Neurons created from skin cells give hope for Alzheimer's
19 August 2011
Columbia University Medical Center researchers have for the
first time directly converted human skin cells into functional forebrain
neurons, without the need for stem cells of any kind.
The findings offer a new and potentially more direct way to produce
replacement cell therapies for Alzheimer’s and other
neurodegenerative diseases. Such cells may prove especially useful
for testing new therapeutic leads. The study was published 4 August
2011 online in the journal Cell.
In another first, the researchers used this method — called
direct reprogramming — to generate neurons from skin cells of
patients with familial (early-onset) Alzheimer’s disease. The
induced neurons were found to differ significantly from those made
from healthy individuals, providing new insights into the
development of the disease, reports study leader Asa Abeliovich, MD,
PhD, associate professor of pathology & cell biology and neurology
in the Taub Institute for Research on Alzheimer’s Disease and the
Aging Brain at Columbia University Medical Center (CUMC).
In the 1980s and 90s, scientists realized that embryonic stem
cells, because of their pluripotency (ability to develop into any
kind of cell) and capacity for self-renewal, might be useful in
regenerating or replacing tissue after injury or disease. However,
the use of cells from human embryos raised ethical issues,
triggering a search for alternatives.
A breakthrough came in 2007, when researchers determined how to
genetically reprogram human skin cells to become induced pluripotent
stem (iPS) cells, which are similar to naturally pluripotent cells.
Although this advance allowed researchers to avoid using embryonic
stem cells, iPS technology remains complex, inefficient, and
time-consuming. Moreover, the pluripotent stem cells by their nature
are capable of forming tumors, leading to potential safety concerns.
In 2010, Stanford University researchers reported turning mouse
skin cells directly into neurons using transcription regulators
(proteins that switch genes on or off), bypassing the need to create
Building on that work, Dr Abeliovich and his team used a
different combination of transcription regulators, plus several
neuronal support factors, to convert human skin cells into forebrain
neurons. The induced neurons appear to be the same as ordinary
neurons, judging from electrophysiological testing and gene
expression profiling. The researchers also showed that the neurons
are able to send and receive signals in laboratory culture and when
transplanted into the central nervous system of mice. These findings
indicate that the induced neurons are capable of neuronal activity.
“Direct reprogramming is fundamentally different from making
neurons with iPS technologies,” says Dr Abeliovich. “Using direct
reprogramming, you could, in theory, take someone’s skin cells and
in a couple of weeks have fully functional neurons ready for
replacement cell therapy.”
“Although the project is still at early stages and certainly not
ready for clinical applications, therapies based on direct
reprogramming seem more realistic than those based on iPS
technology. “What is particularly exciting,” says Dr. Abeliovich,
“is that direct reprogramming is broadly applicable to the study and
treatment of a host of neurological diseases.”
In the second part of the study, Dr Abeliovich compared neurons
made from skin cells of healthy individuals with neurons made from
patients with early-onset Alzheimer’s disease. The latter cells
exhibited altered processing and localization of amyloid precursor
protein (APP) and increased concentration of amyloid beta, a
component of APP (Alzheimer’s is thought to develop when abnormal
amounts of amyloid beta accumulate in the brain, eventually killing
APP was found to collect in the cells’ endosomes, cellular
compartments that sort molecules for degradation or recycling. These
findings suggest that this form of Alzheimer’s is caused, at least
in part, by abnormal endosomal function, the researchers report.
Liang Qiang et al. Directed Conversion Of Alzheimer’s Disease
Patient Skin Fibroblasts Into Functional Neurons. Cell,
published online 4 August 2011.