Astrocytes are the most abundant cell type in the brain, yet the mechanisms involved in astrocyte differentiation and the level of astrocyte heterogeneity in the CNS, particularly in the human cortex, is largely unknown due to the lack of subtype-specific astrocyte markers and inaccessibility of human brain tissue. Here we identified HtrA1 as a BMP responsive molecular marker expressed in a subpopulation of astrocytes in the forebrain of adult mice. We also present an approach for generating astrocyte progenitors and astrocytes using human pluripotent stem cells (hPSCs), allowing us to recapitulate astrocyte development in vitro. We show that sequential exposure to external factors alters astrocyte specification from neural progenitor cells (NPCs). Additionally, using single cell RNA-sequencing we were able to take a molecular snapshot at two different time points of astrocyte differentiation. Due to the heterogenous nature of our culture, we used a combination of surface markers previously identified in mouse astrocytes, and we identified and isolated four different progenitor populations that arise during astrocyte differentiation at the earlier time point. Transcriptional analysis revealed a correlation between gene expression profiles in hPSC-derived neural progenitor populations and glioblastoma (GBM) subtypes. Additional characterization of these progenitor populations revealed genes associated with Notch signaling and TGF-β signaling pathways. These findings suggest that hPSC-derived astrocytes progenitors and astrocytes share developmental mechanisms replicated by the cell types found in GBM tumors. Therefore, understanding how the generation of glioma subtypes is linked to the developmental processes that regulate neural and glial diversification has important implications for the understanding and treatment of this disease.

Creator

• Van Gulden, Stephanie

DOI

• https://doi.org/10.21985/n2-bv3f-b913

Subject

• Neurosciences

Language

• en

Alternate Identifier

• http://dissertations.umi.com/northwestern:15549
• etdadmin_upload_817717

Keyword

• Glioblastoma
• Stem cells
• Astrocyte

Date created

• 2021-01-01

Resource type

• Dissertation

Rights statement

• In Copyright