Biology subjects

Pedroza, A.

Publications and source records attributed to Pedroza, A..

3 recordsLinked to original sources

bioRxiv2024

A cell and transcriptome atlas of the human arterial vasculature

Contiguous arterial segments show different propensities for different vascular pathologies, yet mechanisms explaining these fundamental differences remain unknown. We sought to build a transcriptomic, cellular, and spatial atlas of human arterial cells across multiple different arterial segments to understand these underlying differences. Analysis of multiple isogenic arterial segments from healthy donors reveals a significant stereotyped pattern of cell type-specific segmental heterogeneity in healthy arteries. Combining single cell analysis with spatial transcriptomic data reveals cellular heterogeneity not captured by commonly used cell-type marker genes. Determinants of arterial transcriptomic identities are predominantly encoded in fibroblasts and smooth muscle cells (SMC), and their differentially expressed genes are particularly enriched for different vascular disease-associated genetic risk- loci and risk-genes. Adventitial fibroblast-specific heterogeneity in gene expression coincides with a disproportionally large number of vascular disease genetic signals, suggesting a previously unrecognized role for this cell type in disease risk. Adult arterial cells from different segments cluster not by anatomical proximity, but by embryonic origin. Global regulon analysis of disease related segment-specific gene expression program in fibroblast and SMC enriches for binding sites of transcription factors that are developmental master regulators whose expression persists into adulthood, suggesting an important functional role of the same developmental master regulators in adult gene expression and disease. Lastly, non-coding transcriptomes across arterial cells contain extensive variation in lncRNAs expressed in cell type- and segment-specific patterns, rivaling heterogeneity in protein coding transcriptomes. Differentially expressed LncRNA demonstrate enrichment for non-coding genetic signals for vascular diseases, suggesting a potential global role of segmental specific LncRNAs in regulating inherited human vascular disease risk.

cell biology↗

bioRxiv2021

Non-canonical Wnt/Ror2 signaling status regulates cell-matrix crosstalk to prompt directional tumor cell invasion and dissemination in breast cancer

Bidirectional cell-extracellular matrix (ECM) interactions represent fundamental exchanges during tumor progression. We demonstrate the noncanonical Wnt receptor, Ror2, regulates tumor cell-driven matrix remodeling in models of breast cancer. Wnt/Ror2 loss-of-function triggers tumor cell invasion, accompanied by changes in actin cytoskeleton, adhesion, and collagen crosslinking gene expression programs. E-cadherin levels decline upon Ror2 depletion, and spatially, we pinpoint the upregulation and redistribution of 5 and {beta}3 integrins together with the production of fibronectin in areas of invasion. Wnt/{beta}-catenin-dependent and Wnt/Ror2 alternative Wnt signaling appear to regulate distinct functions for tumor cells regarding their ability to modify cell-ECM exchanges during invasion. Furthermore, blocking either integrin or focal adhesion kinase (FAK), a downstream mediator of integrin-mediated signal transduction, abrogates the enhanced migration observed upon Ror2 loss. These results reveal a critical function for the alternative Wnt receptor, Ror2, as a determinant of reciprocal communication between tumor cells and ECM during cancer invasion and metastasis.

cancer biology↗

bioRxiv2020

Smad3 Regulates Smooth Muscle Cell Fate and Governs Adverse Remodeling and Calcification of Atherosclerotic Plaque

Atherosclerotic plaques consist mostly of smooth muscle cells (SMC), and genes that influence SMC biology can modulate coronary artery disease (CAD) risk. Allelic variation at 15q22.33 has been identified by genome-wide association studies to modify the risk of CAD, and is associated with expression of SMAD3 in SMC, but the mechanism by which this gene modifies CAD risk remains poorly understood. SMC-specific deletion of Smad3 in a murine atherosclerosis model resulted in greater plaque burden, positive remodeling, and increased vascular calcification. Single-cell transcriptomic analyses revealed that loss of Smad3 altered SMC progeny phenotype toward the previously described chondromyocyte fate, but importantly also promoted transition to a novel cell-state that governs remodeling and recruitment of inflammatory cells. This new remodeling population was marked by uniquely high Mmp3 and Cxcl12 expression, and its appearance correlated with higher-risk plaque features such as increased positive remodeling and macrophage content. Further, investigation of transcriptional mechanisms by which Smad3 alters SMC cell-fate revealed novel roles for Hox and Sox transcription factors whose direct interaction with Smad3 regulate an extensive transcriptional program balancing remodeling and vascular ECM with significant implications for human Mendelian aortic aneurysmal diseases. Together, these data suggest that Smad3 expression in SMC inhibits the emergence of specific SMC phenotypic transition cells that mediate adverse plaque features, including positive remodeling, monocyte recruitment, and vascular calcification.

cell biology↗