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Complexity and tumor potential of human embryonic sympatho-adrenal area including neural crest and mesodermal derivatives

ABSTRACT: We addressed heterogeneity of neural crest- and mesoderm-derived lineages developing into adrenal glands, kidneys, endothelium and hematopoietic tissue for understanding transitions, integration and tumor-initiating states between week 6 and 14 of human development. We identified new transitions connecting intermediate mesoderm and progenitors of organ primordia, hematopoietic system and endothelial subtypes. Unexpectedly, we revealed that in humans, contrary to mice, nerve-associated Schwann cell precursors give rise to highly-proliferative sympathoblasts within adrenal gland, which in turn could transit into neuroendocrine chromaffin cells. The analysis of cell state signatures in relation to survival curves of patients suggested Schwann cell precursor-derived sympathoadrenal subtypes as origin for different neuroblastoma tumors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE147821 | GEO | 2021/01/14

REPOSITORIES: GEO

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Developmental heterogeneity of embryonic neuroendocrine chromaffin cells and their maturation dynamics

Project description:During embryonic development, nerve-associated Schwann cell precursors (SCPs) give rise to chromaffin cells of the adrenal gland via the “bridge” transient stage, according to recent functional experiments and single cell data from humans and mice. However, currently existing data do not resolve the finest heterogeneity of developing chromaffin populations. Here we took advantage of deep SmartSeq2 transcriptomic sequencing to expand our collection of individual cells from developing murine sympatho-adrenal anlage and uncover the microheterogeneity of embryonic chromaffin cells and corresponding developmental paths. After improving our atlas of sympatho-adrenal development and performing experimental validations, we discovered that SCPs in the local nerve show high degree of microheterogeneity corresponding to early biases towards either Schwann or chromaffin terminal fates. Furthermore, we found that a post-“bridge” population of developing chromaffin cells gives rise to persisting immature chromaffin cells and the two terminal populations (adrenergic and noradrenergic) via diverging differentiation paths. Taken together, we provide a thorough identification of novel markers of adrenergic and noradrenergic populations in developing adrenal glands and report novel differentiation micro-paths leading to them.

2022-05-27 | GSE204700 | GEO

RNA-seq transcriptomic analysis of mouse sympathetic neuroblasts and adrenal chromaffin cells

Project description:Adrenal chromaffin cells and sympathetic neuron are derived from neural crest precursors and both cell types can give rise to childhood cancer, neuroblastoma. However only limited is known about the mechanism of their development. Better understanding of their transcriptomic profiles during development could gives an insight into the cell fates acquisition as well as the origin of neuroblastoma. Yellow fluorescent protein expressing sympathetic neuroblasts and adrenal chromaffin cells were isolated from E12.5 TH-IRES-Cre;ROSA26-EYFP mouse embryos by fluorescence-activated cell sorting. Transcriptomic profiles of sympathetic neuroblasts and adrenal chromaffin cells from embryonic age (E)12.5 TH-IRES-Cre;ROSA26-EYFP mice were generated by RNA sequencing, in four paired biological replicates.

2019-05-24 | E-MTAB-7086 | biostudies-arrayexpress

11q deletion or ALK activity curbs DLG2 expression to maintain an undifferentiated state in neuroblastoma.

Project description:High-risk 11q deleted neuroblastomas (NBs) typically display an undifferentiated/poorly differentiated morphology. NB is thought to develop from Schwann cell precursors (SCPs) and un-differentiated neural crest derived cells (NCC). It is therefore vital to understand the mechanisms involved in the block of differentiation. We showed that an important and novel role for oncogenic ALK-ERK1/2-SP1 signaling may be the maintenance of an undifferentiated state of transformed NC-derived progenitors that is achieved by repression of DLG2, a tumor suppressor in NB. DLG2 is expressed in the ‘bridge signature’ that represents the transcriptional transition state when neural crest cells or Schwann Cell Precursors (SCP) become chromaffin cells of the adrenal gland. The importance of SP1 and DLG2 in this process is highlighted by our findings that restoring DLG2 expression spontaneously drives NB differentiation. Further, genetic analysis of high-risk 11q deletion NB patient identified genetic lesions in the DLG2 gene, Our data also suggest that further exploration of other ‘bridge genes’ may help to better understand the mechanisms underlying the differentiation of NC-derived progenitors and their contribution to NB.

