Stem Cell Therapy to Cure Eye
Diseases
Stem cells are undifferentiated
cells able to divide indefinitely yet maintain the ability
to differentiate into specific cell types. They are
able to survive throughout the lifetime of the organism,
while maintaining their number, producing populations
of daughter cells (transit amplifying cells) that can
proceed down unique pathways of differentiation. Stem
cells may be obtained from embryonic tissues, umbilical
cord blood, and some differentiated adult tissues. Although
the potential for stem cell-based therapies for a variety
of human diseases is promising, numerous problems remain
to be overcome, such as methods for obtaining, transplanting,
inducing differentiation, developing function, and eliminating
immune reactions. Stem cells have great potential value
in treating eye diseases characterized by irreversible
loss of cells, such as glaucoma and photoreceptor degeneration.
Although stem cells offer
great opportunities for repair of the nervous system
and the eye, their clinical use necessitates that we
first gain an understanding of their proliferation,
migration, differentiation, immunogenicity, and establishment
of functional cell contacts. It will also be necessary
to produce these cells in conditions that meet appropriate
safety and effectiveness standards. Our current understanding
of the critical factors affecting stem cell behavior
remains limited. Rapid progress is being made, and some
of the first applications of stem cells to wound repair
in human eyes have produced successes that offer hope
for the use of stem cells in other ophthalmologic conditions.
Stem cells are very useful in ocular diseases, where
nothing could be offered by conventional treatment.
Sources of Stem Cells
The best understood stem cells are
embryonic stem cells, which derive from early fetal
development. To our knowledge, human embryonic stem
cells were first characterized in 1998. These cells
are pluripotent (able to differentiate into a wide variety
of cell types) and relatively easy to maintain in culture,
but they are necessarily allogeneic (from a different
genetic donor) to the potential recipient. Embryonic
stem cells are continuous cell lines and have the potential
to differentiate into retinal neurons, such as photoreceptors,
so they might serve as an inexhaustible source of neural
progenitors for stem cell therapy in the retina. Adult
stem cells, as the name implies, are derived from mature
organisms and are present only in restricted cellular
compartments. They are multipotent (able to differentiate
into a restricted number of cell types). Stem cells
derived from the central nervous system (CNS) and ocular
tissues have been identified as sources for cells that
may someday be used to repair damaged brain, spinal
cord, and retina. Stem cells within the eye have received
attention because of the possibility that they could
be obtained from a patient with eye disease and used
autologously. Some of the probable sources for ocular
stem cells are:
- Limbal stem cells
- Conjunctival stem cells
- Retinal stem cells
The corneal endothelium may contain
regions for storage (most peripheral), regeneration
(paracentral), and migration of stem cells. An area
of corneal endothelial cells adjacent to the Schwalbe
line may be able to transit amplifying cells and slow-cycling
cells.Endothelial cell density is markedly increased
in this area, as compared with central endothelial cell
density.
Differentiation of Stem Cells
To obtain large numbers of engrafted
stem cells that differentiate in a desired way, strategies
are needed to channel cells into desired phenotypes.
Modification of the microenvironment and/or inhibition
of intracellular signaling cascades in engrafted cells
will be needed for appropriate cellspecific differentiation
into injured tissue.
How stem cells offer hope in ocular
diseases
Stem cells have great potential
value in treating eye diseases characterized by irreversible
loss of cells, such as glaucoma and photoreceptor degeneration.
Ocular diseases, such as retinitis pigmentosa and age-retinitis
pigmentosa and age-related macular dengeration, reflect
damage to specific cells that are not normally repaired
or replaced but they may be treated by stem cells transplantation.
Conditions that destroy the limbal
area of the peripheral cornea, such as the Stevens-Johnson
syndrome, ocular pemphigoid, and chemical and thermal
injuries, can deplete stem cells of the corneal epithelium.
The result is scarring and opacification of the normally
clear cornea. Standard corneal transplantation cannot
treat this form of functional blindness - stem cells
have potential.
In some retinal diseases, photoreceptor
cells die due to an intrinsic abnormality and/or due
to disruption or death of supportive cells in the retinal
pigment epithelium. However some other parts of the
body can cope with similar cell death. This is because
other existing cells in the tissue can divide in a regulated
way to create new cells that replenish the remaining
stock. Unfortunately, this is not the case for mature
retinal photoreceptors. This is why stem cells might
be very handy, because some of them do have the capacity
to divide and form new photoreceptors. It is therefore
hoped that they might be harnessed in the future to
replenish the ailing retina of its photoreceptors.
