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Generation of organized anterior foregut epithelia from pluripotent stem cells using small molecules

ABSTRACT: Anterior foregut endoderm (AFE) gives rise to many tissue types of interest for therapeutic research including the esophagus, salivary glands, lung, thymus, parathyroid and thyroid. Despite its importance, only few reports describe the generation of AFE from pluripotent stem cells (PSCs) by directed differentiation. Here, we describe a novel protocol to derive a subdomain of AFE, identified by expression of Pax9, from PSCs using small molecules and chemically defined conditions. Generation of a reporter PSC line allows isolation and characterization of Pax9+ AFE cells. When transplanted in vivo, Pax9+ AFE can form several distinct types of complex anterior foregut epithelia including mucosal glands and stratified squamous epithelium. Finally, we show that the directed differentiation protocol can be used to generate AFE from DiGeorge Syndrome patient-specific human induced PSCs, thus creating a platform to produce anterior foregut derivatives for therapy and to enable the study of disorders of the AFE.

ORGANISM(S): Mus musculus

PROVIDER: GSE42139 | GEO | 2013/04/15

SECONDARY ACCESSION(S): PRJNA179199

REPOSITORIES: GEO

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Generation of organized anterior foregut epithelia from pluripotent stem cells using small molecules

Project description:Anterior foregut endoderm (AFE) gives rise to many tissue types of interest for therapeutic research including the esophagus, salivary glands, lung, thymus, parathyroid and thyroid. Despite its importance, only few reports describe the generation of AFE from pluripotent stem cells (PSCs) by directed differentiation. Here, we describe a novel protocol to derive a subdomain of AFE, identified by expression of Pax9, from PSCs using small molecules and chemically defined conditions. Generation of a reporter PSC line allows isolation and characterization of Pax9+ AFE cells. When transplanted in vivo, Pax9+ AFE can form several distinct types of complex anterior foregut epithelia including mucosal glands and stratified squamous epithelium. Finally, we show that the directed differentiation protocol can be used to generate AFE from DiGeorge Syndrome patient-specific human induced PSCs, thus creating a platform to produce anterior foregut derivatives for therapy and to enable the study of disorders of the AFE. Total RNA obtained from FACS purified from in vitro dervied mouse definitive endoderm, anterior foregut and ES cells. AFE cells were derived from a 129X1/SvJ background, DE cells from 129X1/SvJ x 129S1/SV-+p+Tyr- cKitlSl-J/+ (R1 ES cells) and non reporter ES cells from a 129P2/OlaHsd background.

2013-04-15 | E-GEOD-42139 | biostudies-arrayexpress

Thyroid progenitors are robustly derived from embryonic stem cells through transient, developmental stage-specific overexpression of Nkx2-1

Project description:The clinical importance of anterior foregut endoderm (AFE) derivatives, such as thyrocytes, has led to intense research efforts for their derivation through directed differentiation of pluripotent stem cells (PSCs). Here we identify transient overexpression of the transcription factor (TF) NKX2-1 as a powerful inductive signal for the robust derivation of thyrocyte-like cells from mouse PSC-derived AFE. This effect is highly developmental stage-specific and dependent upon FOXA2 expression levels and precise modulation of BMP and FGF signaling. The majority of the resulting cells express thyroid TFs (Nkx2-1, Pax8, Foxe1, Hhex) and thyroid hormone synthesis-related genes (Tg, Tpo, Nis, Iyd) at levels similar to adult mouse thyroid and give rise to functional follicle-like epithelial structures in Matrigel culture. Our findings demonstrate that NKX2-1 overexpression converts AFE to thyroid epithelium in a developmental time-sensitive manner and suggest a general methodology for manipulation of cell fate decisions of developmental intermediates.

2016-12-20 | GSE92572 | GEO

A distal lung organoid model to study interstitial lung disease, viral infection and human lung development.

