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Multilineage communication regulates human liver bud self-organization from pluripotency I

ABSTRACT: Conventional 2-D differentiation from pluripotency fails to recapitulate cell interactions occurring during organogenesis. 3-D organoids generate complex organ-like tissues, however it is unclear how heterotypic interactions impact lineage identity. Here we use single-cell RNA-seq to reconstruct hepatocyte-like lineage progression from pluripotency in 2-D culture. We then derive 3-D liver bud (LB) organoids by reconstituting hepatic, stromal, and endothelial interactions, and deconstruct heterogeneity during LB self-organization. We find that LB hepatoblasts differentiate towards hepatocyte fate, and in addition express epithelial migration signatures characteristic of organ budding. We identify hypoxia and inflammation signatures in endothelial and mesenchymal cells, which we suggest induce LB vasculogenesis. We use network analysis to predict autocrine and paracrine signaling in LBs, and show that VEGF crosstalk potentiates endothelial network formation and hepatoblast differentiation. Our molecular dissection reveals inter-lineage communication that is required for self-organization, and illuminates previously inaccessible aspects of human organ development and regeneration.

ORGANISM(S): Homo sapiens

PROVIDER: GSE81252 | GEO | 2017/02/08

SECONDARY ACCESSION(S): PRJNA322308

REPOSITORIES: GEO

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Multilineage communication regulates human liver bud self-organization from pluripotency II

Project description:Conventional 2-D differentiation from pluripotency fails to recapitulate cell interactions occurring during organogenesis. 3-D organoids generate complex organ-like tissues, however it is unclear how heterotypic interactions impact lineage identity. Here we use single-cell RNA-seq to reconstruct hepatocyte-like lineage progression from pluripotency in 2-D culture. We then derive 3-D liver bud (LB) organoids by reconstituting hepatic, stromal, and endothelial interactions, and deconstruct heterogeneity during LB development. We find that LB hepatoblasts diverge from the 2-D lineage, and express epithelial migration signatures characteristic of organ budding. We benchmark 3-D LBs against fetal and adult human liver scRNA-seq data, and find a striking correspondence between the 3-D LB and fetal liver cells. We use a receptor-ligand pairing analysis and a high-throughput inhibitor assay to interrogate signaling in LBs, and show that VEGF crosstalk potentiates endothelial network formation and hepatoblast differentiation. Our molecular dissection reveals interlineage communication regulating organoid development, and illuminates previously inaccessible aspects of human liver development.

2017-06-21 | GSE96981 | GEO

Vascularised and functional human liver from an iPSC-derived organ bud transplant

Project description:Critical shortage of donor organs for treating end-stage organ failure highlights the urgent need for generating organs from induced pluripotent stem cells (hiPSCs). Despite many reports describing functional cell differentiation, no studies have succeeded in generating a three-dimensional vascularised organ such as liver. Here, we show the generation of vascularised and functional human liver from hiPSCs by transplantation of liver buds created in vitro (hiPSC-LBs). Specified hepatic cells self-organised into three-dimensional hiPSC-LBs by recapitulating organogenetic interactions between endothelial and mesenchymal cells. Immunostaining and gene expression analyses revealed resemblance between in vitro grown hiPSC-LBs and in vivo liver buds. Human vasculatures in hiPSC-LB transplants became functional by connecting to the host vessels within 48 hours. The formation of functional vasculatures stimulated the maturation of hiPSC-LBs into tissue resembling the adult liver. Highly metabolic hiPSC-derived tissue performed liver-specific functions such as protein production and human-specific drug metabolism without recipient liver replacement. Comparison of liver developmental gene signatures among hiPSC-LB, hFLC-LB, human adult (30 years old) liver tissues (hALT) and mouse liver tissue (mLT) of various developmental stages (E9.5~P8weeks).

2013-07-01 | E-GEOD-46631 | biostudies-arrayexpress

Vascularised and functional human liver from an iPSC-derived organ bud transplant

2013-07-01 | GSE46631 | GEO

Populus (P. tremula X tremuloides-'T89) Lipidbody proteome

Project description:Seed lipid bodies (LB), previously viewed as paradigmatic, possess a restricted proteome and serve carbon and energy storage. Albeit present in minute quantities, LBs are widespread in post-germinative tissues, where they display vigorous movement, mediate transient organellar interactions, and shuttle enzymes, and signaling molecules. Storage as well as motility and signaling are relevant in shoot meristems of woody perennials, which ahead of winter produce buds that like seeds establish dormancy, dehydrate, express OLEOSIN genes and accumulate LBs. Unlike seeds, buds do not completely desiccate and LBs retain potential signaling functions. Here, we mapped bud LB production under dormancy-inducing conditions. We found that over an 8-week period LBs enlarged significantly. Concomitantly, three major OLEOSIN family genes were transiently upregulated at the start of bud formation, while in their wake expression of lipid biosynthesis gene DGAT1a/b and lipase gene SDP1a/b increased. In parallel, LDAPa/b, LDAP2a, and LDAP3a/b were upregulated, especially LDAP1b. All LDAPs were localized to LBs. The conclusion that OLEOSINs were replaced by LDAPs was supported by the finding that PUX10a, PUX10b and CDC498A1, involved in OLESOSIN ubiquitination and degradation, were significantly upregulated. Our proteomic analysis identified 723 putative LB proteins. These included LB-anchored Caleosin and LDIP, peripherally associated LDAP1/3 and OBL1, and numerous proteins that reflect storage, transport, organellar interaction, opportunistic cargo and contaminants. There is a significant overlap with proteins identified earlier in plasmodesmal proteomes. Collectively, the data support a model in which LBs are part of a pre-installed mechanism that serves dormancy release, survival through winter and regrowth.

