Biology subjects

Lo, Y. M. D.

Publications and source records attributed to Lo, Y. M. D..

3 recordsLinked to original sources

bioRxiv2023

Syncytiotrophoblast 5'-tRNA fragments are placental endocrine signals contributing to sterile inflammation in preeclampsia

BackgroundThe relationship between placental pathology and the maternal syndrome of preeclampsia is incompletely characterised. Mismatch between placental nutrient supply and fetal demands induces stress in the syncytiotrophoblast, the layer of placenta in direct contact with maternal blood. Such stress alters the content and increases the release of extracellular vesicles (STB-EVs) into the maternal circulation. We have previously shown 5-tRNA fragments (5-tRFs) constitute the majority of small RNA in STB-EVs in healthy pregnancy. 5-tRFs are produced in response to stress. We hypothesised STB-EV 5-tRF release might change in preeclampsia. MethodsWe perfused placentas from eight women with early-onset preeclampsia and six controls, comparing small RNA expression in STB-EVs. We used membrane-affinity columns to isolate maternal plasma vesicles and investigate placental 5-tRFs in-vivo. We quantified 5-tRFs from circulating STB-EVs using a placental alkaline phosphatase immunoassay. 5-tRFs and scrambled RNA controls were added to monocyte, macrophage and endothelial cells in culture to investigate transcriptional responses. Results5-tRFs constitute the majority of small RNA in STB-EVs from both preeclampsia and normal pregnancies. >900 small RNA fragments are differentially expressed in preeclampsia STB-EVs. Preeclampsia-dysregulated 5-tRFs are detectable in maternal plasma, where we identified a placentally-derived load. 5-tRF-Glu-CTC, the most abundant preeclampsia-upregulated 5-tRF in perfusion STB-EVs, is also increased in preeclampsia STB-EVs from maternal plasma. 5-tRF-Glu-CTC induced inflammation in macrophages but not monocytes. The conditioned media from 5-tRF-Glu-CTC-activated macrophages reduced eNOS expression in endothelial cells. ConclusionsIncreased release of syncytiotrophoblast-derived vesicle-bound 5-tRF-Glu-CTC contributes to preeclampsia pathophysiology.

molecular biology↗

bioRxiv2020

Applications of genetic-epigenetic tissue mapping for plasma DNA in prenatal testing, transplantation and oncology

We developed Genetic-Epigenetic Tissue Mapping (GETMap) to determine the tissue composition of plasma DNA carrying genetic variants not present in the constitutional genome through comparing their methylation profiles with relevant tissues. We validated this approach by showing that, in pregnant women, circulating DNA carrying fetal-specific alleles was entirely placenta-derived. In lung-transplant recipients, we showed that, at 72 hours after transplantation, the lung contributed only a median of 17% to the plasma DNA carrying donor-specific alleles and hematopoietic cells contributed a median of 78%. In hepatocellular cancer patients, the liver was identified as the predominant source of plasma DNA carrying tumor-specific mutations. In a pregnant woman with lymphoma, plasma DNA molecules carrying cancer mutations and fetal-specific alleles were accurately shown to be derived from the lymphocytes and placenta, respectively. Analysis of tissue origin for plasma DNA carrying genetic variants is potentially useful for noninvasive prenatal testing, transplantation monitoring and cancer screening.

physiology↗

bioRxiv2018

Regulatory T-cells are required for neonatal heart regeneration

Previous work has elegantly demonstrated that, unlike adult mammalian heart, the neonatal heart is able to regenerate after injury from postnatal day (P) 1 to 7. Recently, macrophages are found to be required in the repair process as depletion of which abolishes endogenous regenerative capability of the neonatal heart. Nevertheless, whether innate immunity alone is sufficient for neonatal heart regeneration is obscure. Here, we investigate a hitherto novel role of FOXP3+ regulatory T-cells (Treg) in neonatal heart regeneration. Unlike their wild type counterparts, NOD/SCID mice that are deficient for T-cells but innate immune cells including macrophages fail to regenerate their injured heart as early as P3. In wild type mice, both conventional CD4+ T-cells and Treg are recruited to cardiac muscle within the first week after injury. Treatment with the lytic anti-CD4 antibody that specifically depletes conventional CD4+ T-cells leads to reduced cardiac fibrosis; while treatment with the lytic anti-CD25 antibody that specifically depletes CD4+CD25hiFOXP3+ Treg contributes to increased fibrosis of the neonatal heart after injury. Moreover, adoptive transfer of Treg to NOD/SCID mice results in mitigated fibrosis and increased proliferation and function of cardiac muscle of the neonatal heart after injury. Mechanistically, single cell transcriptomic profiling reveals that Treg are a source of chemokines and cytokines that attract monocytes and macrophages previously known to drive neonatal heart regeneration. Furthermore, Treg directly promote proliferation of both mouse and human cardiomyocytes in a paracrine manner. Our findings uncover an unappreciated mechanism in neonatal heart regeneration; and offer new avenues for developing novel therapeutics targeting Treg-mediated heart regeneration.

developmental biology↗