Project description:Organoid models have been one of the most exciting advancements in stem cell research of the past decade. Here we describe a strategy for directed differentiation of human pluripotent stem cells into distal lung organoids that can be used to model interstitial lung disease, viral infection and human endoderm and lung development. This protocol entails five stages that recapitulate lung development. hPSCs are sequentially specified to definitive endoderm, anterior foregut endoderm, ventral anterior foregut endoderm, lung bud organoids, and finally branching lung organoids that can be maintained, while progressively maturing up to the a stage consistent with the second trimester of human gestation, for more than 180 days. This protocol is conducted in defined, serum-free conditions and does not require lineage-specific reporters or cell purification. We also provide a protocol for the generation of single cell suspensions for single cell RNAseq, and for clearing and 3D light sheet fluorescence imaging.

2023-10-17 | GSE215825 | GEO

Human heart-forming organoids recapitulate early heart and foregut development - microarray data

Project description:Organoid models of early tissue development have been produced for the intestine, brain, kidney and other organs, but similar approaches for the heart have been lacking. Here we generate complex, highly structured, three-dimensional heart-forming organoids (HFOs) by embedding human pluripotent stem cell aggregates in Matrigel followed by directed cardiac differentiation via biphasic WNT pathway modulation with small molecules. HFOs are composed of a myocardial layer lined by endocardial-like cells and surrounded by septum-transversum-like anlagen; they further contain spatially and molecularly distinct anterior versus posterior foregut endoderm tissues and a vascular network. The architecture of HFOs closely resembles aspects of early native heart anlagen before heart tube formation, which is known to require an interplay with foregut endoderm development. We apply HFOs to study genetic defects in vitro by demonstrating that NKX2.5-knockout HFOs show a phenotype reminiscent of cardiac malformations previously observed in transgenic mice.

2020-12-17 | GSE150051 | GEO

Human heart-forming organoids recapitulate early heart and foregut development - single-cell RNA sequencing data

2020-12-17 | GSE150202 | GEO

Genes induced in Xenopus foregut endoderm by mesoderm

Project description:Foregut organogenesis is regulated by inductive interactions between the endoderm and the adjacent mesoderm. We identified genes induced in the foregut progenitors by the adjacent mesoderm. We used microarrays to detail the global programme of early foregut endoderm gene expression resulting from mesoderm induction and identified distinct classes of up-regulated genes during this process. Xenopus foregut endoderm explants cultured from Stages 15 to 23 either intact with mesoderm or as endoderm alone. Total RNA was isolated from the endoderm of these two culture conditions in quadruplicate and were subjected to Affymetrix microarray analysis.

2012-06-11 | E-GEOD-38654 | biostudies-arrayexpress

Genes induced in Xenopus foregut endoderm by mesoderm

2012-06-12 | GSE38654 | GEO

Gene expression profile of adult Drosophila foregut

Project description:Adult Drosophila foregut contains a diverse set of tissue and cell types. We applied single cell RNA sequencing (scRNA-seq) and bulk RNA sequencing (bulk RNA-seq) to delineate the cellular composition and molecular profile of the foregut and its associated physiological functions.

2024-03-05 | GSE243037 | GEO

Characterization of the mid-foregut transcriptome identifies genes regulated during lung bud induction.

Project description:To identify genes expressed during initiation of lung organogenesis, we generated transcriptional profiles of the prospective lung region of the mouse foregut (mid-foregut) microdissected from embryos at three developmental stages between embryonic day 8.5 (E8.5) and E9.5. This period spans from lung specification of foregut cells to the emergence of the primary lung buds. We identified a number of known and novel genes that are temporally regulated as the lung bud forms. Genes that regulate transcription, including DNA binding factors, co-factors, and chromatin remodeling genes, are the main functional groups that change during lung bud formation. Members of key developmental transcription and growth factor families, not previously described to participate in lung organogenesis, are expressed in the mid-foregut during lung bud induction. These studies also show early expression in the mid-foregut of genes that participate in later stages of lung development. This characterization of the mid-foregut transcriptome provides new insights into molecular events leading to lung organogenesis. Three samples (developmental stages), three biological replicates (5-10 pooled mid-foreguts)

2010-01-14 | E-GEOD-19873 | biostudies-arrayexpress

Characterization of the mid-foregut transcriptome identifies genes regulated during lung bud induction.

2010-01-14 | GSE19873 | GEO

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