2020-11-25 | PXD017946 | Pride

Multipotent Peripheral Glial Cells Generate Neuroendocrine Cells of the Adrenal Medulla

Project description:Cells producing adrenalin are largely derived from nerve-associated Schwann cell precursors via an intermediate progenitor “bridge” cell. We demonstrate that large numbers of chromaffin cells arise from peripheral glial stem cells, termed Schwann cell precursors (SCPs)

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The T-box Transcription Factor Eomesodermin Governs Hemogenic Competence of Yolk Sac Mesodermal Progenitors [ChIP-Seq]

Project description:Extra-embryonic mesoderm (ExM), the earliest cells that traverse through the primitive streak, give rise to the endothelium as well as hematopoietic progenitors in the developing yolk-sac (YS). How a specific subset of ExM becomes committed to a hematopoietic fate remains unclear. Here we report that Eomesodermin (Eomes), a T-box transcription factor, is transiently expressed in ExM progenitors that generate virtually all YS hematopoietic and endothelial cells. Using an embryonic stem cell (ESC) differentiation system, we find that Eomes activity is essential for the production of primitive erythrocytes and for the normal development of Runx1+ HE that generates the definitive hematopoietic progenitors. RNA-Seq and ATAC-Seq experiments reveal that Eomes governs the accessibility of numerous hematopoietic enhancers that SCL normally utilizes to specify primitive erythrocytes and HE in Flk-1hi/PdgfRa- hematovascular mesoderm. ChIP-seq experiments suggest that Eomes coordinates the development of hemogenic competent mesoderm in the context of Activin/Nodal and Tead-Yap signaling. Finally, single-cell- RNA-seq (scRNAseq) shows that in the absence of Eomes function diversion towards an endothelial rather than hematopoietic fate occurs after the initial specification of Flk-1+/SCL+ hematovascular mesoderm. Collectively, these experiments demonstrate that Eomes sits at the top of the transcriptional hierarchy, functioning upstream of Runx1 expression and SCL functional activity, and promotes hemogenic competence of the entire YS mesodermal lineage.

2020-11-01 | GSE140000 | GEO

The T-box Transcription Factor Eomesodermin Governs Hemogenic Competence of Yolk Sac Mesodermal Progenitors [RNA-Seq]

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The T-box Transcription Factor Eomesodermin Governs Hemogenic Competence of Yolk Sac Mesodermal Progenitors [scRNA-Seq]

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The T-box Transcription Factor Eomesodermin Governs Hemogenic Competence of Yolk Sac Mesodermal Progenitors [ATAC-Seq]

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Single cell RNA seq of the developing murine adrenal gland reveals correlation of Schwann cell precursor signature to neuroblastoma phenotype.

Project description:Neuroblastoma is the most common extracranial solid tumor and accounts for ~10% of pediatric cancer-related deaths. The exact cell-of-origin has yet to be elucidated, but it is generally accepted that neuroblastoma derives from the neural crest and should thus be considered an embryonal malignancy. About 50% of primary neuroblastoma tumors arise in the adrenal gland. Here we present an atlas of the developing mouse adrenal gland at a single cell level. Five main cell cluster groups (medulla, cortex, endothelial, stroma and immune) make up the mouse adrenal gland during fetal development. The medulla group, which is of neural crest origin, is further divided into seven clusters. Of interest is the Schwann cell precursor (SCP) and the neuroblast cluster, a highly cycling cluster that shares markers with sympathoblasts. The signature of the medullary SCP cluster differentiates neuroblastoma patients based on disease phenotype: the SCP signature score anti- correlates with ALK and MYCN expression, two indicators of poor prognosis. Furthermore, a high SCP signature score is associated with better overall survival rates. This study provides an insight in the developing adrenal gland and introduces the SCP gene signature as being of interest for further research in understanding neuroblastoma phenotype.

2021-02-01 | GSE162238 | GEO

Single-nuclei gene-expression analysis of pheochromocytoma and paraganglioma links tumor subtypes with tumor microenvironment

Project description:Pheochromocytomas and paragangliomas (PCPG) are rare neuroendocrine tumors associated with autonomic nerves. We used single nuclei-RNA-seq (snRNA-seq) for analysis of 30 PCPG representing 13 known driver genes, plus two normal adrenal medullas to dissect cell composition, refine PCPG subtypes and compare PCPG and normal tissue expression. Incorporating bulk-tissue and snRNA-seq data we identified seven PCPG gene-expression subtypes with genotype and cell type associations. The tumor microenvironment reflected HIF pathway activation and neovascularization by detection of abundant tip-like endothelial cells and pericytes concordant with VEGFA expression in neoplastic cells with mutations in VHL, genes encoding SDH subunits and MAML3-fusions. Macrophages were abundant in PCPG with distinct tumor-associated features. Schwann-cell-like cells were also enriched in some subtypes. The transcriptional profile of neoplastic PCPG cells resembled normal chromaffin cells but early chromaffin and neuroblast cell markers were expressed in some subtypes including GPR139, a putative therapeutic target for a subset of pseudohypoxic PCPG.

| EGAS00001005861 | EGA

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