Human iPSC modeling recapitulates in vivo sympathoadrenal development and reveals an aberrant developmental subpopulation in familial neuroblastoma
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE211664 | GEO | 2023/10/16
REPOSITORIES: GEO
Similar Datasets
Project description:Studies defining normal and disrupted human neural crest cell development have been challenging given its early timing and intricacy of development. Consequently, insight into the early disruptive events causing a neural crest related disease such as pediatric cancer neuroblastoma is limited. To overcome this problem, we developed an in vitro differentiation model to recapitulate the normal in vivo developmental process of the sympathoadrenal lineage which gives rise to neuroblastoma. We used human in vitro pluripotent stem cells and single-cell RNA sequencing to recapitulate the molecular events during sympathoadrenal development. We provide a detailed map of dynamically regulated transcriptomes during sympathoblast formation and illustrate the power of this model to study early events of the development of human neuroblastoma, identifying a distinct subpopulation of cell marked by SOX2 expression in developing sympathoblast obtained from patient derived iPSC cells harboring a germline activating mutation in the anaplastic lymphoma kinase (ALK) gene.
| S-EPMC10784699 | biostudies-literature
Project description:Pediatric malignancies, including neuroblastoma, are best understood as disorders of development. Neuroblastoma explicitly represents a failure of sympathoadrenal development. Yet, its molecular pathogenesis remains elusive. The application of an in vitro model of human sympathoadrenal development would allow for studying the normal developmental trajectory. Such a model could also interrogate the early steps toward neuroblastoma transformation utilizing genetic manipulation. However, in vitro models have thus far been unable to generate the cells of interest reliably. We developed and characterized a human in vitro pluripotent stem cell-based model via sequential single-cell RNA sequencing throughout sympathoadrenal development. We demonstrate the power of our model to study early events of the development of human neuroblastoma. We do so by identifying the differences between normal and patient-specific induced pluripotent stem cells, derived from a child with familial neuroblastoma, harboring a germline mutation in the Anaplastic Lymphoma Kinase (ALK) gene.
2023-10-16 | GSE211661 | GEO
Project description:Pediatric malignancies, including neuroblastoma, are best understood as disorders of development. Neuroblastoma explicitly represents a failure of sympathoadrenal development. Yet, its molecular pathogenesis remains elusive. The application of an in vitro model of human sympathoadrenal development would allow for studying the normal developmental trajectory. Such a model could also interrogate the early steps toward neuroblastoma transformation utilizing genetic manipulation. However, in vitro models have thus far been unable to generate the cells of interest reliably. We developed and characterized a human in vitro pluripotent stem cell-based model via sequential single-cell RNA sequencing throughout sympathoadrenal development. We demonstrate the power of our model to study early events of the development of human neuroblastoma. We do so by identifying the differences between normal and patient-specific induced pluripotent stem cells, derived from a child with familial neuroblastoma, harboring a germline mutation in the Anaplastic Lymphoma Kinase (ALK) gene.
2023-10-16 | GSE211660 | GEO
Project description:Human iPSC modeling recapitulates in vivo sympathoadrenal development and reveals an aberrant developmental subpopulation in familial neuroblastoma
| PRJNA871269 | ENA
Project description:Human iPSC modeling recapitulates in vivo sympathoadrenal development and reveals an aberrant developmental subpopulation in familial neuroblastoma [scRNA-seq]
| PRJNA871268 | ENA
Project description:Human iPSC modeling recapitulates in vivo sympathoadrenal development and reveals an aberrant developmental subpopulation in familial neuroblastoma [Bulk RNA-seq]
| PRJNA871265 | ENA
Project description:In vitro modeling of human disease has recently become feasible with the adoption of induced pluripotent stem cell (iPSC) technology. Here, we established patient-derived iPSCs from an Li-Fraumeni Syndrome (LFS) family and investigated the role of mutant p53 in the development of osteosarcoma (OS). Several members of this family carried a heterozygous p53(G245D) mutation and presented with a broad spectrum of tumors including OS. Osteoblasts (OBs) differentiated from iPSC-derived mesenchymal stem cells (MSCs) recapitulated OS features including defective osteoblastic differentiation (OB differentiation) as well as tumorigenic ability. Systematic analyses revealed that the expression of genes enriched in LFS-derived OBs strongly correlated with decreased time to tumor recurrence and poor patient survival. In silico cytogenetic region enrichment analysis (CREA) demonstrated that LFS-derived OBs do not have genomic rearrangements and hence are a particularly valuable tool for elucidating early oncogenic events prior to the accumulation of secondary alterations. LFS OBs exhibited impaired upregulation of the imprinted gene H19 during osteogenesis. Restoration of H19 expression in LFS OBs facilitated osteogenic differentiation and repressed tumorigenic potential. By integrating human imprinted gene network (IGN) and functional genomic analyses, we found that H19-mediates suppression of LFS-associated OS through the IGN component DECORIN (DCN). Downregulation of DCN impairs H19-mediated osteogenic differentiation and tumor suppression. In summary, these findings demonstrate the feasibility of studying inherited human cancer syndromes with iPSCs and also provide molecular insights into the role of the IGN in p53 mutation-mediated tumorigenesis. mRNAseq profiling during mesenchymal stem cell differentiation to osteoblasts.
