StemCell Therapy

Scientists have observed that some genetic variations in microglia show a strong correlation with an increased risk of Alzheimers disease. One such correlation involves a gene called TREM2, which plays an essential role in in how microglia detect and address neurodegeneration. Certain genetic variants of TREM2 are among the strongest genetic risk factors for Alzheimers disease, Wernig said.

The data are convincing that microglial dysfunction can cause neurodegeneration in the brain, so it makes sense that restoring defective microglial function might be a way to fight neurodegeneration in Alzheimers disease, he added.

In the study, mice with a defective TREM2 gene received hematopoietic stem and progenitor cell transplants from mice with normal TREM2 function. The researchers found that the transplanted cells reconstituted the blood system and that some of them efficiently incorporated into the recipients brains and became cells that looked and behaved like microglia.

We showed that most of the brains original microglia were replaced by healthy cells, which led to a restoration of normal TREM2 activity, Wernig said.

Next, they investigated whether the restored TREM2 activity was enough to improve the brain health of the TREM2-deficient mice. Indeed, in the transplanted mice we saw a clear reduction in the deposits of amyloid plaques normally seen TREM2-deficient mice, Wernig said. They were also able to show a restoration of microglial function and reduction of other disease markers, indicating that functional restoration of this one gene had widespread positive effects.

Wernig and colleagues said they could transplant cells engineered to have supercharged TREM2 activity that may have an even greater effect.

They caution, however, that the microglia that formed from the transplanted cells were slightly different from the natural microglia in mouse brains. These differences might in some way have their own detrimental effect, Wernig said. We have to look at that very carefully.

In addition, the current procedure would be highly risky if it were developed for human therapy because transplantation of blood stem cells requires the recipient to undergo a highly toxic chemotherapy or radiation treatment to kill off native blood stem cells. However, many researchers, including some at the Institute for Stem Cell Biology and Regenerative Medicine, are developing less toxic methods of preconditioning patients for stem cell transplants. A brain cell therapy could then piggyback on such improved and safer transplantation methods.

The work was supported by the Kleberg Foundation, the Emerson Collective, a Howard Hughes Medical Institute faculty scholar award, a New York Stem Cell Foundation Druckenmiller award, a postdoctoral overseas training fellowship from the National Research Foundation of Korea and the German Research Foundation.

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Researchers find success with stem cell therapy in mice model of ...

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