Stem cell models of human brain development

Laura Pellegrini

Wellcome Trust CDA Research Fellow

The Pellegrini Lab’s focus is centred on the comprehensive understanding of the cerebrospinal fluid (CSF) and the choroid plexus (ChP), the sole cell layer responsible for CSF secretion and the formation of the blood-CSF-barrier. Given the critical role of dynamic CSF signals in brain development and the association of CSF abnormalities with various neurological disorders such as microcephaly, autism, and schizophrenia, the laboratory employs an innovative ChP organoid model to delve into the intricate dynamics of early ChP and CSF and their influence on brain development.

The research journey begins with the application of single-cell RNA sequencing and proteomics to analyse the origin of cellular diversity in the ChP and the contribution of diverse cell subtypes to the CSF proteome. This analytical approach is further corroborated with fetal ChP tissue validations. The lab also undertakes an exploration of CSF signals' impact on cortical development using ChP-cortical organoids, examining the effects of CSF component secretion on neuroepithelial cell proliferation and differentiation through synchronised trafficking assays. An additional area of research focuses on understanding the role of the ChP as a barrier, providing insights into trafficking mechanisms and secretion of biomarkers in health and disease conditions such as multiple sclerosis (MS), with the goal to advance methods of diagnosis and developed targeted approaches for drug delivery across this barrier.

Research Questions:

  1. What is the origin and diversity of cells in the ChP, and how do different cell subtypes contribute to the CSF proteome?
  2. How do CSF signals influence cortical development, specifically impacting neuroepithelial cell proliferation and differentiation?
  3. What role does the ChP barrier play in disease such as multiple sclerosis? How is CSF secretion altered? How can we target this barrier to improve drug delivery across the brain? 

By addressing these fundamental questions, the Pellegrini Lab aspires to unravel the complexities of the brain's development and function, contributing significantly to the field of neurological research and potential therapeutic interventions.