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Development and Applications of in vitro Models to Study Human Brain Evolution and Disease

Grassi, Daniela LU (2020) In Lund University, Faculty of Medicine Doctoral Dissertation Series
Abstract
Neuroscience focusing on human development and disease has long been hampered due to ethical reasons, low tissue availability, and low translatability from animal models. To circumvent these obstacles, we have developed two methods for the investigation of human neural cells in culture. Firstly, we present a robust 2-week protocol for the differentiation of human pluripotent stem cells (PSCs) into forebrain neural progenitor cells. Furthermore, we have used this protocol to differentiate PSCs from humans and chimpanzees. We show that human and chimpanzee cells differentiate in a similar manner and that the difference in interspecies protein abundance is higher than transcript-level differences, suggesting that post-transcriptional... (More)
Neuroscience focusing on human development and disease has long been hampered due to ethical reasons, low tissue availability, and low translatability from animal models. To circumvent these obstacles, we have developed two methods for the investigation of human neural cells in culture. Firstly, we present a robust 2-week protocol for the differentiation of human pluripotent stem cells (PSCs) into forebrain neural progenitor cells. Furthermore, we have used this protocol to differentiate PSCs from humans and chimpanzees. We show that human and chimpanzee cells differentiate in a similar manner and that the difference in interspecies protein abundance is higher than transcript-level differences, suggesting that post-transcriptional mechanisms play a role in the difference between human and chimpanzee brain development. Secondly, we have developed an all-in-one vector-based strategy to convert adult human dermal fibroblasts directly from Huntington’s disease (HD) patients and control individuals into induced neurons (iNs). After 4 weeks of conversion, we performed global analyses of RNA and protein levels by RNA-sequencing and mass spectrometry. In line with our previous results, we found that there are marked differences between HD patients and controls at the protein level but not at the transcriptional level. Taken together, our results suggest that post-transcriptional mechanisms play an important role in the brain both during development and in the adult brain. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Associate Professor Hjerling-Leffler, Jens, Karolinska Institutet
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Neural reprogramming, Neural differentiation, Brain development, Huntington's disease, Induced Neuron, Neural Progenitor Cell, Brain evolution
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
issue
2020:41
pages
68 pages
publisher
Lund University, Faculty of Medicine
defense location
Segerfalksalen, BMC A10, Sölvegatan 17 i Lund or by Zoom at https://lu-se.zoom.us/j/221230404
defense date
2020-04-23 09:00:00
ISSN
1652-8220
ISBN
978-91-7619-902-2
language
English
LU publication?
yes
id
81522620-26f5-4e00-8537-5f07c36d47c0
date added to LUP
2020-03-25 12:23:53
date last changed
2020-06-16 15:30:47
@phdthesis{81522620-26f5-4e00-8537-5f07c36d47c0,
  abstract     = {{Neuroscience focusing on human development and disease has long been hampered due to ethical reasons, low tissue availability, and low translatability from animal models. To circumvent these obstacles, we have developed two methods for the investigation of human neural cells in culture. Firstly, we present a robust 2-week protocol for the differentiation of human pluripotent stem cells (PSCs) into forebrain neural progenitor cells. Furthermore, we have used this protocol to differentiate PSCs from humans and chimpanzees. We show that human and chimpanzee cells differentiate in a similar manner and that the difference in interspecies protein abundance is higher than transcript-level differences, suggesting that post-transcriptional mechanisms play a role in the difference between human and chimpanzee brain development. Secondly, we have developed an all-in-one vector-based strategy to convert adult human dermal fibroblasts directly from Huntington’s disease (HD) patients and control individuals into induced neurons (iNs). After 4 weeks of conversion, we performed global analyses of RNA and protein levels by RNA-sequencing and mass spectrometry. In line with our previous results, we found that there are marked differences between HD patients and controls at the protein level but not at the transcriptional level. Taken together, our results suggest that post-transcriptional mechanisms play an important role in the brain both during development and in the adult brain.}},
  author       = {{Grassi, Daniela}},
  isbn         = {{978-91-7619-902-2}},
  issn         = {{1652-8220}},
  keywords     = {{Neural reprogramming; Neural differentiation; Brain development; Huntington's disease; Induced Neuron; Neural Progenitor Cell; Brain evolution}},
  language     = {{eng}},
  number       = {{2020:41}},
  publisher    = {{Lund University, Faculty of Medicine}},
  school       = {{Lund University}},
  series       = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{Development and Applications of in vitro Models to Study Human Brain Evolution and Disease}},
  year         = {{2020}},
}