p53 controls genomic stability and temporal differentiation of human neural stem cells and affects neural organization in human brain organoids
(2020) In Cell Death & Disease 11(1). p.52-52- Abstract
In this study, we take advantage of human induced pluripotent stem (iPS) cell-derived neural stem cells and brain organoids to study the role of p53 during human brain development. We knocked down (KD) p53 in human neuroepithelial stem (NES) cells derived from iPS cells. Upon p53KD, NES cells rapidly show centrosome amplification and genomic instability. Furthermore, a reduced proliferation rate, downregulation of genes involved in oxidative phosphorylation (OXPHOS), and an upregulation of glycolytic capacity was apparent upon loss of p53. In addition, p53KD neural stem cells display an increased pace of differentiating into neurons and exhibit a phenotype corresponding to more mature neurons compared to control neurons. Using brain... (More)
In this study, we take advantage of human induced pluripotent stem (iPS) cell-derived neural stem cells and brain organoids to study the role of p53 during human brain development. We knocked down (KD) p53 in human neuroepithelial stem (NES) cells derived from iPS cells. Upon p53KD, NES cells rapidly show centrosome amplification and genomic instability. Furthermore, a reduced proliferation rate, downregulation of genes involved in oxidative phosphorylation (OXPHOS), and an upregulation of glycolytic capacity was apparent upon loss of p53. In addition, p53KD neural stem cells display an increased pace of differentiating into neurons and exhibit a phenotype corresponding to more mature neurons compared to control neurons. Using brain organoids, we modeled more specifically cortical neurogenesis. Here we found that p53 loss resulted in brain organoids with disorganized stem cell layer and reduced cortical progenitor cells and neurons. Similar to NES cells, neural progenitors isolated from brain organoids also show a downregulation in several OXPHOS genes. Taken together, this demonstrates an important role for p53 in controlling genomic stability of neural stem cells and regulation of neuronal differentiation, as well as maintaining structural organization and proper metabolic gene profile of neural progenitors in human brain organoids.
(Less)
- author
- Marin Navarro, Ana ; Pronk, Robin Johan ; van der Geest, Astrid Tjitske ; Oliynyk, Ganna ; Nordgren, Ann ; Arsenian-Henriksson, Marie ; Falk, Anna LU and Wilhelm, Margareta
- publishing date
- 2020-01-23
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Brain/cytology, Cell Differentiation/genetics, Cell Division/genetics, Cell Line, Cell Proliferation/genetics, Genomic Instability, Humans, Induced Pluripotent Stem Cells/cytology, Kinetics, Metabolic Networks and Pathways/genetics, Neural Stem Cells/cytology, Neurogenesis, Neurons/cytology, Organoids/cytology, Transcriptome/genetics, Tumor Suppressor Protein p53/metabolism
- in
- Cell Death & Disease
- volume
- 11
- issue
- 1
- pages
- 52 - 52
- publisher
- Nature Publishing Group
- external identifiers
-
- pmid:31974372
- scopus:85078139606
- ISSN
- 2041-4889
- DOI
- 10.1038/s41419-019-2208-7
- language
- English
- LU publication?
- no
- id
- 108e0082-3e7b-4ef0-a457-5a38280fa36a
- date added to LUP
- 2021-08-09 14:35:21
- date last changed
- 2024-06-15 13:55:45
@article{108e0082-3e7b-4ef0-a457-5a38280fa36a,
abstract = {{<p>In this study, we take advantage of human induced pluripotent stem (iPS) cell-derived neural stem cells and brain organoids to study the role of p53 during human brain development. We knocked down (KD) p53 in human neuroepithelial stem (NES) cells derived from iPS cells. Upon p53KD, NES cells rapidly show centrosome amplification and genomic instability. Furthermore, a reduced proliferation rate, downregulation of genes involved in oxidative phosphorylation (OXPHOS), and an upregulation of glycolytic capacity was apparent upon loss of p53. In addition, p53KD neural stem cells display an increased pace of differentiating into neurons and exhibit a phenotype corresponding to more mature neurons compared to control neurons. Using brain organoids, we modeled more specifically cortical neurogenesis. Here we found that p53 loss resulted in brain organoids with disorganized stem cell layer and reduced cortical progenitor cells and neurons. Similar to NES cells, neural progenitors isolated from brain organoids also show a downregulation in several OXPHOS genes. Taken together, this demonstrates an important role for p53 in controlling genomic stability of neural stem cells and regulation of neuronal differentiation, as well as maintaining structural organization and proper metabolic gene profile of neural progenitors in human brain organoids.</p>}},
author = {{Marin Navarro, Ana and Pronk, Robin Johan and van der Geest, Astrid Tjitske and Oliynyk, Ganna and Nordgren, Ann and Arsenian-Henriksson, Marie and Falk, Anna and Wilhelm, Margareta}},
issn = {{2041-4889}},
keywords = {{Brain/cytology; Cell Differentiation/genetics; Cell Division/genetics; Cell Line; Cell Proliferation/genetics; Genomic Instability; Humans; Induced Pluripotent Stem Cells/cytology; Kinetics; Metabolic Networks and Pathways/genetics; Neural Stem Cells/cytology; Neurogenesis; Neurons/cytology; Organoids/cytology; Transcriptome/genetics; Tumor Suppressor Protein p53/metabolism}},
language = {{eng}},
month = {{01}},
number = {{1}},
pages = {{52--52}},
publisher = {{Nature Publishing Group}},
series = {{Cell Death & Disease}},
title = {{p53 controls genomic stability and temporal differentiation of human neural stem cells and affects neural organization in human brain organoids}},
url = {{https://lup.lub.lu.se/search/files/101032965/p53_controls_genomic_stability.pdf}},
doi = {{10.1038/s41419-019-2208-7}},
volume = {{11}},
year = {{2020}},
}