Tracing the roots of cardiac fibrosis: role of endothelial-to-mesenchymal transition
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PGRMC2 is a pressure-volume regulator critical for myocardial responses to stress in mice
Progesterone receptors are classified into nuclear and membrane-bound receptor families. Previous unbiased proteomic studies indicate a potential association between cardiac diseases and the progesterone receptor membrane-bound component-2 (PGRMC2); however, the role of PGRMC2 in the heart remains unknown. In this study, we use a heart-specific knockout (KO) mouse model (MyH6•Pgrmc2flox/flox) in which the Pgrmc2 gene was selectively deleted in cardiomyocytes. Here we show that PGRMC2 serves as a mediator of steroid hormones for rapid calcium signaling in cardiomyocytes to maintain cardiac contraction, sufficient stroke volume, and adequate cardiac output by regulating the cardiac pressure-volume relationship. The KO hearts from male and female mice exhibit an impairment in pressure-volume relationship. Under hypoxic conditions, this pressure-volume dysregulation progresses to congestive left and right ventricular failure in the KO hearts. Overall, we propose that PGRMC2 is a cardiac pressure-volume regulator to maintain normal cardiac physiology, especially during hypoxic stress.
Conserved immunomodulation and variation in host association by Xanthomonadales commensals in Arabidopsis root microbiota
Suppression of chronic Arabidopsis immune responses is a widespread but typically strain-specific trait across the major bacterial lineages of the plant microbiota. We show by phylogenetic analysis and in planta associations with representative strains that immunomodulation is a highly conserved, ancestral trait across Xanthomonadales, and preceded specialization of some of these bacteria as host-adapted pathogens. Rhodanobacter R179 activates immune responses, yet root transcriptomics suggest this commensal evades host immune perception upon prolonged association. R179 camouflage likely results from combined activities of two transporter complexes (dssAB) and the selective elimination of immunogenic peptides derived from all partners. The ability of R179 to mask itself and other commensals from the plant immune system is consistent with a convergence of distinct root transcriptomes triggered by immunosuppressive or non-suppressive synthetic microbiota upon R179 co-inoculation. Immunomodulation through dssAB provided R179 with a competitive advantage in synthetic communities in the root compartment. We propose that extensive immunomodulation by Xanthomonadales is related to their adaptation to terrestrial habitats and might have contributed to variation in strain-specific root association, which together accounts for their prominent role in plant microbiota establishment.
Endothelial senescence induced by PAI-1 promotes endometrial fibrosis
Intrauterine adhesions (IUAs), also known as Asherman’s syndrome (AS), represent a significant cause of uterine infertility for which effective treatment remains elusive. The endometrium’s ability to regenerate cyclically depends heavily on the growth and regression of its blood vessels. However, trauma to the endometrial basal layer can disrupt the subepithelial capillary plexus, impeding regeneration. This damage results in the replacement of native cells with fibroblasts and myofibroblasts, ultimately leading to fibrosis. Endothelial cells (ECs) play a pivotal role in the vascular system, extending beyond their traditional barrier function. Through single-cell sequencing and experimental validation, we discovered that ECs undergo senescence in IUA patients, impairing angiogenesis and fostering stromal cell fibrosis. Further analysis revealed significant interactions between ECs and PAI-1+ stromal cells. PAI-1, derived from stromal cells, promotes EC senescence via the urokinase-type plasminogen activator receptor (uPAR). Notably, prior to fibrosis onset, TGF-β upregulates PAI-1 expression in stromal cells in a SMAD dependent manner. In an IUA mouse model, inhibiting PAI-1 mitigated EC senescence and endometrial fibrosis. Our findings underscore the crucial role of EC senescence in IUA pathogenesis, contributing to vascular reduction and fibrosis. Targeting PAI-1 represents a promising therapeutic strategy to suppress EC senescence and alleviate endometrial fibrosis, offering new insights into the treatment of IUAs.
Iron homeostasis and ferroptosis in muscle diseases and disorders: mechanisms and therapeutic prospects
The muscular system plays a critical role in the human body by governing skeletal movement, cardiovascular function, and the activities of digestive organs. Additionally, muscle tissues serve an endocrine function by secreting myogenic cytokines, thereby regulating metabolism throughout the entire body. Maintaining muscle function requires iron homeostasis. Recent studies suggest that disruptions in iron metabolism and ferroptosis, a form of iron-dependent cell death, are essential contributors to the progression of a wide range of muscle diseases and disorders, including sarcopenia, cardiomyopathy, and amyotrophic lateral sclerosis. Thus, a comprehensive overview of the mechanisms regulating iron metabolism and ferroptosis in these conditions is crucial for identifying potential therapeutic targets and developing new strategies for disease treatment and/or prevention. This review aims to summarize recent advances in understanding the molecular mechanisms underlying ferroptosis in the context of muscle injury, as well as associated muscle diseases and disorders. Moreover, we discuss potential targets within the ferroptosis pathway and possible strategies for managing muscle disorders. Finally, we shed new light on current limitations and future prospects for therapeutic interventions targeting ferroptosis.
Pancreatic organogenesis mapped through space and time
The spatial organization of cells within a tissue is dictated throughout dynamic developmental processes. We sought to understand whether cells geometrically coordinate with one another throughout development to achieve their organization. The pancreas is a complex cellular organ with a particular spatial organization. Signals from the mesenchyme, neurons, and endothelial cells instruct epithelial cell differentiation during pancreatic development. To understand the cellular diversity and spatial organization of the developing pancreatic niche, we mapped the spatial relationships between single cells over time. We found that four transcriptionally unique subtypes of mesenchyme in the developing pancreas spatially coordinate throughout development, with each subtype at fixed locations in space and time in relation to other cells, including beta cells, vasculature, and epithelial cells. Our work provides insight into the mechanisms of pancreatic development by showing that cells are organized in a space and time manner.
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