Computational Modelling of Nephron Progenitor Cell Movement and Aggregation during Kidney Organogenesis

AbstractDuring 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.

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Computational Modelling of Nephron Progenitor Cell Movement and Aggregation During Kidney Organogenesis

10.21203/rs.2.22766/v1 ◽

2020 ◽

Author(s):

Pauli Tikka ◽

Moritz Mercker ◽

Ilya Skovorodkin ◽

Ulla Saarela ◽

Seppo Vainio ◽

...

Keyword(s):

Cell Adhesion ◽

Potts Model ◽

Ex Vivo ◽

Computational Modelling ◽

Cell Movement ◽

Model Parameters ◽

Cellular Potts Model ◽

Kidney Organogenesis ◽

Nephron Progenitor ◽

Cell Cell

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Computational modelling of nephron progenitor cell movement and aggregation during kidney organogenesis

Mathematical Biosciences ◽

10.1016/j.mbs.2021.108759 ◽

2021 ◽

pp. 108759

Author(s):

Pauli Tikka ◽

Moritz Mercker ◽

Ilya Skovorodkin ◽

Ulla Saarela ◽

Seppo Vainio ◽

...

Keyword(s):

Progenitor Cell ◽

Computational Modelling ◽

Cell Movement ◽

Kidney Organogenesis ◽

Nephron Progenitor

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Mechanisms of endothelial cell coverage by pericytes: computational modelling of cell wrapping and in vitro experiments

Journal of The Royal Society Interface ◽

10.1098/rsif.2019.0739 ◽

2020 ◽

Vol 17 (162) ◽

pp. 20190739

Author(s):

Kei Sugihara ◽

Saori Sasaki ◽

Akiyoshi Uemura ◽

Satoru Kidoaki ◽

Takashi Miura

Keyword(s):

Cell Adhesion ◽

Three Dimensional ◽

Computational Modelling ◽

Cellular Level ◽

Cellular Potts Model ◽

Contributing Factors ◽

Modelling Framework ◽

Cell Cell

Pericytes (PCs) wrap around endothelial cells (ECs) and perform diverse functions in physiological and pathological processes. Although molecular interactions between ECs and PCs have been extensively studied, the morphological processes at the cellular level and their underlying mechanisms have remained elusive. In this study, using a simple cellular Potts model, we explored the mechanisms for EC wrapping by PCs. Based on the observed in vitro cell wrapping in three-dimensional PC–EC coculture, the model identified four putative contributing factors: preferential adhesion of PCs to the extracellular matrix (ECM), strong cell–cell adhesion, PC surface softness and larger PC size. While cell–cell adhesion can contribute to the prevention of cell segregation and the degree of cell wrapping, it cannot determine the orientation of cell wrapping alone. While atomic force microscopy revealed that PCs have a larger Young’s modulus than ECs, the experimental analyses supported preferential ECM adhesion and size asymmetry. We also formulated the corresponding energy minimization problem and numerically solved this problem for specific cases. These results give biological insights into the role of PC–ECM adhesion in PC coverage. The modelling framework presented here should also be applicable to other cell wrapping phenomena observed in vivo .

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Macrophages restrict the nephrogenic field and promote endothelial connections during kidney development

eLife ◽

10.7554/elife.43271 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 13

Author(s):

David AD Munro ◽

Yishay Wineberg ◽

Julia Tarnick ◽

Chris S Vink ◽

Zhuan Li ◽

...

Keyword(s):

Progenitor Cell ◽

Kidney Development ◽

Developmental Abnormalities ◽

Macrophage Depletion ◽

Cell Clearance ◽

Galectin 3 ◽

Kidney Organogenesis ◽

Developing Kidney ◽

Nephron Progenitor ◽

Renal Organogenesis

The origins and functions of kidney macrophages in the adult have been explored, but their roles during development remain largely unknown. Here we characterise macrophage arrival, localisation, heterogeneity, and functions during kidney organogenesis. Using genetic approaches to ablate macrophages, we identify a role for macrophages in nephron progenitor cell clearance as mouse kidney development begins. Throughout renal organogenesis, most kidney macrophages are perivascular and express F4/80 and CD206. These macrophages are enriched for mRNAs linked to developmental processes, such as blood vessel morphogenesis. Using antibody-mediated macrophage-depletion, we show macrophages support vascular anastomoses in cultured kidney explants. We also characterise a subpopulation of galectin-3+ (Gal3+) myeloid cells within the developing kidney. Our findings may stimulate research into macrophage-based therapies for renal developmental abnormalities and have implications for the generation of bioengineered kidney tissues.

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Branching morphogenesis in the developing kidney is not impacted by nephron formation or integration

eLife ◽

10.7554/elife.38992 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 7

Author(s):

Kieran M Short ◽

Alexander N Combes ◽

Valerie Lisnyak ◽

James G Lefevre ◽

Lynelle K Jones ◽

...

