Biology subjects

Roostalu, U.

Publications and source records attributed to Roostalu, U..

5 recordsLinked to original sources

bioRxiv2026

Circulating soluble urokinase-type plasminogen activator receptor reflects disease severity in a mouse model of diabetic kidney disease and heart failure with preserved ejection fraction

Circulating biomarkers are increasingly used for patient risk stratification in chronic kidney disease (CKD) and heart failure with preserved ejection fraction (HFpEF). However, clinically relevant circulating biomarkers remain insufficiently characterized in rodent models recapitulating diabetic cardiorenal disease with HFpEF. To address this gap, we evaluated 20 translationally relevant inflammation-associated biomarkers in the diabetic db/db uninephrectomized (UNx)-ReninAAV mouse model of CKD and HFpEF. db/db UNx-ReninAAV mice exhibited marked increases in circulating soluble urokinase-type plasminogen activator receptor (suPAR) and monocyte chemoattractant protein-1 (MCP-1), and in interleukin 10 (IL-10) at late stages of disease. Histological analyses confirmed increased tissue expression of suPAR in the heart and kidney and of MCP-1 in the heart. Notably, circulating suPAR levels correlated with disease severity, including systolic and diastolic cardiac dysfunction and albuminuria. Together, these results provide a systematic analysis of biomarkers in a rodent model of diabetes, CKD and HFpEF and identify suPAR as the biomarker most closely associated with disease severity.

physiology↗

bioRxiv2025

Deep Learning-Enhanced Light Sheet Microscopy Unveils Semaglutide Impact on Cardiac Fibrosis

BackgroundExtensive preclinical research aims to develop novel therapeutics for myocardial fibrosis (MF), a condition marked by collagen accumulation that impairs cardiac function. MF is particularly relevant in heart failure with preserved ejection fraction (HFpEF), a growing clinical challenge with limited treatment options. However, current methods for quantifying MF in mouse models struggle to accurately capture its heterogeneous regional distribution, creating a significant barrier to reliably assessing the efficacy of therapeutics. PurposeTo develop a whole-heart fibrosis imaging and deep learning (DL)-based quantification method and validate the workflow by assessing the efficacy of a glucagon-like peptide-1 receptor (GLP-1R) agonist in mouse HFpEF model. Experimental ApproachBy utilizing a fluorescent collagen-labelling dye, tissue clearing and 3D light sheet microscopy, we developed a high-throughput imaging platform for MF. We established DL framework to quantify perivascular and replacement fibrosis, as well as hypertrophy, in 17 left ventricular (LV) segments. The antifibrotic effects of the GLP-1R agonist semaglutide were evaluated in the db/db UNx-ReninAAV mouse model, which exhibits diabetes, kidney failure, obesity, and hypertension. Key ResultsWhole-heart 3D light sheet microscopy, combined with artificial intelligence, enables micrometer-resolution analysis of MF distribution in rodents. This approach allows for detailed characterization of distinct regional fibrosis patterns. Chronic semaglutide treatment significantly reduced LV hypertrophy and perivascular fibrosis but had no significant effect on replacement fibrosis. Conclusions and ImplicationsThe established 3D imaging and quantification approach provides a powerful tool for evaluating the therapeutic efficacy of antifibrotic compounds and studying the cellular and pathological mechanisms underlying cardiovascular diseases.

pathology↗

bioRxiv2022

Whole-Brain Three-Dimensional Imaging of RNAs at Single-Cell Resolution

Whole-brain three-dimensional (3D) imaging is desirable to obtain a comprehensive and unbiased view of architecture and neural circuitry. However, current spatial analytic methods for brain RNAs are limited to thin sections or small samples. Here, we combined multiple new techniques to develop TRIC-DISCO, a new pipeline that allows imaging of RNA spatial distributions in whole adult mouse brains. First, we developed Tris-mediated retention of in situ hybridization signal during clearing (TRIC), which produces highly transparent tissue while maintaining the RNA signal intensities. We then combined TRIC with DISCO clearing (TRIC-DISCO) by controlling temperature during the in situ hybridization chain reaction (isHCR) to ensure uniform whole-brain staining. This pipeline eliminates the requirements for both strict RNase-free environments and workflow-compatible RNase inhibitors. Our TRIC-DISCO pipeline enables simple and robust, single-cell, whole-brain, 3D imaging of transcriptional signatures, cell-identity markers, and noncoding RNAs across the entire brain.

neuroscience↗

bioRxiv2019

TNAP limits TGF-β-dependent cardiac and skeletal muscle fibrosis by inactivating SMAD2/3 transcription factors

Fibrosis is associated with almost all forms of chronic cardiac and skeletal muscle diseases. The accumulation of extracellular matrix impairs the contractility of muscle cells contributing to organ failure. Transforming growth factor beta (TGF-{beta}) plays a pivotal role in fibrosis, activating pro-fibrotic gene programs via phosphorylation of SMAD2/3 transcription factors. However, the mechanisms that control de-phosphorylation of SMAD2/3 have remained poorly characterized. Here we show that tissue non-specific alkaline phosphatase (TNAP) is highly upregulated in hypertrophic hearts and in dystrophic skeletal muscles, and the abrogation of TGF-{beta} signalling in TNAP positive cells reduces vascular and interstitial fibrosis. We show that TNAP co-localizes and interacts with SMAD2. TNAP inhibitor MLS-0038949 increases SMAD2/3 phosphorylation, while TNAP overexpression reduces SMAD2/3 phosphorylation and the expression of downstream fibrotic genes. Overall our data demonstrate that TNAP negatively regulates TGF-{beta} signalling and likely represents a mechanism to limit fibrosis.\n\nSummary statementThis paper shows that tissue non-specific alkaline phosphatase negatively regulates TGF-{beta} signalling and may represent a mechanism to limit fibrosis through SMAD dephosphorylation.

cell biology↗

bioRxiv2017

MCAM controls cell autonomous polarity in myogenic and chondrogenic differentiation

Cell polarity has a fundamental role in shaping the morphology of cells and growing tissues. Polarity is commonly thought to be established in response to extracellular signals. Here we used a minimal in vitro assay that enabled us to monitor the determination of cell polarity in myogenic and chondrogenic differentiation in the absence of external signalling gradients. We demonstrate that the initiation of cell polarity is regulated by melanoma cell adhesion molecule (MCAM). We found highly polarized localization of MCAM, Moesin (MSN), Scribble (SCRIB) and Van-Gogh-like 2 (VANGL2) at the distal end of elongating myotubes. Knockout of MCAM or elimination of its endocytosis motif does not impair the initiation of myogenesis or myoblast fusion, but prevents myotube elongation. MSN, SCRIB and VANGL2 remain uniformly distributed in MCAM knockout cells. We show that MCAM is also required at early stages of chondrogenic differentiation. In both myogenic and chondrogenic differentiation MCAM knockout leads to transcriptional downregulation of Scrib and enhanced MAP kinase activity. Our data demonstrates the importance of cell autonomous polarity in differentiation.

cell biology↗