Modeling neural cellular signaling via an iPSC-derived co-culture platform
Abstract/Contents
- Abstract
- Much of modern therapeutic development is oriented towards modulating cell-cell communication, yet we do not have a comprehensive understanding of how neural cell types signal to each other and how this network of signals is dysregulated in disease states. Microglia, the dominant brain-resident immune cell, contribute significantly to this network but are highly sensitive to their environment and are thus difficult to profile in a standardized fashion using existing coculture models which are not optimized to support microglial homeostasis. Here, we present a simple coculture model of iPSC-derived neurons, astrocytes, and microglia in defined medium which is fully self-sustaining through endogenous signaling and stable in long-term culture past 54 days of coculture. All three cell types become functional as they mature, with microglia demonstrating phagocytic, surveillance, and immune cytokine production capabilities and settling into a carrying capacity of 5-15% of the culture. Orthologous scRNA-seq and snRNA-seq analysis show that it resembles primary human brain tissue, is distinct from human brain organoids, and its astrocytic and microglial states are distinct from diseased primary astrocytes and microglia. Inferring ligand-receptor relationships between cell types, we characterized the complete network of active autocrine and paracrine signaling pathways in the culture and found that astrocytes form the nexus of this network. These data indicate that standardized, self-sustaining iPSC-derived tricultures can be effectively combined with increasingly powerful computational methods to better measure how diseased human neural tissue deviates from homeostasis and to guide therapeutic development in neurological disease.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2023; ©2023 |
| Publication date | 2023; 2023 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Kumar, Ishan |
|---|---|
| Degree supervisor | Wernig, Marius |
| Thesis advisor | Wernig, Marius |
| Thesis advisor | Desai, Tushar |
| Thesis advisor | Gitler, Aaron D |
| Thesis advisor | Majeti, Ravindra, 1972- |
| Thesis advisor | Malenka, Robert C |
| Degree committee member | Desai, Tushar |
| Degree committee member | Gitler, Aaron D |
| Degree committee member | Majeti, Ravindra, 1972- |
| Degree committee member | Malenka, Robert C |
| Associated with | Stanford University, School of Medicine |
| Associated with | Stanford University, Department of Stem Cell Biology and Regenerative Medicine |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Ishan R. Kumar. |
|---|---|
| Note | Submitted to the Department of Stem Cell Biology and Regenerative Medicine. |
| Thesis | Thesis Ph.D. Stanford University 2023. |
| Location | https://purl.stanford.edu/td577rf1258 |
Access conditions
- Copyright
- © 2023 by Ishan Kumar
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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