Biology subjects

Yimlamai, D.

Publications and source records attributed to Yimlamai, D..

5 recordsLinked to original sources

bioRxiv2025

Fetal and maternal immune cells exhibit tandem maturation across gestation and dysregulation in preterm birth

Appropriate regulation of maternal immune cells in the pregnant uterus is essential for successful pregnancy, yet the impact of immune cells in placental villi (PV) on placental health remain understudied. We enriched immune cells from term and preterm PV for transcriptomic and functional analyses. Maternal and fetal immune cells were abundant, with maternal chimerism increasing at term. Fetal lymphocytes displayed enhanced prostaglandin-D signatures, while maternal lymphocytes were enriched for antigen presentation pathways. Inflammatory cytokines and expanded maternal and fetal T cell clones peaked at term but did not induce cytotoxicity in placental organoids, whereas expanded T cells from idiopathic preterm cases impaired trophoblast growth and endocrine function ex vivo. These findings reveal significant immune chimerism within PV in both health and disease yet implicate PV T cells in idiopathic preterm birth. One Sentence SummaryFetal-maternal immune chimerism is characteristic of all placental villi, yet unchecked T cells and cytokines can hinder trophoblast growth and potentially precipitate preterm birth.

immunology↗

bioRxiv2025

Liver lipid droplet cholesterol content is a key determinant of metabolic dysfunction-associated steatohepatitis

Metabolic dysfunction-associated steatohepatitis (MASH) represents a progressive form of steatotic liver disease which increases the risk for fibrosis and advanced liver disease. The accumulation of discrete species of bioactive lipids has been postulated to activate signaling pathways that promote inflammation and fibrosis. However, the key pathogenic lipid species is a matter of debate. We explored candidates using various dietary, molecular, and genetic models. Mice fed a choline-deficient L-amino acid-defined high-fat diet (CDAHFD) developed steatohepatitis and manifested early markers of liver fibrosis associated with increased cholesterol content in liver lipid droplets within 5 days without any changes in total liver cholesterol content. Treating mice with antisense oligonucleotides (ASOs) against Coenzyme A synthase (Cosay) or treatment with bempedoic acid or atorvastatin decreased liver lipid droplet cholesterol content and prevented CDAHFD-induced MASH and the fibrotic response. All these salutary effects were abrogated with dietary cholesterol supplementation. Analysis of human liver samples demonstrated that cholesterol in liver lipid droplets was increased in humans with MASH and liver fibrosis and was higher in PNPLA3 I148M (variants rs738409) than in HSD17B13 variants (rs72613567). Together, these data identify cholesterol in liver lipid droplets as a critical mediator of MASH and demonstrate that COASY knockdown and bempedoic acid are novel therapeutic approaches to reduce liver lipid droplet cholesterol content and thereby prevent the development of MASH and liver fibrosis. Significance StatementMetabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease linked to fibrosis. The role of specific lipid species in its pathogenesis remains debated. Using dietary, molecular, and genetic models, we found that mice on a choline-deficient, high-fat diet (CDAHFD) developed steatohepatitis and early fibrosis, marked by increased cholesterol in liver lipid droplets within five days. Targeting COASY with antisense oligonucleotides or treating with bempedoic acid or atorvastatin reduced lipid droplet cholesterol and prevented MASH. However, dietary cholesterol supplementation negated these effects. Human liver samples confirmed elevated lipid droplet cholesterol in MASH and fibrosis, especially in PNPLA3 I148M carriers. These findings highlight cholesterol reduction as a potential MASH therapy.

pathology↗

bioRxiv2021

Human placental villi immune cells help maintain homeostasis in utero

Maintenance of healthy pregnancy is reliant on successful balance between the fetal and maternal immune systems. Although maternal mechanisms responsible have been well studied, those used by the fetal immune system remain poorly understood. Using suspension mass cytometry and various imaging modalities, we report a complex immune system within the mid-gestation (17-23 weeks) human placental villi (PV). Further, we identified immunosuppressive signatures in innate immune cells and antigen presenting cells that potentially maintain immune homeostasis in utero. Consistent with recent reports in other fetal organs, T cells with memory phenotypes were detected within the PV tissue and vasculature. Moreover, we determined PV T cells could be activated to upregulate CD69 and proliferate after T cell receptor (TCR) stimulation and when exposed to maternal uterine antigens. Finally, we report that cytokine production by PV T cells is sensitive to TCR stimulation and varies between mid-gestation, preterm (26-35 weeks) and term deliveries (37-40 weeks). Collectively, we elucidated the complexity and functional maturity of fetal immune cells within the PV and highlighted their immunosuppressive potential.

immunology↗

bioRxiv2019

Control of cytokinesis by β-adrenergic receptors indicates an approach for regulating cardiomyocyte endowment

ABSTRACT/SUMMARYOne million patients with congenital heart disease (CHD) live in the US. They have a lifelong risk of developing heart failure. Current concepts do not sufficiently address mechanisms of heart failure development specifically for these patients. We show that cardiomyocyte cytokinesis failure is increased in tetralogy of Fallot with pulmonary stenosis (ToF/PS), a common form of CHD. Labeling of a ToF/PS baby with isotope-tagged thymidine showed cytokinesis failure after birth. We used single-cell transcriptional profiling to discover that the underlying mechanism is repression of the cytokinesis gene ECT2, and show that this is downstream of {beta}-adrenergic receptors ({beta}-AR). Inactivation of the {beta}-AR genes and administration of the {beta}-blocker propranolol increased cardiomyocyte division in neonatal mice, which increased the endowment and conferred benefit after myocardial infarction in adults. Propranolol enabled the division of ToF/PS cardiomyocytes. These results suggest that {beta}-blockers should be evaluated for increasing cardiomyocyte division in patients with ToF/PS and other types of CHD.

cell biology↗

bioRxiv2018

Yap regulates glucose utilization and sustains nucleotide synthesis to enable organ growth

The Hippo pathway and its nuclear effector Yap regulate organ size and cancer formation. While many modulators of Hippo activity have been identified, little is known about the Yap target genes that mediate these growth effects. Here, we show that yap-/- mutant zebrafish exhibit defects in hepatic progenitor potential and liver growth due to impaired glucose transport and nucleotide biosynthesis: transcriptomic and metabolomic analyses reveal that Yap regulates expression of glucose transporter glut1, causing decreased glucose uptake and use for nucleotide biosynthesis in yap-/- mutants, and impaired glucose tolerance in adults. Nucleotide supplementation improved Yap-deficiency phenotypes, indicating functional importance of glucose-fuelled nucleotide biosynthesis. Yap-regulated Glut1 expression and glucose uptake are conserved in mammals, suggesting that stimulation of anabolic glucose metabolism is an evolutionarily conserved mechanism by which the Hippo pathway controls organ growth. Together, our results reveal a central role for Hippo signalling in metabolic homeostasis.

developmental biology↗