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

På svenska

Author

  • Daniela Grassi

Summary, in English

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.

Publishing year

2020

Language

English

Publication/Series

Lund University, Faculty of Medicine Doctoral Dissertation Series

Issue

2020:41

Document type

Dissertation

Publisher

Lund University, Faculty of Medicine

Topic

  • Neurosciences

Keywords

  • Neural reprogramming
  • Neural differentiation
  • Brain development
  • Huntington's disease
  • Induced Neuron
  • Neural Progenitor Cell
  • Brain evolution

Status

Published

Research group

  • Molecular Neurogenetics

ISBN/ISSN/Other

  • ISSN: 1652-8220
  • ISBN: 978-91-7619-902-2

Defence date

23 April 2020

Defence time

09:00

Defence place

Segerfalksalen, BMC A10, Sölvegatan 17 i Lund or by Zoom at https://lu-se.zoom.us/j/221230404

Opponent

  • Jens Hjerling-Leffler (Associate Professor)