Biology subjects

Treutlein, B.

Publications and source records attributed to Treutlein, B..

41 records · Page 3Linked to original sources

bioRxiv2020

Resolving brain organoid heterogeneity by mapping single cell genomic data to a spatial reference

Self-organizing tissues resembling brain regions grown in vitro from human stem cells (so-called organoids or spheroids) offer exciting possibilities to study human brain development, disease, and evolution. Brain organoids or spheroids are complex and can contain cells at various stages of differentiation from different brain structures. Single-cell genomic methods provide powerful approaches to explore cell composition, differentiation trajectories, gene regulation, and genetic perturbations in brain organoid systems. However, it remains a major challenge to understand the cellular heterogeneity observed within and between individual organoids. Here, we have developed a computational approach (VoxHunt) to assess brain organoid patterning, developmental state, and cell composition through systematic comparisons to three-dimensional in situ hybridization data from the Allen Brain Atlas. Cellular transcriptomes as well as accessible chromatin landscapes can be compared to spatial transcript patterns in the developing mammalian brain, which enables characterization and visualization of organoid cell compositions. VoxHunt will be useful to assess novel organoid engineering protocols and to annotate cell fates that emerge in organoids during genetic and environmental perturbation experiments.

bioinformatics↗

bioRxiv2019

Single-cell-resolution transcriptome map of human, chimpanzee, bonobo, and macaque brains

Identification of gene expression traits unique to the human brain sheds light on the mechanisms of human cognition. Here we searched for gene expression traits separating humans from other primates by analyzing 88,047 cell nuclei and 422 tissue samples representing 33 brain regions of humans, chimpanzees, bonobos, and macaques. We show that gene expression evolves rapidly within cell types, with more than two-thirds of cell type-specific differences not detected using conventional RNA sequencing of tissue samples. Neurons tend to evolve faster in all hominids, but non-neuronal cell types, such as astrocytes and oligodendrocyte progenitors, show more differences on the human lineage, including alterations of spatial distribution across neocortical layers.

evolutionary biology↗

bioRxiv2019

Single-cell genomic atlas of great ape cerebral organoids uncovers human-specific features of brain development

The human brain has changed dramatically since humans diverged from our closest living relatives, chimpanzees and the other great apes1-5. However, the genetic and developmental programs underlying this divergence are not fully understood6-8. Here, we have analyzed stem cell-derived cerebral organoids using single-cell transcriptomics (scRNA-seq) and accessible chromatin profiling (scATAC-seq) to explore gene regulatory changes that are specific to humans. We first analyze cell composition and reconstruct differentiation trajectories over the entire course of human cerebral organoid development from pluripotency, through neuroectoderm and neuroepithelial stages, followed by divergence into neuronal fates within the dorsal and ventral forebrain, midbrain and hindbrain regions. We find that brain region composition varies in organoids from different iPSC lines, yet regional gene expression patterns are largely reproducible across individuals. We then analyze chimpanzee and macaque cerebral organoids and find that human neuronal development proceeds at a delayed pace relative to the other two primates. Through pseudotemporal alignment of differentiation paths, we identify human-specific gene expression resolved to distinct cell states along progenitor to neuron lineages in the cortex. We find that chromatin accessibility is dynamic during cortex development, and identify instances of accessibility divergence between human and chimpanzee that correlate with human-specific gene expression and genetic change. Finally, we map human-specific expression in adult prefrontal cortex using single-nucleus RNA-seq and find developmental differences that persist into adulthood, as well as cell state-specific changes that occur exclusively in the adult brain. Our data provide a temporal cell atlas of great ape forebrain development, and illuminate dynamic gene regulatory features that are unique to humans.

developmental biology↗

bioRxiv2018

Basal stem cell fate specification is mediated by SMAD signaling in the developing human lung

Basal stem cells (basal cells), located in the bronchi and trachea of the human lung epithelium, play a critical role in normal airway homeostasis and repair, and have been implicated in the development of diseases such as cancer1-4. Additionally, basal-like cells contribute to alveolar regeneration and fibrosis following severe injury5-8. However, the developmental origin of basal cells in humans is unclear. Previous work has shown that specialized progenitor cells exist at the tips of epithelial tubes during lung branching morphogenesis, and in mice, give rise to all alveolar and airway lineages9,10. These bud tip progenitor cells have also been described in the developing human lung11-13, but the mechanisms controlling bud tip differentiation into specific cell lineages, including basal cells, are unknown. Here, we interrogated the bud tip-to-basal cell transition using human tissue specimens, bud tip progenitor organoid cultures11, and single-cell transcriptomics. We used single-cell mRNA sequencing (scRNAseq) of developing human lung specimens from 15-21 weeks gestation to identify molecular signatures and cell states in the developing human airway epithelium. We then inferred differentiation trajectories during bud tip-to-airway differentiation, which revealed a previously undescribed transitional cell state ( hub progenitors) and implicated SMAD signaling as a regulator of the bud tip-to-basal cell transition. We used bud tip progenitor organoids to show that TGFT1 and BMP4 mediated SMAD signaling robustly induced the transition into functional basal-like cells, and these in vitro-derived basal cells exhibited clonal expansion, self-renewal and multilineage differentiation. This work provides a framework for deducing and validating key regulators of cell fate decisions using single cell transcriptomics and human organoid models. Further, the identification of SMAD signaling as a critical regulator of newly born basal cells in the lung may have implications for regenerative medicine, basal cell development in other organs, and understanding basal cell misregulation in disease.

developmental biology↗

bioRxiv2018

Reconstructing complex lineage trees from scRNA-seq data using MERLoT

Advances in single-cell transcriptomics techniques are revolutionizing studies of cellular differentiation and heterogeneity. Consequently, it becomes possible to track the trajectory of thousands of genes across the cellular lineage trees that represent the temporal emergence of cell types during dynamic processes. However, reconstruction of cellular lineage trees with more than a few cell fates has proved challenging. We present MERLoT (https://github.com/soedinglab/merlot), a flexible and user-friendly tool to reconstruct complex lineage trees from single-cell transcriptomics data and further impute temporal gene expression profiles along the reconstructed tree structures. We demonstrate MERLoTs capabilities on various real cases and hundreds of simulated datasets.

bioinformatics↗