Biology subjects

Ronkainen, V.-P.

Publications and source records attributed to Ronkainen, V.-P..

3 recordsLinked to original sources

bioRxiv2021

Temporally and Spatially Regulated Collagen XVIII Isoforms Impact Ureteric Patterning Through Their TSP1-like Domain

Collagen XVIII (ColXVIII) is a component of the extracellular matrix implicated in embryogenesis and control of homeostasis. We provide evidence that ColXVIII has a specific role in kidney ontogenesis by regulating the interaction between mesenchymal and epithelial tissues as observed in analyses of total and isoform-specific knockout embryos, mice, and ex vivo organ primordia. ColXVIII deficiency, both temporally and spatially, impacts the 3D pattern of ureteric tree branching morphogenesis via its specific isoforms. Proper development of ureteric tree depends on a tight control of the nephron progenitor cells (NPCs). ColXVIII-deficient NPCs are leaving the NPC pool faster than in controls. Moreover, the data suggests that ColXVIII mediates the kidney epithelial tree patterning via its N-terminal domains, and especially the Thrombospondin-1-like domain, and that this morphogenetic effect involves ureteric epithelial integrins. Altogether, the results propose a significant role for ColXVIII in a complex signalling network regulating renal progenitors and kidney development.

developmental biology↗

bioRxiv2020

Computational Modelling of Cell Movements and Aggregations during Kidney Organogenesis

During early kidney organogenesis, nephron progenitor (NP) cells move from the tip to the corner region of the ureteric bud (UB) branches in order to form the pretubular aggregate, the early structure giving rise to nephron formation. Chemotaxis and cell-cell adhesion differences are believed to drive cell patterning during this critical period of organogenesis, but the spatiotemporal organization of this process is incompletely understood. We applied a Cellular Potts model to explore to how these processes contribute to directed cell movement and aggregation. Model parameters were estimated based on fitting to experimental data obtained in ex vivo kidney explant and dissociation-reaggregation organoid culture studies. Our simulations indicated that optimal enrichment and aggregation of NP cells in the UB corner niche requires chemoattractant secretion from both the UB epithelial cells and the NP cells themselves, as well as differences in cell-cell adhesion energies. Furthermore, NP cells were observed, both experimentally and by modelling, to move at higher speed in the UB corner as compared to the tip region where they originated. The existence of different cell speed domains along the UB was confirmed using self-organizing map analysis. In summary, we demonstrated the suitability of a Cellular Potts Model approach to simulate cell movement and patterning during early nephrogenesis. Further refinement of the model should allow us to recapitulate the effects of developmental changes of cell phenotypes and molecular crosstalk during organ development. Author SummaryThe emergence of tissue patterns during vertebrate development is a major interest of both experimental research and biocomputational modelling. In this study, we established a Cellular Potts Model to explore cellular processes during early kidney development. The goal was to elucidate movements and aggregations of nephron progenitor cells. These precursor cells derive from mesenchymal cells around the ureteric buds and eventually form the epithelial structure of the nephron. Moreover, we wanted to explore computationally the mechanisms how these cells segregate from metanephric mesenchyme and move towards the location where the nephron will be formed. Utilizing the Compucell3D simulation software, we developed a model which assumes that nephron progenitor movement and aggregation is governed by only two mechanisms, i.e. cell-cell adhesion differences between cell types and nephron progenitor cell chemotaxis in response to chemoattractant secretion from two sources. These sources were either the epithelial cells of a static ureteric bud and/or the nephron progenitor cells themselves. The simulations indicated faster average cell speeds near the ureteric bud corner, the target region of cell movement and aggregation, and slower speeds near the place of origin, the tip of ureteric bud. The results were validated by comparison of the model predictions with experimental data from two ex vivo embryonic kidney models and a computational optimization protocol.

systems biology↗

bioRxiv2019

Trisk95 as Novel Skin Mirror for Normal and Diabetic Systemic Glucose Level

Coping with diabetes requires frequent and even today mostly invasive blood glucose-based monitoring. Partly due to this invasive nature and the associated reduced skin wound healing and increased risk of infection, non-invasive glucose monitoring technologies would represent considerable progress. Edited keratinocytes may enable such a function.\n\nTo address this hypothesis, we conducted a proteomic screen in the skin by making use of the experimental in vivo mouse model of type I diabetes alongside controls. We identified Trisk 95 as the only protein whose expression is induced in response to high blood glucose. A luciferase reporter assay demonstrated that induction of Trisk 95 expression occurs not only at the protein level but also transcriptionally. This induction was associated with a marked elevation in the Fluo-4 signal, suggesting a role for intracellular calcium changes in the signalling cascade. Strikingly, these changes lead concurrently to fragmentation of the mitochondria. As judged from the knockout findings, both the calcium flux and the mitochondrial phenotype were dependent on Trisk 95 function, since the phenotypes in question were abolished.\n\nThe data demonstrate that the skin represents an organ that reacts robustly and thus mirrors changes in systemic blood glucose levels. The findings are also consistent with a channelling model of Trisk 95 that serves as an insulin-independent but glucose-responsive biomarker taking part in releasing calcium from the cellular stores in the skin. The skin cells may thus provide a novel mean for glucose monitoring when analysing changes in labelled Trisk 95 and calcium. By that, this study is the first proof of the concept of our registered patent (No. PCT FI2016/050917), which proposes the use of cells as biosensors for developing personalized health-monitoring devices.

cell biology↗