Biology subjects

Teixeira, J. M.

Publications and source records attributed to Teixeira, J. M..

5 recordsLinked to original sources

bioRxiv2026

Endometrial Hyperplasia Risk Is Increased by High-Fat Diet Via Estrogen-Driven Stromal Fibroblast Reprogramming Toward a Pro-Fibrotic State

The uterine endometrium is capable of scarless regeneration under coordinated estrogen and progesterone signaling across the menstrual cycle. Obesity suppresses progesterone production, leading to chronic estrogen exposure and increased endometrial hyperplasia (EH) risk. To define how obesity alters endometrial cell states, endometrial tissues from control and EH-predisposed mice fed either a control diet or a high-fat diet (HFD) were analyzed by single-cell RNA sequencing and tissue phenotyping. HFD reprogrammed endometrial stroma towards an inflammatory, pro-fibrotic state, reducing progesterone receptor-network-associated Aldh1a2+ fibroblasts and expanding estrogen receptor-network-associated Gsn fibroblasts. HFD further impaired macrophage recruitment and promoted hyperplastic epithelial signatures, consistent with increased disease severity in an EH mouse model. Stromal deletion of Estrogen Receptor established stromal estrogen signaling as a driver of HFD-induced extracellular matrix (ECM) accumulation. Collectively, these findings identify HFD-driven fibroblast reprogramming as a central mechanism linking estrogen dominance to stromal fibrosis, defective immune clearance, and heightened EH susceptibility. We propose that, in response to progesterone, fibroblast-mediated ECM remodeling is vital to normal endometrial homeostasis. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=161 SRC="FIGDIR/small/713224v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@1f79ceborg.highwire.dtl.DTLVardef@15f128aorg.highwire.dtl.DTLVardef@ba5604org.highwire.dtl.DTLVardef@16543dc_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO HFD-induced estrogen dominance disrupts endometrial fibroblast homeostasis to predispose the endometrium to diseaseThis study demonstrates that HFD drives estrogen-dependent reprogramming of stromal fibroblasts, characterized by inflammation, stromal ECM accumulation and fibrosis, and a post-ovulatory shift from PGR-network-associated Aldh1a2+ Fibroblasts toward increasing ER-network-associated Gsn+ Fibroblasts. These fibroblast changes are accompanied by a reduction in endometrial macrophages and a transcriptomic shift of HFD epithelium toward hyperplastic epithelium seen in a mouse model of EH. Figure made with BioRender. C_FIG

physiology↗

bioRxiv2024

Unraveling the Molecular Landscape of Uterine Fibroids, Insights into HMGA2 and Stem Cell Involvement

Uterine fibroids are prevalent benign tumors in women that exhibit considerable heterogeneity in clinical presentation and molecular characteristics, necessitating a deeper understanding of their etiology and pathogenesis. HMGA2 overexpression has been associated with fibroid development, yet its precise role remains elusive. Mutations in fibroids are mutually exclusive and largely clonal, suggesting that tumors originate from a single mutant cell. We explored a possible role for HMGA2 overexpression in differentiated myometrial cells, hypothesizing its potential to induce a stem cell-like or dedifferentiating phenotype and drive fibroid development. Myometrial cells were immortalized and transduced with an HMGA2 lentivirus to produce HMGA2hi cells. In vitro stem cell assays were conducted and RNA from HMGA2hi and control cells and fibroid-free myometrial and HMGA2 fibroid (HMGA2F) tissues were submitted for RNA-sequencing. HMGA2hi cells have enhanced self-renewal capacity, decreased proliferation, and have a greater ability to differentiate into other mesenchymal cell types. HMGA2hi cells exhibit a stem cell-like signature and share transcriptomic similarities with HMGA2F. Moreover, dysregulated extracellular matrix pathways are observed in both HMGA2hi cells and HMGA2F. Our findings suggest that HMGA2 overexpression drives myometrial cells to dedifferentiate into a more plastic phenotype and underscore a pivotal role for HMGA2 in fibroid pathogenesis.

molecular biology↗

bioRxiv2023

Cysteine-Rich Intestinal Protein 1 is a Novel Surface Marker for Myometrial Stem/Progenitor Cells.

Myometrial stem/progenitor cells (MyoSPCs) have been proposed as the cells of origin for uterine fibroids, which are benign tumors that develop in the myometrium of most reproductive age women, but the identity of the MyoSPC has not been well established. We previously identified SUSD2 as a possible MyoSPC marker, but the relatively poor enrichment in stem cell characteristics of SUSD2+ over SUSD2- cells compelled us to find better discerning markers for more rigorous downstream analyses. We combined bulk RNA-seq of SUSD2+/- cells with single cell RNA-seq to identify markers capable of further enriching for MyoSPCs. We observed seven distinct cell clusters within the myometrium, with the vascular myocyte cluster most highly enriched for MyoSPC characteristics and markers, including SUSD2. CRIP1 expression was found highly upregulated in both techniques and was used as a marker to sort CRIP1+/PECAM1- cells that were both enriched for colony forming potential and able to differentiate into mesenchymal lineages, suggesting that CRIP1+/PECAM1- cells could be used to better study the etiology of uterine fibroids.

developmental biology↗

bioRxiv2020

Insights on cross-species transmission of SARS-CoV-2 from structural modeling

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the ongoing global pandemic that has infected more than 14 million people in more than 180 countries worldwide. Like other coronaviruses, SARS-CoV-2 is thought to have been transmitted to humans from wild animals. Given the scale and widespread geographical distribution of the current pandemic, the question emerges whether human-to-animal transmission is possible and if so, which animal species are most at risk. Here, we investigated the structural properties of several ACE2 orthologs bound to the SARS-CoV-2 spike protein. We found that species known not to be susceptible to SARS-CoV-2 infection have non-conservative mutations in several ACE2 amino acid residues that disrupt key polar and charged contacts with the viral spike protein. Our models also predict affinity-enhancing mutations that could be used to design ACE2 variants for therapeutic purposes. Finally, our study provides a blueprint for modeling viral-host protein interactions and highlights several important considerations when designing these computational studies and analyzing their results.

bioinformatics↗

bioRxiv2018

Integrated epigenome, exome and transcriptome analyses reveal molecular subtypes and homeotic transformation in uterine fibroids.

Uterine fibroids are benign myometrial smooth muscle tumors of unknown etiology that when symptomatic are the most common indication for hysterectomy in the USA. We conducted an integrated analysis of fibroids and adjacent normal myometria by whole exome sequencing, Infinium MethylationEPIC array, and RNA-sequencing. Unsupervised clustering by DNA methylation segregated normal myometria from fibroids, and further separated the fibroids into subtypes marked by MED12 mutation, HMGA2 activation (HMGA2hi) and HMGA1 activation (HMGA1hi). Upregulation of HMGA2 expression in HMGA2hi fibroids did not always appear to be dependent on translocation, as has been historically described, and was associated with hypomethylation in the HMGA2 gene body. Furthermore, we found that expression of HOXA13 was highly upregulated in fibroids and that overexpression of HOXA13 in a myometrial cell line induced expression of genes classically associated with uterine fibroids. Transcriptome analyses of the most differentially expressed genes between cervix and myometrium also showed that uterine fibroids and normal cervix clustered together and apart from normal myometria. Together, our integrated analysis shows a role for epigenetic modification in fibroid biology and strongly suggests that homeotic transformation of myometrium cells to a more cervical phenotype is important for the etiology of the disease.

physiology↗