HUMAN SKIN CELLS REPROGRAMMED DIRECTLY IN TO BRAIN CELLS
Scientists have
described a way to convert human skin cells directly into a specific type of
brain cell affected by Huntington's disease, an ultimately fatal
neurodegenerative disorder. Unlike other techniques that turn one cell type
into another, this new process does not pass through a stem cell phase,
avoiding the production of multiple cell types, the study's authors report.
The researchers, at
Washington University School of Medicine in St. Louis, demonstrated that these
converted cells survived at least six months after injection into the brains of
mice and behaved similarly to native cells in the brain.
"Not only did
these transplanted cells survive in the mouse brain, they showed functional
properties similar to those of native cells," said senior author Andrew S.
Yoo, PhD, assistant professor of developmental biology. "These cells are
known to extend projections into certain brain regions. And we found the human
transplanted cells also connected to these distant targets in the mouse brain.
That's a landmark point about this paper."
The work appears Oct.
22 in the journal Neuron.
The investigators
produced a specific type of brain cell called medium spiny neurons, which are
important for controlling movement. They are the primary cells affected in
Huntington's disease, an inherited genetic disorder that causes involuntary
muscle movements and cognitive decline usually beginning in middle-adulthood.
Patients with the condition live about 20 years following the onset of
symptoms, which steadily worsen over time.
The research involved
adult human skin cells, rather than more commonly studied mouse cells or even
human cells at an earlier stage of development. In regard to potential future
therapies, the ability to convert adult human cells presents the possibility of
using a patient's own skin cells, which are easily accessible and won't be
rejected by the immune system.
To reprogram these cells,
Yoo and his colleagues put the skin cells in an environment that closely mimics
the environment of brain cells. They knew from past work that exposure to two
small molecules of RNA, a close chemical cousin of DNA, could turn skin cells
into a mix of different types of neurons.
In a skin cell, the
DNA instructions for how to be a brain cell, or any other type of cell, is
neatly packed away, unused. In past research published in Nature, Yoo and his
colleagues showed that exposure to two microRNAs called miR-9 and miR-124
altered the machinery that governs packaging of DNA. Though the investigators
still are unraveling the details of this complex process, these microRNAs
appear to be opening up the tightly packaged sections of DNA important for
brain cells, allowing expression of genes governing development and function of
neurons.
Knowing exposure to
these microRNAs alone could change skin cells into a mix of neurons, the
researchers then started to fine tune the chemical signals, exposing the cells
to additional molecules called transcription factors that they knew were
present in the part of the brain where medium spiny neurons are common.
"We think that
the microRNAs are really doing the heavy lifting," said co-first author
Matheus B. Victor, a graduate student in neuroscience. "They are priming
the skin cells to become neurons. The transcription factors we add then guide
the skin cells to become a specific subtype, in this case medium spiny neurons.
We think we could produce different types of neurons by switching out different
transcription factors."
Yoo also explained
that the microRNAs, but not the transcription factors, are important components
for the general reprogramming of human skin cells directly to neurons. His
team, including co-first author Michelle C. Richner, senior research
technician, showed that when the skin cells were exposed to the transcription
factors alone, without the microRNAs, the conversion into neurons wasn't
successful.
The researchers
performed extensive tests to demonstrate that these newly converted brain cells
did indeed look and behave like native medium spiny neurons. The converted
cells expressed genes specific to native human medium spiny neurons and did not
express genes for other types of neurons. When transplanted into the mouse
brain, the converted cells showed morphological and functional properties
similar to native neurons.
To study the cellular
properties associated with the disease, the investigators now are taking skin
cells from patients with Huntington's disease and reprogramming them into
medium spiny neurons using the approach described in the new paper. They also
plan to inject healthy reprogrammed human cells into mice with a model of
Huntington's disease to see if this has any effect on the symptoms.
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