Single-cell trajectory inference guided enhancement of thyroid maturation<i>in vitro</i>using TGF-beta inhibition

Romitti, Mírian; Eski, Sema Elif; Fonseca, Bárbara F.; Singh, Sumeet; Costagliola, Sabine

doi:10.1101/2021.01.18.427103

Cited by 2 publications

(7 citation statements)

References 51 publications

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“…S3E • Rat pituitary (GSE132224) 37 , rat in Fig. S3E • Mouse thyroid organoids (GSE163818) 19 Normalisation, visualisation, and standard processing of datasets was done through Seurat 38 . For label transfer of mouse and rat pituitary datasets from the human pituitary reference: mouse and rat genes were first converted to their human homologs (as obtained via BioMart 39 ), and ambiguously annotated genes were filtered out, prior to cross-species integration.…”

Section: Single-cell Rna-seq Analysesmentioning

confidence: 99%

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Loss of function variant in SMIM1 is associated with reduced energy expenditure and weight gain

Frontini

Stefanucci

Moslemi

et al. 2022

Preprint

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Blood group antigens are the archetypal example of human genetic variation. Here, we characterised the functional metabolic consequences in individuals homozygous for a 17bp deletion in SMIM1 (rs566629828; minor allele frequency 0.0147) and thus lacking the protein defining the Vel blood group. Our analysis, in separate cohorts of SMIM1-/- individuals (UK Biobank, NHS Blood and Transplant, Danish Blood Donor Study, Copenhagen Hospital Biobank) and a mouse model, identified an increase in body weight accompanied by a range of metabolic differences, including dyslipidemia, changes in the leptin-adiponectin ratio, increased liver enzymes and lower total thyroid hormone levels. These changes in the metabolic state were at least in part due to a reduction in resting energy expenditure, as assessed during an in-depth clinical assessment of SMIM1-/- individuals. Additionally, electronic health records suggest that individuals lacking this 78-amino-acid type II transmembrane protein may be more prone to cerebral bleeds and thrombotic stroke.

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Section: Single-cell Rna-seq Analysesmentioning

confidence: 99%

“…S3C). Whilst, in human thyroid organoids and mouse thyroid 19 (GSE163818) low-level expression was detected mainly in thyrocytes and as yet uncharacterised Flt1-positive cells (Fig. S3C).…”

mentioning

confidence: 99%

Loss of function variant in SMIM1 is associated with reduced energy expenditure and weight gain

Frontini

Stefanucci

Moslemi

et al. 2022

Preprint

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“…Integrative single-cell RNAseq analysis: For better understanding of Foxe1KO effect, we compared Nkx2-1+ cells derived from Foxe1KO line with a previous scRNAseq dataset performed in a control mESC line (Romitti et al, 2021). For this, we extracted Nkx2-1+ cells from both datasets, combined in an unique object and calculated pairwise correspondences between individual cells using Integration features from R toolkit (Stuart et al, 2019).…”

Section: Iodide Organification Assaymentioning

confidence: 99%

“…In this line, transient overexpression of Nkx2-1 and Pax8, followed by 2weeks treatment with hTSH/ or c-AMP analogues, yields self-organized thyroid follicles that secrete T4 hormone in vitro with high efficiency (Antonica et al, 2012) (Figure 1A-B). In addition, differentiation efficiency can be visually assessed using an EGFP transgene inserted into the hypoxanthine phosphoribosyltransferase (HPRT) locus of mESC lines under the control of a bovine-responsive thyroglobulin (Tg) promoter (Romitti et al, 2021).…”

Section: Foxe1 Is Required For Thyroid Development In Vitromentioning

confidence: 99%

“…In the present work, we investigated the role of Foxe1 in the differentiation of thyroid lineage and asked whether Foxe1 absence can influence lineage decision of Nkx2-1+ progenitors in vitro. For this, we used our mESC-based model, in which thyroid differentiation is induced by Nkx2-1 and Pax8 transient overexpression and formation of functional thyroid follicle-like structures is obtained by recombinant TSH treatment (Antonica et al, 2012;Romitti et al, 2021). Here we show that, without Foxe1, Nkx2-1+ precursors fail to form polarized and mature thyroid follicular cells whereas a large subset of Nkx2-1+ cells are able to diverge to an alternative lineage pathway, giving rise to multiple lung cell types in vitro.…”

Section: Introductionmentioning

confidence: 99%

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Foxe1 orchestrates thyroid and lung cell lineage divergence in mouse stem cell-derived organoids

Fonseca

Barbée

Romitti

et al. 2022

Preprint

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SummaryPatterning of endoderm into lung and thyroid lineages depends upon a correct early expression of a homeobox domain-containing transcription factor, Nkx2-1. However, the gene networks distinguishing the differentiation of those lineages remain largely unknown. In the present work, by using mouse embryonic stem cell lines, single-cell RNA sequencing, and transcriptomic and chromatin accessibility profiling, we show that knockout of Foxe1 drastically impairs Nkx2-1+ cells differentiation and maturation into thyroid follicular-like cells. Concomitantly, a subset of Foxe1 null/Nkx2-1+ cells have a remarkable ability in vitro to undergo a lung epithelial differentiation program and form lung-like organoids harboring cells transcriptionally similar with mouse fetal airway and alveolar cell types. These results demonstrate, for the first time, lung lineage derivation at the expense of thyroid lineage, by a simple removal of a transcription factor, and provide insights into the intricated mechanisms of fate decisions of endodermal cell types.Highlights- Forward programming of mESCs with transient Nkx2-1 and Pax8 overexpression, followed by c-AMP treatment, leads to differentiation of functional thyroid follicles in vitro;- In absence of Foxe1, thyroid follicle-like structures, derived from mESCs, are scarce and non-functional;- Concomitantly, a subset of Nkx2-1-expressing cells generated from Foxe1KO mESCs spontaneously form lung organoids containing multiple differentiated lung cell types;- ATACseq analyses show higher chromatin remodeling in Nkx2-1-expressing cells in control compared to Foxe1KO cells, especially for genes involved in thyroid maturation and maintenance of the 3D structure of the follicle.

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Single-cell trajectory inference guided enhancement of thyroid maturationin vitrousing TGF-beta inhibition

Cited by 2 publications

References 51 publications

Loss of function variant in SMIM1 is associated with reduced energy expenditure and weight gain

Loss of function variant in SMIM1 is associated with reduced energy expenditure and weight gain

Foxe1 orchestrates thyroid and lung cell lineage divergence in mouse stem cell-derived organoids

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