Summary: Researchers generate new neurons from stem cells derived from the skin. They believe their findings could help advance the understanding of the role microglia plays in Alzheimer’s.

Source: UC Irvine.

UCI-led study to advance understanding of the role of microglia in Alzheimer’s disease.

Using human skin cells, University of California, Irvine neurobiologists and their colleagues have created a method to generate one of the principle cell types of the brain called microglia, which play a key role in preserving the function of neural networks and responding to injury and disease.

The finding marks an important step in the use of induced pluripotent stem (iPS) cells for targeted approaches to better understand and potentially treat neurological diseases such as Alzheimer’s. These iPS cells are derived from existing adult skin cells and show increasing utility as a promising approach for studying human disease and developing new therapies.

Skin cells were donated from patients at the UCI Alzheimer’s Disease Research Center (ADRC). The study, led by Edsel Abud, Wayne Poon and Mathew Blurton-Jones of UCI, used a genetic process to reprogram these cells into a pluripotent state capable of developing into any type of cell or tissue of the body.

The researchers then guided these pluripotent cells to a new state by exposing the cells to a series of differentiation factors which mimicked the developmental origin of microglia. The resulting cells act very much like human microglial cells. Their study appears in the current issue of Neuron.

In the brain, microglia mediate inflammation and the removal of dead cells and debris. These cells make up 10- to 15-percent of brain cells and are needed for the development and maintenance of neural networks.

“Microglia play an important role in Alzheimer’s and other diseases of the central nervous system. Recent research has revealed that newly discovered Alzheimer’s-risk genes influence microglia behavior. Using these cells, we can understand the biology of these genes and test potential new therapies,” said Blurton-Jones, an assistant professor of the Department of Neurobiology & Behavior and Director of the ADRC iPS Core.

“Scientists have had to rely on mouse microglia to study the immunology of Alzheimer’s disease. This discovery provides a powerful new approach to better model human disease and develop new therapies,” added Poon, a UCI MIND associate researcher.

Along those lines, the researchers examined the genetic and physical interactions between Alzheimer’s disease pathology and iPS-microglia. They are now using these cells in three-dimensional brain models to understand how microglia interact with other brain cells and influence Alzheimer’s disease and the development of other neurological diseases.

“Our findings provide a renewable and high-throughput method for understanding the role of inflammation in Alzheimer’s disease using human cells,” said Abud, an M.D./Ph.D. student. “These translational studies will better inform disease-modulating therapeutic strategies.”

Source: Tom Vasich – UC Irvine
Image Source: NeuroscienceNews.com image is adapted from the UC Irvine news release.
Original Research: Full open access research for “iPSC-Derived Human Microglia-like Cells to Study Neurological Diseases” by Edsel M. Abud, Ricardo N. Ramirez, Eric S. Martinez, Luke M. Healy, Cecilia H.H. Nguyen, Sean A. Newman, Andriy V. Yeromin, Vanessa M. Scarfone, Samuel E. Marsh, Cristhian Fimbres, Chad A. Caraway, Gianna M. Fote, Abdullah M. Madany, Anshu Agrawal, Rakez Kayed, Karen H. Gylys, Michael D. Cahalan, Brian J. Cummings, Jack P. Antel, Ali Mortazavi, Monica J. Carson, Wayne W. Poon, and Mathew Blurton-Jones in Neuron. Published online March 28 2017 doi:10.1016/j.neuron.2017.03.042

Abstract

iPSC-Derived Human Microglia-like Cells to Study Neurological Diseases

Highlights
•Fully defined and efficient generation of human microglial-like cells from iPSCs
•Whole-transcriptome and functional validation of iPSC-derived microglia (iMGLs)
•Novel in vitro and in vivo applications for studying neurological diseases
•iMGLs can be used to interrogate AD gene function

Summary
Microglia play critical roles in brain development, homeostasis, and neurological disorders. Here, we report that human microglial-like cells (iMGLs) can be differentiated from iPSCs to study their function in neurological diseases, like Alzheimer’s disease (AD). We find that iMGLs develop in vitro similarly to microglia in vivo, and whole-transcriptome analysis demonstrates that they are highly similar to cultured adult and fetal human microglia.

Functional assessment of iMGLs reveals that they secrete cytokines in response to inflammatory stimuli, migrate and undergo calcium transients, and robustly phagocytose CNS substrates.

iMGLs were used to examine the effects of Aβ fibrils and brain-derived tau oligomers on AD-related gene expression and to interrogate mechanisms involved in synaptic pruning.

Furthermore, iMGLs transplanted into transgenic mice and human brain organoids resemble microglia in vivo. Together, these findings demonstrate that iMGLs can be used to study microglial function, providing important new insight into human neurological disease.

“iPSC-Derived Human Microglia-like Cells to Study Neurological Diseases” by Edsel M. Abud, Ricardo N. Ramirez, Eric S. Martinez, Luke M. Healy, Cecilia H.H. Nguyen, Sean A. Newman, Andriy V. Yeromin, Vanessa M. Scarfone, Samuel E. Marsh, Cristhian Fimbres, Chad A. Caraway, Gianna M. Fote, Abdullah M. Madany, Anshu Agrawal, Rakez Kayed, Karen H. Gylys, Michael D. Cahalan, Brian J. Cummings, Jack P. Antel, Ali Mortazavi, Monica J. Carson, Wayne W. Poon, and Mathew Blurton-Jones in Neuron. Published online March 28 2017 doi:10.1016/j.neuron.2017.03.042