Biology subjects

Lye, S.

Publications and source records attributed to Lye, S..

3 recordsLinked to original sources

bioRxiv2026

Macrophage to Myocyte Mitochondrial Transfer in the Myometrium: A Novel Mechanism for the Initiation of Labor

Labor initiation involves influx of peripheral monocytes into uterine tissue, where they differentiate into macrophages (Macs) and polarize toward pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes. Crosstalk between uterine myocytes (MYO) and Macs is implicated in myometrial activation, but the underlying mechanisms remain unclear. Using immunofluorescence and live-cell imaging, we show that M1-Macs (but not M2-Macs) form tunneling nanotubes (TNT) with MYOs, enabling direct, unidirectional mitochondrial transfer. TNT-mediated mitochondrial transfer enhances ATP production and 20-HSD expression in MYO. Functionally, M1-Macs induce intracellular and functional progesterone (P4) withdrawal in MYOs via 20-HSD mediated P4 metabolism and increased PR-A phosphorylation. In vivo, transfer of monocytes, carrying dendra-labelled mitochondria in pregnant mice confirm their myometrial recruitment, differentiation, polarization to M1-Macs, and M1-Mac/MYO mitochondrial transfer. Increased M1-Macs and mitochondrial transfer to MYOs are observed before labor onset, implicating M1-Macs/MYO interaction as key regulator of labor initiation and potentially a therapeutic target to prevent preterm birth.

immunology↗

bioRxiv2026

A Broad-Spectrum Chemokine Inhibitor Prevents Preterm Labor in Mice by Supressing Inflammation Induced by Intra-Amniotic Injection of Interleukin-1 alpha

Preterm birth (PTB) is a leading cause of perinatal and infant mortality worldwide. PTB can be induced by systemic maternal or intra-uterine infection or by sterile intra-amniotic inflammation driven by alarmins such as interleukin-1 (IL-1). We reported earlier that a Broad-Spectrum Chemokine Inhibitor (BSCI) prevented PTB in murine and non-human primate models of infection-mediated preterm labor. Here, we investigated whether BSCI can prevent PTB in pregnant C57BL/6 mice following ultrasound-guided intra-amniotic injection of IL-1 (400 ng per sac) on gestational day (GD)16.5. Half the mice received BSCI (10 mg/kg, intravenous daily) beginning GD15.5 and through to term. The impact of IL-1 alone or IL-1 plus BSCI was assessed on (i) injection-to-delivery interval, fetal survival, placental and neonatal weight; (ii) cytokine and chemokine levels in maternal plasma and amniotic fluid and inflammatory gene expression in maternal and fetal tissues (Real-Time RT-qPCR); (iii) global transcriptomic profiling of myometrial tissues at 2 and 24 hrs (RNA sequencing) together with examination of myometrial chromatin accessibility (Assay for transposase accessible chromatin sequencing) at 24 hrs; (iv) uterine leukocyte infiltration (immunofluorescence). Pretreatment with BSCI i) prevented IL-1-induced PTB; (ii) significantly attenuated cytokine and chemokine signals in maternal plasma, myometrium, decidua, and placenta, and amniotic fluid; (iii) suppressed myometrial contraction-associated genes, including Nfkb1, Ptgs2, Akr1c18, and Gja1; (iv) prevented global IL-1-induced changes in myometrial gene expression and chromatin accessibility (v) reduced uterine macrophage (F4/80+) counts and prevented the increase in pro-inflammatory M1-like macrophages observed with IL-1-treatment. BSCI-treated dams that delivered at term had live pups with normal placental and fetal weight. Taken together, BSCI reduced the incidence of IL-1-mediated PTB and maintained uterine quiescence by suppressing uterine inflammation and genome-wide changes in labor gene expression and chromatin accessibility. BSCI represents a promising therapeutic approach for PTB prevention in high-risk pregnant women.

physiology↗

bioRxiv2019

MicroRNA-transcriptome networks in whole blood and monocytes of women undergoing preterm labor

Preterm birth is attributed to neonatal morbidity as well as cognitive and physiological challenges. We have previously identified significant differences in mRNA expression in whole blood and monocytes, as well as differences in miRNA concentration in blood plasma, extracellular vesicles (EV) and EV-depleted plasma in women undergoing spontaneous preterm labor (sPTL). The goal of this analysis was to identify differences in miRNA expression within whole blood (WB) and peripheral monocytes (PM) from the same population of women undergoing sPTL compared to nonlaboring controls matched by gestational age. We performed single end small RNA sequencing in whole blood and peripheral monocytes from women undergoing sPTL with active contractions(24-34 weeks of gestation, N=15) matched for gestational age to healthy pregnant non laboring controls (>37 weeks gestation, N=30) who later delivered at term as a part of the Ontario Birth Study (Toronto, Ontario CA). We identified significant differences in expression of 16 miRNAs in PMs and 9 miRNAs in WB in women undergoing sPTL. In PMs, these miRNAs were predicted targets of 541 genes, including 28 previously associated with sPTL. In WB, miRNAs were predicted to target 303 genes, including 9 previously associated with sPTL. These genes were involved in a variety of immune pathways, including interleukin 2 signaling. This study is the first to identify changes in miRNA expression in WB and PMs of women undergoing sPTL. Our results shed light on potential mechanisms by which miRNAs may play a role in mediating systemic inflammatory response in pregnant women that deliver prematurely.

systems biology↗