Single cell analysis of iPS derived neural stem cells and neurons

In vitro derived neural stem cells can be used to model events of neurogenesis and neurodevelopmental dysfunction. Formation of stable neural stem cell environments relies on cellular components to stabilize cell-to-cell connections. Cell-to-cell connections are required to stabilize cell-to-cell communication and cell-signaling events that are required to maintain cell identity and cell integrity. Identifying gene expression profiles and protein expression profiles aid in discovery of cellular events governing functional neurogenesis and events leading to neurodevelopmental dysfunction.

In Paper 1, we used single cell RNA-seq and identified cell adhesion molecule neurexin-1 alpha (NRXN1-α) as important for establishing functional efficient neural stem cells and for establishing functional neurons. In Paper 2, we used single cell RNA-seq and identified presence of inherent neurogenic progenitors and gliogenic progenitors in functional efficient neural stem cells and the neuronal or glial differentiation outcome to be linked to presence of predetermined progenitor cell types. In Paper 3, we identified microtubule stabilizing molecule doublecortin (DCX) as important for neuronal dendrite elongation, neuronal differentiation, and neuronal migration.

In summary, this thesis demonstrates the potential of modeling neurodevelopment by using neural stem cells as a tool for investigation.

List of scientific papers

I. Matti Lam, Mohsen Moslem, Julien Bryois, Robin J Pronk, Elias Uhlin, Ivar Dehnisch Ellström, Loora Laan, Jessica Olive, Rebecca Morse, Harriet Rönnholm, Lauri Louhivuori, Sergiy V Korol, Niklas Dahl, Per Uhlén, Britt-Marie Anderlid, Malin Kele, Patrick F Sullivan, Anna Falk. Single cell analysis of autism patient with bi-allelic NRXN1-alpha deletion reveals skewed fate choice in neural progenitors and impaired neuronal functionality. Experimental Cell Research. 2019.
https://doi.org/10.1016/j.yexcr.2019.06.014

II. Matti Lam, Tsukasa Sanosaka, Anders Lundin, Kent Imaizumi, Damla Etal, Jonathan Cairns, Ryan Hicks, Jun Kohyama, Malin Kele, Hideyuki Okano, Anna Falk. Single cell study of neural stem cells derived from human iPSCs reveal distinct progenitor populations with neurogenic and gliogenic potential. Genes to Cells. 2019.
https://doi.org/10.1111/gtc.12731

III. M Shahsavani, R J Pronk, R Falk, Matti Lam, M Moslem, S B Linker, J Salma, K Day, J Schuster, B-M Anderlid, N Dahl, F H Gage, A Falk. An in vitro model of lissencephaly: expanding the role of DCX during neurogenesis. Molecular Psychology. 2018 Jul;23(7):1674-1684.
https://doi.org/10.1038/mp.2017.175