Dataset Information

Insulin-producing β-cells regenerate ectopically from a mesodermal origin under the perturbation of hemato-endothelial specification.

ABSTRACT: To investigate the role of the vasculature in pancreatic β-cell regeneration, we crossed a zebrafish β-cell ablation model into the avascular npas4l mutant (i.e. cloche). Surprisingly, β-cell regeneration increased markedly in npas4l mutants owing to the ectopic differentiation of β-cells in the mesenchyme, a phenotype not previously reported in any models. The ectopic β-cells expressed endocrine markers of pancreatic β-cells, and also responded to glucose with increased calcium influx. Through lineage tracing, we determined that the vast majority of these ectopic β-cells has a mesodermal origin. Notably, ectopic β-cells were found in npas4l mutants as well as following knockdown of the endothelial/myeloid determinant Etsrp. Together, these data indicate that under the perturbation of endothelial/myeloid specification, mesodermal cells possess a remarkable plasticity enabling them to form β-cells, which are normally endodermal in origin. Understanding the restriction of this differentiation plasticity will help exploit an alternative source for β-cell regeneration.

SUBMITTER: Liu KC

PROVIDER: S-EPMC8370765 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Insulin-producing β-cells regenerate ectopically from a mesodermal origin under the perturbation of hemato-endothelial specification.

Liu Ka-Cheuk KC Villasenor Alethia A Bertuzzi Maria M Schmitner Nicole N Radros Niki N Rautio Linn L Mattonet Kenny K Matsuoka Ryota L RL Reischauer Sven S Stainier Didier Yr DY Andersson Olov O

eLife 20210817

To investigate the role of the vasculature in pancreatic β-cell regeneration, we crossed a zebrafish β-cell ablation model into the avascular npas4l mutant (i.e. cloche). Surprisingly, β-cell regeneration increased markedly in npas4l mutants owing to the ectopic differentiation of β-cells in the mesenchyme, a phenotype not previously reported in any models. The ectopic β-cells expressed endocrine markers of pancreatic β-cells, and also responded to glucose with increased cal ...[more]

PMID: 34403334

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Project description:The MLL-AF4 fusion gene is a hallmark genomic aberration in high-risk acute lymphoblastic leukemia in infants. Although it is well-established that MLL-AF4 arises pre-natally during human development, its effects on hematopoietic development in utero remains unexplored. We have created a human-specific in vitro system to study early hemato-endothelial development in MLL-AF4-expressing human embryonic stem cells (hESCs). Differentiation and functional studies as well as clonal analyses and gene expression profiling reveal that expression of MLL-AF4 in hESCs has a phenotypic, functional and gene expression impact. It enhances the specification of hemogenic precursors from hESCs and impairs further hematopoietic commitment of these precursors in favour of the endothelial cell fate. Similar to that reported in cord blood CD34+ hematopoietic stem/progenitor cells (HSPCs), MLL-AF4 expression is not sufficient to transform hESC-derived hematopoietic cells in vitro or in vivo, indicating that additional events may be required to initiate leukemogenesis or that embryonic hematopoiesis is not the appropriate human cellular target for MLL-AF4-mediated leukemogenesis. This work illustrates how hESCs can provide unique insights into human development and further our understanding of how leukemic fusion genes known to arise pre-natally regulate human embryonic hematopoietic specification. MLL is involved in transcriptional regulation and most MLL translocations appear to result in increased expression of Hox genes and hematopoietic genes. We therefore assessed the impact of MLL-AF4 expression on the transcriptome of hESCs. Gene expression profiling performed in MLL-AF4 hESCs revealed that MLL-AF4 preferentially activates transcription. 1826 out of the 3001 genes (61%) expressed were up-regulated in MLL-AF4 hESCs. Human ESC samples were collected during the exponential cell growth phase and stabilized in RNA later. 500 ng of each total RNA sample was labelled with Cy3 using the Quick-Amp Labelling kit and hybridized with the Gene Expression Hybridization kit to a Whole Human Genome Oligo Microarray (Agilent Technologies) following the Manufacturer’s instructions. Each cell line was analyzed as independent duplicates. NEO-expressing (empty lentivector) hESC line was used as the baseline.

Dataset Information

Insulin-producing β-cells regenerate ectopically from a mesodermal origin under the perturbation of hemato-endothelial specification.

Publications

Insulin-producing β-cells regenerate ectopically from a mesodermal origin under the perturbation of hemato-endothelial specification.

Similar Datasets

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