GEO Logo
   NCBI > GEO > Accession DisplayHelp Not logged in | LoginHelp
GEO help: Mouse over screen elements for information.
Series GSE207889 Query DataSets for GSE207889
Status Public on Oct 02, 2023
Title Stem cell-derived human liver organoids to model the progression of inflammatory and fibrotic injury in non-alcoholic fatty liver disease
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary Chronic liver injury promotes fibrosis, which can progress to cirrhosis, a major cause of morbidity and mortality worldwide. Resolving the cell-type-specific transcriptional changes orchestrating this transformation remains challenging. Recent advances in differentiation protocols allow the generation of multi-lineage human liver organoids (HLOs) from human pluripotent stem cells (hPSCs), providing a new model system to study evolving liver injury. We differentiated hPSCs into HLOs and defined optimal 3D culture conditions for liver injury induction. We modeled steatohepatitis through treatment with palmitic acid (PA) and fibrotic injury through treatment with transforming growth factor beta 1 (TGF-β1). For each injury type, we evaluated the development of fibrosis and inflammation by monitoring changes in morphology, gene expression, and histology. We then performed single-cell RNA-sequencing (scRNA-seq) to investigate cell-type diversity in healthy organoids at different time-points and to understand how TGF-β1- and PA-mediated injury affects each cell type. We observed transcriptional response signatures in injured HLOs to be both cell-type- and injury-specific. TGF-β1 treatment expanded hepatic stellate cell (HSC)-like populations and remodeled cell-cycle patterning. Gene set scoring revealed increased fibroblast activity with TGF-β1 treatment, while PA treatment was associated with inflammatory activity. Differential gene expression analysis at the subpopulation level showed induced profibrotic and extracellular matrix-remodeling pathways with TGF-β1 and non-alcoholic fatty liver disease (NAFLD) expression signatures with PA treatment. Evaluation of receptor and ligand expression defined hepatocyte-, cholangiocyte-, and HSC-like cell-cell interactions induced upon TGF-β1 treatment, an effect not observed with PA treatment. Tracing the changes at receptor-ligand pair resolution revealed specific COL1A1-Integrin complex interactions with TGF-β1 treatment and inflammation-specific interactions including CXCR7 and HLA-C with PA treatment. Treatment of HLOs with PA and TGF-β1 also demonstrated a sequential increase in expression of gene sets that predict clinical disease progression in non-alcoholic steatohepatitis (NASH). Our results demonstrate the applicability of hPSC-derived HLOs as a dynamic in vitro 3D human liver model system for the study of fibrotic and inflammatory liver injury.
Overall design hPSC-derived HLOs cultured on an orbital shaker (OS) were stimulated with TGF-β1 (10 ng/ml) or PA (500 µM) for five days and subjected to scRNAseq at day 25. Additionally, naive (untreated) HLOs cultured on ultra-low attachment (ULA) plates were analyzed by scRNAseq at day 21 and day 34 of the differentiation protocol.
Contributor(s) Hess A, Gentile SD, Rahman RU, Mullen AC
Citation(s) 37962490
Submission date Jul 11, 2022
Last update date Jan 02, 2024
Contact name Alan C. Mullen
Organization name Massachusetts General Hospital
Department Department of Medicine
Street address 55 Fruit St.
City Boston
State/province MA
ZIP/Postal code 02135
Country USA
Platforms (2)
GPL24676 Illumina NovaSeq 6000 (Homo sapiens)
GPL30173 NextSeq 2000 (Homo sapiens)
Samples (19)
GSM6322568 Day 21 ULA-HLOs, replicate 1, scRNAseq
GSM6322569 Day 21 ULA-HLOs, replicate 2, scRNAseq
GSM6322570 Day 21 ULA-HLOs, replicate 3, scRNAseq
BioProject PRJNA857590

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE207889_GEO_supplementary_files.xlsx 9.1 Kb (ftp)(http) XLSX
GSE207889_RAW.tar 1.1 Gb (http)(custom) TAR (of MTX, TSV)
GSE207889_day21.h5ad.gz 184.2 Mb (ftp)(http) H5AD
GSE207889_masld-hlos_merged.h5ad.gz 613.9 Mb (ftp)(http) H5AD
GSE207889_os.h5ad.gz 652.5 Mb (ftp)(http) H5AD
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

| NLM | NIH | GEO Help | Disclaimer | Accessibility |
NCBI Home NCBI Search NCBI SiteMap