Biology subjects

Stolper, J.

Publications and source records attributed to Stolper, J..

4 recordsLinked to original sources

bioRxiv2021

The human FLT1 regulatory element directs vascular expression and modulates angiogenesis pathways in vitro and in vivo

There is growing evidence that mutations in non-coding cis-regulatory elements (CREs) disrupt proper development. However, little is known about human CREs that are crucial for cardiovascular development. To address this, we bioinformatically identified cardiovascular CREs based on the occupancy of the CRE by the homeodomain protein NKX2-5 and cardiac chromatin histone modifications. This search defined a highly conserved CRE within the FLT1 locus termed enFLT1. We show that the human enFLT1 is an enhancer capable of driving reporter transgene expression in vivo throughout the developing cardiovascular system of medaka. Deletion of the human enFLT1 enhancer ({Delta}enFLT1) triggered molecular perturbations in extracellular matrix organisation and blood vessel morphogenesis in vitro in endothelial cells derived from human embryonic stem cells and vascular defects in vivo in medaka. These findings highlight the crucial role of the human FLT1 enhancer and its function as a regulator and buffer of transcriptional regulation in cardiovascular development.

genomics↗

bioRxiv2020

Identifying stem cell numbers and functional heterogeneities during post-embryonic organ growth

Uncovering the number of stem cells necessary to grow an organ has been challenging in most vertebrate systems. Here, we have developed a mathematical model that we use to characterise stem cells in the fish gill, an organ that displays non-exhaustive growth. Our work employs a Markov model, first stochastically simulated via an adapted Gillespie algorithm, and further improved by using probability theory. The stochastic algorithm produces a simulated data set for comparison with experimental data by inspecting quantifiable properties, while the analytical approach skips the step of in silico data generation and goes directly to the quantification, being more abstract and very efficient. By applying the model to a large clonal experimental dataset, we report that a reduced number of stem cells are responsible for growing and maintaining the fish gill. The model also highlights a functional heterogeneity among the stem cells involved, where activation and quiescence phases determine their relative growth contribution. Overall, our work presents an easy-to-apply algorithm to infer the number of stem cells functionally required in a life-long growing system.

systems biology↗

bioRxiv2018

Hierarchical stem cell topography splits growth and homeostatic functions in the fish gill

While lower vertebrates contain adult stem cells (aSCs) that maintain homeostasis and drive unexhaustive organismal growth, mammalian aSCs display mainly the homeostatic function. Understanding aSC-driven growth is of paramount importance to promote organ regeneration and prevent tumor formation in mammals. Here we present a clonal approach to address common or dedicated populations of aSCs for homeostasis and growth. Our functional assays on medaka gills demonstrate the existence of separate homeostatic and growth aSCs, which are clonal but differ in their topology. While homeostatic aSCs are fixed, embedded in the tissue, growth aSCs locate at the expanding peripheral zone. Modifications in tissue architecture can convert the homeostatic zone into a growth zone, indicating a leading role for the physical niche defining stem cell output. We hypothesize that physical niches are main players to restrict aSCs to a homeostatic function in animals with a fixed adult size.

developmental biology↗

bioRxiv2017

Neural stem cells induce the formation of their physical niche during organogenesis

Most organs rely on stem cells to maintain homeostasis during post-embryonic life. Typically, stem cells of independent lineages work coordinately within mature organs to ensure proper ratios of cell types. Little is known, however, on how these different stem cells locate to forming organs during development. Here we show that neuromasts of the posterior lateral line in medaka are composed of two independent life-long lineages with different embryonic origins. Clonal analysis and 4D imaging revealed a hierarchical organisation with instructing and responding roles: an inner, neural lineage induces the formation of an outer, border cell lineage (nBC) from the skin epithelium. Our results demonstrate that the neural lineage is necessary and sufficient to generate nBCs highlighting self-organisation principles at the level of the entire embryo. We hypothesise that transformation of surrounding tissues plays a major role during the establishment of vertebrate stem cell niches.

developmental biology↗