Derived neural immune cells enable new facet of neurodegeneration research

CAMBRIDGE, Mass. – Whitehead Institute scientists have devised a protocol for pushing human pluripotent stem cells to become microglia—the specialized immune cells that maintain the brain and care for it after injury. Microglia play an important role in neurodegenerative diseases, including Parkinson’s and Alzheimer’s.

Although microglia are crucial in proper brain development and in the pathology of several neurological disorders, researchers still know little about them. In the embryo, microglia migrate to the developing neural tube before the blood-brain barrier is established.  After the barrier is closed, microglia are the resident macrophages, sculpting the neuronal networks as the brain matures. Until recently, the function of microglia was primarily studied when injury or disease force them into action.

One reason that the function of microglia remains shrouded is their inherent plasticity, making isolation and cultures of these cells particularly difficult. Residing deep in the brain, they cannot be easily accessed for observation and manipulation, even in animal models.

“There were no really reliable methods to culture these cells in the laboratory,” says Julien Muffat, a postdoctoral researcher in Whitehead Founding Member Rudolf Jaenisch’s lab and co-author of the study. “We need to study these cells to model neurodegeneration, psychiatric disorders, and neural developmental disorders. They’ve been largely missing from in vitro studies, and even in vivo, they are only now taking center stage.”

To facilitate the research of these fascinating cells, the team of Whitehead scientists created a set of methods for pushing human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) into becoming microglia, and established an environment that mimics brain tissue to support and maintain the cells in their resident state. Their work is described this week in the journal Nature Medicine.

Using a profile of genetic markers that are highly expressed in microglia, the team compared their microglia-like cells to primary human fetal microglia. In addition to sharing strikingly similar gene expression profiles, the two cell types also had in common many key functional characteristics.

“Thanks to our novel 3D-culture system, we can study the behavior of these cells live, as they mature, react, and change morphology in a human brain-like environment.” says Muffat.

“Historically, scientists used transformed macrophage cell lines that poorly resemble the real thing, or primary microglia whose identity would quickly change over time in culture,” says Yun Li, a postdoctoral researcher in the Jaenisch lab and co-author with Muffat of the Nature Medicine paper. “These were the only available material. Our marker analysis highlights how different such lines actually are for the purpose of disease modeling or any understanding of the microglia’s phenotypes. The cells we generate very beautifully reflect the primary cells’ physiology.”

With the model microglial cells in hand, Jaenisch sees numerous research possibilities.

“We think the cells we’ve derived are very similar to primary, in vivo microglia, so I think it would be of great, great interest to use these cells to study diseases like Alzheimer’s and Parkinson’s, where microglia are thought to play an important role,” says Jaenisch, who is also a professor of biology at MIT. “Because we can make the right cell types from human embryonic stem cells and induced pluripotent stem cells, now we can dissect much better the interactions between other neural cells and microglia.”

This work was supported by the European Leukodystrophy Association, the Brain & Behavior Research Foundation, the Simons Foundation (grant SFARI 204106), the International Rett Syndrome Foundation (IRSF), the Amgen Scholars program, the Howard Hughes Medical Institute (HHMI), the National Institutes of Health (NIH grants HD 045022, R37-CA084198, 1RF1 AG042978637), the European Leukodystrophies Association (ELA) Foundation, the Emerald Foundation, and Biogen.

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Rudolf Jaenisch's primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a professor of biology at Massachusetts Institute of Technology.

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Citation

Muffat, J., Li, Y., Yuan, B., Mitalipova, M., Omer, A., Corcoran, S., ... & Jaenisch, R. (2016). Efficient derivation of microglia-like cells from human pluripotent stem cells. Nature medicine, 22(11), 1358-1367.