Keyword(s):

Progenitor Cell ◽

Kidney Development ◽

Developmental Process ◽

Branching Morphogenesis ◽

Ureteric Bud ◽

Collecting Ducts ◽

Developing Kidney ◽

Developmental Feature ◽

Nephron Progenitor ◽

The Impact

Branching morphogenesis of the ureteric bud is integral to kidney development; establishing the collecting ducts of the adult organ and driving organ expansion via peripheral interactions with nephron progenitor cells. A recent study suggested that termination of tip branching within the developing kidney involved stochastic exhaustion in response to nephron formation, with such a termination event representing a unifying developmental process evident in many organs. To examine this possibility, we have profiled the impact of nephron formation and maturation on elaboration of the ureteric bud during mouse kidney development. We find a distinct absence of random branch termination events within the kidney or evidence that nephrogenesis impacts the branching program or cell proliferation in either tip or progenitor cell niches. Instead, organogenesis proceeds in a manner indifferent to the development of these structures. Hence, stochastic cessation of branching is not a unifying developmental feature in all branching organs.

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Dicer function is required in the metanephric mesenchyme for early kidney development

AJP Renal Physiology ◽

10.1152/ajprenal.00426.2013 ◽

2014 ◽

Vol 306 (7) ◽

pp. F764-F772 ◽

Cited By ~ 25

Author(s):

Jessica Y. S. Chu ◽

Sunder Sims-Lucas ◽

Daniel S. Bushnell ◽

Andrew J. Bodnar ◽

Jordan A. Kreidberg ◽

...

Keyword(s):

Target Genes ◽

Kidney Development ◽

Metanephric Mesenchyme ◽

Ureteric Bud ◽

Rnase Iii ◽

Nephron Progenitors ◽

Proapoptotic Protein ◽

Kidney Organogenesis ◽

Regulatory Rnas ◽

Nephron Progenitor

MicroRNAs (miRNAs) are small, noncoding regulatory RNAs that act as posttranscriptional repressors by binding to the 3′-untranslated region (3′-UTR) of target genes. They require processing by Dicer, an RNase III enzyme, to become mature regulatory RNAs. Previous work from our laboratory revealed critical roles for miRNAs in nephron progenitors at midgestation (Ho J, Pandey P, Schatton T, Sims-Lucas S, Khalid M, Frank MH, Hartwig S, Kreidberg JA. J Am Soc Nephrol 22: 1053–1063, 2011). To interrogate roles for miRNAs in the early metanephric mesenchyme, which gives rise to nephron progenitors as well as the renal stroma during kidney development, we conditionally ablated Dicer function in this lineage. Despite normal ureteric bud outgrowth and condensation of the metanephric mesenchyme to form nephron progenitors, early loss of miRNAs in the metanephric mesenchyme resulted in severe renal dysgenesis. Nephron progenitors are initially correctly specified in the mutant kidneys, with normal expression of several transcription factors known to be critical in progenitors, including Six2, Pax2, Sall1, and Wt1. However, there is premature loss of the nephron progenitor marker Cited1, marked apoptosis, and increased expression of the proapoptotic protein Bim shortly after the initial inductive events in early kidney development. Subsequently, there is a failure in ureteric bud branching and nephron progenitor differentiation. Taken together, our data demonstrate a previously undetermined requirement for miRNAs during early kidney organogenesis and indicate a crucial role for miRNAs in regulating the survival of this lineage.

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Repulsive cues combined with physical barriers and cell–cell adhesion determine progenitor cell positioning during organogenesis

Nature Communications ◽

10.1038/ncomms11288 ◽

2016 ◽

Vol 7 (1) ◽

Cited By ~ 22

Author(s):

Azadeh Paksa ◽

Jan Bandemer ◽

Burkhard Hoeckendorf ◽

Nitzan Razin ◽

Katsiaryna Tarbashevich ◽

...

Keyword(s):

Cell Adhesion ◽

Progenitor Cell ◽

Physical Barriers ◽

Cell Positioning ◽

Cell Cell

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A Cellular Potts Model for Analyzing Cell Migration across Constraining Pillar Arrays

Axioms ◽

10.3390/axioms10010032 ◽

2021 ◽

Vol 10 (1) ◽

pp. 32

Author(s):

Marco Scianna ◽

Luigi Preziosi

Keyword(s):

Cell Migration ◽

Potts Model ◽

Large Fraction ◽

Cell Movement ◽

Stochastic Approach ◽

Cellular Potts Model ◽

Cell Dynamics ◽

Experimental Systems ◽

Pillar Arrays ◽

Constrained Environments

Cell migration in highly constrained environments is fundamental in a wide variety of physiological and pathological phenomena. In particular, it has been experimentally shown that the migratory capacity of most cell lines depends on their ability to transmigrate through narrow constrictions, which in turn relies on their deformation capacity. In this respect, the nucleus, which occupies a large fraction of the cell volume and is substantially stiffer than the surrounding cytoplasm, imposes a major obstacle. This aspect has also been investigated with the use of microfluidic devices formed by dozens of arrays of aligned polymeric pillars that limit the available space for cell movement. Such experimental systems, in particular, in the designs developed by the groups of Denais and of Davidson, were here reproduced with a tailored version of the Cellular Potts model, a grid-based stochastic approach where cell dynamics are established by a Metropolis algorithm for energy minimization. The proposed model allowed quantitatively analyzing selected cell migratory determinants (e.g., the cell and nuclear speed and deformation, and forces acting at the nuclear membrane) in the case of different experimental setups. Most of the numerical results show a remarkable agreement with the corresponding empirical data.

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