Universal prediction of cell-cycle position using transfer learning.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadBackground: The cell cycle is a highly conserved, continuous process which controls faithful replication and division of cells. Single-cell technologies have enabled increasingly precise measurements of the cell cycle both as a biological process of interest and as a possible confounding factor. Despite its importance and conservation, there is no universally applicable approach to infer position in the cell cycle with high-resolution from single-cell RNA-seq data. Results: Here, we present tricycle, an R/Bioconductor package, to address this challenge by leveraging key features of the biology of the cell cycle, the mathematical properties of principal component analysis of periodic functions, and the use of transfer learning. We estimate a cell-cycle embedding using a fixed reference dataset and project new data into this reference embedding, an approach that overcomes key limitations of learning a dataset-dependent embedding. Tricycle then predicts a cell-specific position in the cell cycle based on the data projection. The accuracy of tricycle compares favorably to gold-standard experimental assays, which generally require specialized measurements in specifically constructed in vitro systems. Using internal controls which are available for any dataset, we show that tricycle predictions generalize to datasets with multiple cell types, across tissues, species, and even sequencing assays. Conclusions: Tricycle generalizes across datasets and is highly scalable and applicable to atlas-level single-cell RNA-seq data. Keywords: Cell cycle; Single-cell RNA-sequencing; Transfer learning.Chan Zuckerberg Initiative DAF Silicon Valley Community Foundation United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of General Medical Sciences (NIGMS) Appeared in source as:National Institute of General Medical Sciences of the National Institutes of Health National Science Foundation (NSF) National Institute of Agin Maryland Stem Cell Research Foundation Kavli Neurodiscovery Institute Johns Hopkins Provost Award Program BRAIN Initiative United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of Neurological Disorders & Stroke (NINDS) Appeared in source as:National Institute of Neurological Disorder

Age-associated changes in lineage composition of the enteric nervous system regulate gut health and disease

The enteric nervous system (ENS), a collection of neural cells contained in the wall of the gut, is of fundamental importance to gastrointestinal and systemic health. According to the prevailing paradigm, the ENS arises from progenitor cells migrating from the neural crest and remains largely unchanged thereafter. Here, we show that the lineage composition of maturing ENS changes with time, with a decline in the canonical lineage of neural-crest derived neurons and their replacement by a newly identified lineage of mesoderm-derived neurons. Single cell transcriptomics and immunochemical approaches establish a distinct expression profile of mesoderm-derived neurons. The dynamic balance between the proportions of neurons from these two different lineages in the post-natal gut is dependent on the availability of their respective trophic signals, GDNF-RET and HGF-MET. With increasing age, the mesoderm-derived neurons become the dominant form of neurons in the ENS, a change associated with significant functional effects on intestinal motility which can be reversed by GDNF supplementation. Transcriptomic analyses of human gut tissues show reduced GDNF-RET signaling in patients with intestinal dysmotility which is associated with reduction in neural crest-derived neuronal markers and concomitant increase in transcriptional patterns specific to mesoderm-derived neurons. Normal intestinal function in the adult gastrointestinal tract therefore appears to require an optimal balance between these two distinct lineages within the ENS