Scientists
from Schepens Eye Research Institute are the first to regenerate large
areas of damaged retinas and improve visual function using IPS cells
(induced pluripotent stem cells) derived from skin. The results of
their study, which is published in PLoS ONE this month, hold great
promise for future treatments and cures for diseases such as age-related
macular degeneration, retinitis pigmentosa, diabetic retinopathy and
other retinal diseases that affect millions worldwide.
“We
are very excited about these results,” says Dr. Budd A. Tucker, the
study’s first author. “While other researchers have been successful in
converting skin cells into induced pluripotent stem cells (iPSCs) and
subsequently into retinal neurons, we believe that this is the first
time that this degree of retinal reconstruction and restoration of
visual function has been detected,” he adds. Tucker, who is currently an
Assistant Professor of Ophthalmology at the University of Iowa, Carver
College of Medicine, completed the study at Schepens Eye Research
Institute in collaboration with Dr. Michael J. Young, the principle
investigator of the study, who heads the Institute’s regenerative
medicine center.
Today,
diseases such as retinitis pigmentosa (RP) and age-related macular
degeneration (AMD) are the leading causes of incurable blindness in the
western world. In these diseases, retinal cells, also known as
photoreceptors, begin to die and with them the eye’s ability to capture
light and transmit this information to the brain. Once destroyed,
retinal cells, like other cells of the central nervous system have
limited capacity for endogenous regeneration.
“Stem
cell regeneration of this precious tissue is our best hope for treating
and someday curing these disorders,” says Young, who has been at the
forefront of vision stem cell research for more than a decade.
While
Tucker, Young and other scientists were beginning to tap the potential
of embryonic and adult stem cells early in the decade, the discovery
that skin cells could be transformed into “pluripotent” cells, nearly
identical to embryonic cells, stirred excitement in the vision research
community. Since 2006 when researchers in Japan first used a set of four
“transcription factors” to signal skin cells to become iPSCs, vision
scientists have been exploring ways to use this new technology. Like
embryonic stem cells, iPSCs have the ability to become any other cell
in the body, but are not fraught with the ethical, emotional and
political issues associated with the use of tissue from human embryos.
Tucker
and Young harvested skin cells from the tails of red fluorescent mice.
They used red mice, because the red tissue would be easy to track when
transplanted in the eyes of non-fluorescent diseased mice.
By
forcing these cells to express the four Yamanaka transcription factors
(named for their discoverer) the group generated red fluorescent IPSCs,
and, with additional chemical coaxing, precursors of retinal cells.
Precursor cells are immature photoreceptors that only mature in their
natural habitat—the eye.
Within
33 days the cells were ready to be transplanted and were introduced
into the eyes of a mouse model of retina degenerative disease. Due to a
genetic mutation, the retinas of these recipient mice quickly
degenerate, the photoreceptor cells die and at the time of transplant
electrical activity, as detected by ERG (electroretinography), is
absent.
Within
four to six weeks, the researchers observed that the transplanted “red”
cells had taken up residence in the appropriate retinal area
(photoreceptor layer) of the eye and had begun to integrate and assemble
into healthily looking retinal tissue.
The
team then retested the mice with ERG and found a significant increase
in electrical activity in the newly reconstructed retinal tissue. In
fact, the amount of electrical activity was approximately half of what
would be expected in a normal retina. They also conducted a dark
adaption test to see if connections were being made between the new
photoreceptor cells and the rest of the retina. In brief, the group
found that by stimulating the newly integrated photoreceptor cells with
light they could detect a signal in the downstream neurons, which was
absent in the other untreated eye.
Based
on the results of their study, Tucker and Young believe that harvesting
skin cells for use in retinal regeneration is and will continue to be a
promising resource for the future.
The
two scientists say their next step will be to take this technology into
large animal models of retinal degenerative disease and eventually
toward human clinical trials.
Other
scientists involved in the PLoS ONE study include In-Hyun Park, Sara D.
Qi, Henry J. Klassen, Caihui Jiang, Jing Yao, Stephen Redenti, and
George Q. Daley.