On astrocytes and neural stem cells : a study of reactive and canonical neurogenesis

The mammalian central nervous system has limited regenerative capacity and the long-lasting functional impairment resulting from trauma and neurodegenerative disease derives from a failure to repopulate neuronal cell populations that are lost to injury. The studies included in the present thesis aim at proposing astrocytes as a novel source for achieving widespread replacement of neurons. Central to this work are notions within the field of astrocyte biology, adult neurogenesis, and regenerative medicine, which are discussed in the literature review.

Astrocytes are an abundant cell population that supports neuronal development, survival and activity in health and participate in inflammation and injury resolution in disease. Learning about astrocyte biology allows us to develop tools for selectively targeting these cells or their specific functions. It will also help us learn about heterogeneous subtypes with distinctive functional properties or differential potential for regenerative repair.

Adult neurogenesis is the process through which new neurons are added throughout life to a pre-existing neural circuitry. This process has been extensively explored in model organisms, but it has been challenging to achieve the same level of resolution and detail for the study of human neurogenesis. It is nevertheless important to identify and characterize neurogenic cells in the human brain and investigate their functional impact on cognition, as well as how their dysregulation may be linked to neurodegenerative and psychiatric diseases. In the context of this thesis, learning about the molecular dynamics driving neurogenesis allowed us to demonstrate that astrocytes, once recruited, unfold a process of differentiation like that seen in neural stem cells (Paper I and Paper II). We, furthermore, profiled the transcriptome of young and adult human hippocampal cells and depicted, for the first time, a comprehensive molecular framework that describes the neurogenic program in the human dentate gyrus (Paper III).

Cell replacement therapies are obtaining promising results in pre-clinical settings and are starting to be successfully used in patients to replace specific cell populations depleted due to neurodegeneration or injury. The present thesis discusses the two main strategies to approach cell replacement, namely transplantation and recruitment of endogenous cells with stem cell properties. The latter has gained momentum in recent years to overcome limitations characteristic of cell transplantation. Work within this thesis is aimed in this direction and provides evidence that parenchymal astrocytes can be considered latent neural stem cells and can be recruited to replace neurons after injury (Paper I and Paper II).

From the methodological point of view, genomics technologies and computational approaches are important concepts to this thesis and have been applied, here, to study canonical and reactive neurogenesis. Published single-cell omics data across organs, developmental times, and species have enabled comprehensive investigations of cell processes and interactions that had remained until now elusive. Here, we leveraged transcriptome-wide analysis to investigate the molecular dynamics underlying astrocyte-mediated neurogenesis in the striatum (Paper I) and the cortex (Paper II), and to study human hippocampal neurogenesis with an unparalleled level of detail, which we used to identify markers of neural progenitors and to compare molecular processes across species (Paper III).

List of scientific papers

I. Magnusson, J. P., Zamboni, M.*, Santopolo, G.*, Mold, J. E., Barrientos-Somarribas, M., Talavera-Lopez, C., Andersson, B., & Frisen, J. Activation of a neural stem cell transcriptional program in parenchymal astrocytes. Elife. (Aug 3, 2020)
https://doi.org/10.7554/eLife.59733

II. Zamboni, M., Llorens-Bobadilla, E., Magnusson, J. P., & Frisen, J. (2020). A Widespread Neurogenic Potential of Neocortical Astrocytes Is Induced by Injury. Cell Stem Cell. 27(4), 605-617.
https://doi.org/10.1016/j.stem.2020.07.006

III. Dumitru I.*, Paterlini M.*, Zamboni M.‡, Ziegenhain C.‡, Tata M., Giatrellis S., Alkass K., Druid H., Sandberg R., & Frisén J. Delineation of a neurogenic cell trajectory in the human hippocampus. [Manuscript]