVELOPMENT

Male germ cell development is dependent on the orchestrated regulation of gene networks. TATA-box binding protein associated factors (TAFs) facilitate interactions of TATA-binding protein with the TATA element, which is known to coordinate gene transcription during organogenesis. TAF7 like (Taf7l) is situated on the X chromosome and has been implicated in testis development. We examined the biology of TAF7L in testis development using the rat. Taf7l was prominently expressed in preleptotene to leptotene spermatocytes. To study the impact of TAF7L on the testis we generated a global loss-of-function rat model using CRISPR/Cas9 genome editing. Exon 3 of the Taf7l gene was targeted. A founder was generated possessing a 110 bp deletion within the Taf7l locus, which resulted in a frameshift and the premature appearance of a stop codon. The mutation was effectively transmitted through the germline. Deficits in TAF7L did not adversely affect pregnancy or postnatal survival. However, the Taf7l disruption resulted in male infertility due to compromised testis development and failed sperm production. Mutant germ cells suffer meiotic arrest at the zygotene stage, with defects in sex body formation and meiotic sex chromosome inactivation. This testis phenotype was more pronounced than previously described for the subfertile Taf7l null mouse. We conclude that TAF7L is essential for male germ cell development in the rat.

developmental biology↗

bioRxiv2023

CONDITIONALLY MUTANT ANIMAL MODEL FOR INVESTIGATING THE INVASIVE TROPHOBLAST CELL LINEAGE

Placental development involves coordinated expansion and differentiation of trophoblast cell lineages possessing specialized functions. Among the differentiated trophoblast cell lineages are invasive trophoblast cells, which exit the placenta and invade into the uterus where they restructure the uterine parenchyma and facilitate remodeling of uterine spiral arteries. The rat exhibits deep intrauterine trophoblast cell invasion, a feature shared with human placentation, and is also amenable to gene manipulation using genome editing techniques. In this investigation, we generated a conditional rat model targeting the invasive trophoblast cell lineage. Prolactin family 7, subfamily b, member 1 (Prl7b1) is uniquely and abundantly expressed in the rat invasive trophoblast cell lineage. Disruption of Prl7b1 did not adversely affect placental development. We demonstrated that the Prl7b1 locus could be effectively used to drive the expression of Cre recombinase in invasive trophoblast cells. Our rat model represents a new tool for investigating candidate genes contributing to the regulation of invasive trophoblast cells and their contributions to trophoblast-guided uterine spiral artery remodeling.

developmental biology↗

bioRxiv2022

CITED2 Is A Conserved Regulator Of Deep Hemochorial Placentation

Establishment of the hemochorial uterine-placental interface requires exodus of trophoblast cells from the placenta and their transformative actions on the uterus, which represent processes critical for a successful pregnancy, but are poorly understood. We examined the involvement of CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl terminal domain 2 (CITED2) in rat and human trophoblast cell development. The rat and human exhibit deep hemochorial placentation. CITED2 was distinctively expressed in the junctional zone and invasive trophoblast cells of the rat. Homozygous Cited2 gene deletion resulted in placental and fetal growth restriction. Small Cited2 null placentas were characterized by disruptions in the junctional zone, delays in intrauterine trophoblast cell invasion, and compromised plasticity. In the human placentation site, CITED2 was uniquely expressed in the extravillous trophoblast (EVT) cell column and importantly contributed to development of the EVT cell lineage. We conclude that CITED2 is a conserved regulator of deep hemochorial placentation. Significance StatementThe process of establishing the uterine-placental interface is a poorly understood tissue re-engineering event that involves genetically foreign trophoblast cells breaching the immunologically secure uterus. When optimal, mother and fetus thrive, whereas failures represent the root cause of life-threatening diseases of pregnancy. CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl terminal domain 2 (CITED2) is a transcriptional co-regulator with a conspicuous presence in trophoblast cell lineages infiltrating the uterine parenchyma. CITED2 helps coordinate the differentiation of rat and human trophoblast cells into invasive/extravillous trophoblast cells capable of transforming the uterus. These actions ensure requisite placental development and adaptations to physiological stressors. CITED2 exemplifies a conserved regulator of transcriptional events essential for establishing the uterine-placental interface.

developmental biology↗