2015-04-10 | E-GEOD-58123 | biostudies-arrayexpress
Project description:In vitro modeling of human disease has recently become feasible with the adoption of induced pluripotent stem cell (iPSC) technology. Here, we established patient-derived iPSCs from an Li-Fraumeni Syndrome (LFS) family and investigated the role of mutant p53 in the development of osteosarcoma (OS). Several members of this family carried a heterozygous p53(G245D) mutation and presented with a broad spectrum of tumors including OS. Osteoblasts (OBs) differentiated from iPSC-derived mesenchymal stem cells (MSCs) recapitulated OS features including defective osteoblastic differentiation (OB differentiation) as well as tumorigenic ability. Systematic analyses revealed that the expression of genes enriched in LFS-derived OBs strongly correlated with decreased time to tumor recurrence and poor patient survival. In silico cytogenetic region enrichment analysis (CREA) demonstrated that LFS-derived OBs do not have genomic rearrangements and hence are a particularly valuable tool for elucidating early oncogenic events prior to the accumulation of secondary alterations. LFS OBs exhibited impaired upregulation of the imprinted gene H19 during osteogenesis. Restoration of H19 expression in LFS OBs facilitated osteogenic differentiation and repressed tumorigenic potential. By integrating human imprinted gene network (IGN) and functional genomic analyses, we found that H19-mediates suppression of LFS-associated OS through the IGN component DECORIN (DCN). Downregulation of DCN impairs H19-mediated osteogenic differentiation and tumor suppression. In summary, these findings demonstrate the feasibility of studying inherited human cancer syndromes with iPSCs and also provide molecular insights into the role of the IGN in p53 mutation-mediated tumorigenesis.
2015-04-10 | GSE58123 | GEO
Project description:Tyrosine hydroxylase deficiency (THD) is a rare genetic disorder leading to dopaminergic depletion and early-onset Parkinsonism. Affected children present with either a severe form that does not respond to L-Dopa treatment (THD-B) or a milder L-Dopa responsive form (THD-A). We generated induced pluripotent stem cells (iPSCs) from THD patients that were differentiated into dopaminergic neurons (DAn) and compared with control-DAn from healthy individuals and gene-corrected isogenic controls. Consistent with patients, THD iPSC-DAn displayed lower levels of DA metabolites and reduced TH expression, when compared to controls. Moreover, THD iPSC-DAn showed abnormal morphology, including reduced total neurite length and neurite arborization defects, which were not evident in DAn differentiated from control-iPSC. Treatment of THD-iPSC-DAn with L-Dopa rescued the neuronal defects and disease phenotype only in THDA-DAn. Interestingly, L-Dopa treatment at the stage of neuronal precursors could prevent the alterations in THDB-iPSC-DAn, thus suggesting the existence of a critical developmental window in THD. Our iPSC-based model recapitulates THD disease phenotypes and response to treatment, representing a promising tool for investigating pathogenic mechanisms, drug screening, and personalized management.
| S-EPMC9994475 | biostudies-literature
Project description:Neuroblastoma (NB) is the most common cancer in infants and it accounts for six percent of all pediatric malignancies. There are several hypotheses proposed on the origins of NB. While there is little genetic evidence to support this, the prevailing model is that NB originates from neural crest stem cells (NCSCs). Utilizing in vivo mouse models, we demonstrate that targeting MYCN oncogene to NCSCs causes perinatal lethality. During sympathoadrenal (SA) lineage development, SOX transcriptional factors drive the transition from NCSCs to lineage-specific progenitors, characterized by the sequential activation of Sox9/Sox10/Sox4/Sox11 genes. We find the NCSCs factor SOX10 is not expressed in neuroblasts, but rather restricted to the Schwannian stroma and is associated with a good prognosis. On the other hand, SOX9 expression in NB cells was associated with several key biological processes including migration, invasion and differentiation. Moreover, manipulating SOX9 gene predominantly affects lineage-restricted SA progenitors. Our findings highlight a unique molecular SOX signature associated with NB that is highly reminiscent of SA progenitor transcriptional program during embryonic development, providing novel insights into NB pathobiology. In summary, we provide multiple lines of evidence suggesting that multipotent NCSCs do not contribute to NB initiation and maintenance.
| S-EPMC7299536 | biostudies-literature