2021-06-29 | PXD020099 | Pride

Gene expression level changes during the formation of a-synuclein newly formed fibrils and their maturation into LB-like inclusions in a neuronal seeding model

Project description:Parkinson’s disease (PD) is characterized by the accumulation of misfolded and aggregated alpha-synuclein (α-syn) into intraneuronal inclusions named Lewy bodies (LB). Although it is widely believed that α-syn plays a central role in the pathogenesis of PD, the processes that govern α-syn fibrillization and LB formation remain poorly understood. In this work, we sought to dissect the spatiotemporal events involved in the biogenesis of the LBs at the genetic, molecular, biochemical, structural, and cellular levels. Towards this goal, we further developed a seeding-based model of α-syn fibrillization to generate a neuronal model that reproduces all the key events leading to LB formation; including seeding, fibrillization, and the formation of inclusions that recapitulate many of the biochemical, structural, and organizational features of bona fide LBs. Using an integrative omics, biochemical and imaging approach, we dissected the molecular events associated with the different stages of LB formation and their contribution to neuronal dysfunction and degeneration. In addition, we demonstrate that LB formation involves a complex interplay between α-syn fibrillization, post-translational modifications, and interactions between α-syn aggregates and membranous organelles, including mitochondria, the autophagosome and endolysosome. Finally, we show that the process of LB formation, rather than simply fibril formation, is the major driver of neurodegeneration through disruption of cellular functions and inducing mitochondria damage and deficits, and synaptic dysfunctions. We believe that this model represents a powerful platform to further investigate the mechanisms of LB formation and clearance and to screen and evaluate novel therapeutics targeting α-syn aggregation and LB formation.

2020-01-15 | GSE142416 | GEO

Temporal proteomic analyses of the protein contents found in the insoluble fraction of the a-synuclein PFF-treated neurons

2020-01-15 | PXD016850 | Pride

Use of Human Adult Stem Cell-Derived Organoid Cultures to Model Enterohepatic Circulation [Ileal organoids]

Project description:Organ to organ interactions have not yet been modeled with human organoid cultures. This work demonstrates the coupling of intestinal and liver organoids recapitulates aspects of enterohepatic bile signaling. The integration of organoids can be used to probe intra-organ interactions. Total RNA-Seq studies were performed in human ileal organoids to examine expression of bile acid signaling molecules.

2021-08-21 | GSE168005 | GEO

Use of Human Adult Stem Cell-Derived Organoid Cultures to Model Enterohepatic Circulation

Project description:Organ to organ interactions have not yet been modeled with human organoid cultures. This work demonstrates the coupling of intestinal and liver organoids recapitulates aspects of enterohepatic bile signaling. The integration of organoids can be used to probe intra-organ interactions. Single cell RNA-Seq studies were performed in human liver organoids to examine the heterogeneity of the cultures.

2021-07-28 | GSE166589 | GEO

Alteration of lipid homeostasis by hydroxypropyl cyclodextrin improves amiodarone-induced alveolar cell disorder

Project description:We developed LB cells overexpressing ABCA3, SFTPB, SFTPC, and SFTPD in A549 cells. Using LB cells in high content screening, we identified HPbCD. HPbCD improved amiodarone-induced LB abnormality in iPS cell-derived alveolar organoids.

2021-02-20 | GSE146612 | GEO

4DNESX5HHBRP - Replicate experiments of DNase Hi-C on RUES2 differentiated to mesoderm with DNaseI

Project description:Vascular endothelial cells are a mesoderm-derived lineage with many essential functions, including angiogenesis and coagulation. The gene-regulatory mechanisms underpinning endothelial specialization are largely unknown, as are the roles of chromatin organization in regulating endothelial cell transcription. To investigate the relationships between chromatin organization and gene expression, we induced endothelial cell differentiation from human pluripotent stem cells and performed Hi-C and RNA-sequencing assays at specific time points. Long-range intrachromosomal contacts increase over the course of differentiation, accompanied by widespread heteroeuchromatic compartment transitions that are tightly associated with transcription. Dynamic topologically associating domain boundaries strengthen and converge on an endothelial cell state, and function to regulate gene expression. Chromatin pairwise point interactions (DNA loops) increase in frequency during differentiation and are linked to the expression of genes essential to vascular biology. Chromatin dynamics guide transcription in endothelial cell development and promote the divergence of endothelial cells from cardiomyocytes.

2023-01-18 | GSE222307 | GEO

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