Biology subjects

Greulich, P.

Publications and source records attributed to Greulich, P..

6 recordsLinked to original sources

bioRxiv2024

Self-renewal without niche instruction, feedback or fine-tuning

To self-renew, stem cells must precisely balance proliferation and differentiation. Typically, this is achieved under feedback from the niche; yet many stem cells also possess an intrinsic self-renewal program that allows them to do so autonomously, as required. However, because self-renewal implies a stable equilibrium - in which the expected stem cell number neither increases nor decreases over time - this seems to require fine-tuning to a critical point. Here, we show that this is not the case: self-renewal can, in principle, be easily achieved without the need for extrinsic instruction, feedback or finetuning, by a simple dimerization cycle that uses partitioning errors at cell division to reliably establish asymmetric divisions and perfectly balance symmetric divisions.

cell biology↗

bioRxiv2024

Dynamic spatiotemporal activation of a pervasive neurogenic competence in striatal astrocytes supports continuous neurogenesis following injury

Adult brain neural stem cells (NSCs) are conventionally regarded as rare cells restricted to two niches: the subventricular zone (SVZ) and the subgranular zone. Parenchymal astrocytes can also contribute to neurogenesis after injury, however the prevalence, distribution, and behaviour of these latent NSCs remained elusive. To tackle these issues, we reconstructed the spatiotemporal pattern of striatal astrocytes neurogenic activation after excitotoxic lesion in mice. Our results indicate that a neurogenic potential is broadly distributed throughout the striatum but is focally activated at the lesion border. In this region, similarly to canonical niches, steady state neurogenesis is ensured by the continuous stochastic activation of local astrocytes. Activated astrocytes quickly return to quiescence, while their progeny locally proliferate for about 10 days following a stochastic behaviour that features an acceleration in differentiation propensity. Notably, striatal astrocytes activation rate matches that of SVZ astrocytes indicating a comparable prevalence of NSC potential.

neuroscience↗

bioRxiv2023

Emergent order in epithelial sheets by interplay of cell divisions and cell fate regulation

The fate choices of stem cells between self-renewal and differentiation are often tightly regulated by paracrine (cell-cell) signalling. Here, we assess how the interplay between cell division, differentiation, and short range paracrine signalling can affect the macroscopic ordering of cell types in self-renewing epithelial sheets, by studying a simple spatial cell fate model with cells being arranged on a 2D lattice. We show in this model that if cells commit to their fate directly upon cell division, macroscopic domains of cells of the same type emerge, if at least a small proportion of divisions are symmetric, except if signalling interactions are laterally inhibiting. In contrast, if cells are first licensed to differentiate, yet retaining the possibility to return to their naive state, macroscopic order only emerges if the signalling strength exceeds a critical threshold: if then the signalling interactions are laterally inducing, macroscopic domains emerge as well. Lateral inhibition, on the other hand, can in that case generate macroscopic patterns of alternating cell types (checkerboard pattern), yet only if the proportion of symmetric divisions is sufficiently low. These results can be understood theoretically by an analogy to phase transitions in spin systems known from statistical physics. Author summaryA fundamental question in stem cell biology is how a cells choice to differentiate or not (cell fate choices), is regulated through communication with other cells in a tissue, and whether these choices are a one-way path or to some degree reversible. However, measuring this in living animals is very difficult and often impossible, since this requires to make videos of cells inside the body with a microscope. Here, we employ a simple mathematical model for the fate choices of stem cells when they are regulated by communication with nearby cells in the tissue. We show that different means of cell fate choice and cell communication can lead to qualitatively different patterns of cell types: macroscopic domains, checkerboard patterns, or randomly disordered distributions, depending on the character of cell communication, and whether cell fate is one-way or reversible. Our analysis therefore shows that those aspects of stem cell activity, which are otherwise difficult to measure, can be distinguished by observing macroscopic patterns of cell types.

developmental biology↗

bioRxiv2022

Microglial colonisation of the developing brain is facilitated by clonal expansion of highly proliferative progenitors and follows an allometric scaling

Microglia are the resident immune cells of the brain and arise from yolk sac-derived macrophages during early embryogenesis. On entering the brain, microglia undergo in situ proliferation and eventually colonise the entire brain by the second and third postnatal weeks in mice. However, the intricate dynamics of their developmental expansion remain unclear. Here, we examine and characterise the proliferative dynamics of microglia during embryonic and postnatal development. Using complementary fate-mapping techniques, we demonstrate that the developmental colonisation of the brain by microglia is facilitated by clonal expansion of highly proliferative microglial progenitors that occupy spatial niches throughout the brain. We also find that the distribution of microglia switches from a clustered to a random pattern between embryonic and late postnatal development. Moreover, the developmental increase in microglia follows the proportional growth of the brain in an allometric manner with the density of microglia eventually stabilising when the mosaic distribution has been established. Overall, our findings offer insight into how the competition for space acts as a driving force for microglial colonisation by clonal expansion during development.

neuroscience↗

bioRxiv2020

Universality of clonal dynamics poses fundamental limits to identify stem cell self-renewal strategies

How adult stem cells maintain self-renewing tissues is in vivo commonly assessed by analysing clonal data from cell lineage tracing assays. To identify strategies of stem cell self-renewal requires that different models of stem cell fate choice predict sufficiently different clonal statistics. Here we show that models of cell fate choice can, in homeostatic tissues, be categorized by exactly two universality classes, whereby models of the same class predict, under asymptotic conditions, the same clonal statistics. Those classes relate to generalizations of the canonical asymmetric vs. symmetric stem cell self-renewal strategies and are differentiated by a conservation law. This poses both challenges and opportunities to identify stem cell self-renewal strategies: while under asymptotic conditions, self-renewal models of the same universality class cannot be distinguished by clonal data only, models of different classes can be distinguished by simple means.

systems biology↗

bioRxiv2018

Mathematical modelling reveals how MeCP2 restrains transcriptional elongation in human neurons

Patterns of gene expression are primarily determined by proteins that locally enhance or repress transcription. While many transcription factors target a restricted number of genes, others appear to modulate transcription levels globally. An example is MeCP2, an abundant methylated-DNA binding protein that is mutated in the neurological disorder Rett Syndrome. Despite much research, the molecular mechanism by which MeCP2 regulates gene expression is not fully resolved. Here we integrate quantitative, multi-dimensional experimental analysis and mathematical modelling to show that MeCP2 is a novel type of global transcriptional regulator whose binding to DNA creates "slow sites" in gene bodies. Waves of slowed-down RNA polymerase II formed behind these sites travel backward and indirectly affect initiation, reminiscent of defect-induced shock waves in non-equilibrium physics transport models. This mechanism differs from conventional gene regulation mechanisms, which often involve direct modulation of transcription initiation. Our findings uncover a genome-wide function of DNA methylation that may account for the reversibility of Rett syndrome in mice. Moreover, our combined theoretical and experimental approach provides a general method for understanding how global gene expression patterns are choreographed.

biophysics↗