They could be surgically transplanted
into the eye or drugs could be developed to activate
suitable populations of stem cells naturally present
within the patient's body. With respect to transplantation,
stem cells may be triggered to partially or fully specialise
into photoreceptors in the laboratory before being transplanted
into the eye. Once in the retina it is hoped that the
new retinal cells will mature and incorporate within
the existing tissue. This process may be helped naturally
by the degenerating retina, which emits signals into
the local environment of the eye, to indicate its state
of damage.
Age related macular degeneration
Age-related macular degeneration
(ARMD) is a degenerative condition of the macula. ARMD
is caused by hardening of the arteries that nourish
the retina. This deprives the sensitive retinal tissue
of oxygen and nutrients that it needs to function and
thrive. As a result, the central vision deteriorates.
Retinal stem cell research explodes
the myth that macular degeneration is irreversible.
These studies demonstrate that, in adult eyes, one can
resurrect vision-related cells like photoreceptors and
induce production of critical visual process dependent
chemicals such as rhodopsin.
Glaucoma
Eye has pressure just like your
blood, and when this intraocular pressure (IOP) increases
to dangerous levels, it damages the optic nerve. This
can result in decreased peripheral vision and, eventually,
blindness. Glaucoma is similar to ocular hypertension
but with accompanying optic nerve damage and vision
loss.
There are at least three potential targets for stem
cell therapy in glaucoma:
- RGC
- Optic nerve head
- Trabecular meshwork
Stem Cell research in glaucoma mainly
focused on replacing RGCs because their death is the
final common pathway for visual loss in glaucoma and
other optic neuropathies. HumanRGCsaremammalian CNS
neurons that cannot divide and differentiate to replace
other cells lost from disease. Blindness from glaucoma
is irreversible. Finding a way to differentiate stem
cells into RGCs and allow them to connect to their appropriate
targets would be a major step in repopulating the neurons
lost in glaucoma.
Retinitis Pigmentosa
Retinitis pigmentosa (RP) is the
name given to a group of inherited eye diseases that
affect the retina. Retinitis pigmentosa causes the degeneration
of photoreceptor cells in the retina. Photoreceptor
cells capture and process light helping us to see. As
these cells degenerate and die, patients experience
progressive vision loss.
Derivation of retinal cells from
human embryonic stem cells can be used potentially to
treat retinitis pigmentosa. Loss of retinal vasculature
is a presumed metabolic consequence of photoreceptor
de-generation. Studies show that autologous bone marrowderived
lineage-negative hematopoietic stem cells, which incorporate
into the degenerating blood vessels in patients of retinitis
pigmentosa, prevent cone loss. The use of autologous
bone marrow might avoid problems with rejection.
Ocular Tumors
Benign and malignant cancers can
sometimes attack the eyes. Left untreated, ocular tumors
threaten not only a person’s vision, but his or
her life as well. Symptoms of eye cancer include blurry
vision, distorted vision, blind spots, decreased side
vision, white pupils, red eye, eye pain and complete
vision loss. Sometimes ocular tumors present no symptoms
at all.
Choroidal melanoma is a malignant
cancer caused by uncontrolled cell growth within the
eye. It occurs most frequently in patients 60 to 65
years old. Retinoblastoma, a cancer originating in the
retina, is most common in children under five. Nationwide,
over 500 new cases of retinoblastoma are diagnosed every
year. Ocular cancers also include those that spread
to the eyes from other parts of the body, especially
breast, lung and bowel cancer.
Clinical use for adult stem cells
has shown positive results in treating metastatic ocular
tumors. The spreading ocular tumor has a poor prognosis
with conventional treatments. Adult stem cells along
with chemotherapy have been successful with different
ocular tumors.
A localized retinoblastoma
of the left eye in a 7-year-old girl, was treated by
enucleation and received no additional therapy. Four
months later, metastases of retinoblastoma in the lymph
nodes, bone and bone marrow were diagnosed. Relapse
chemotherapy consisting of three courses of vincristine,
cyclophosphamide, etoposide and carboplatin led to a
second complete remission. Subsequent high-dose chemotherapy
with thiotepa, etoposide and carboplatin and autologous
stem cell transplantation with CD34-selected stem cells
were successful, with no adverse effects. No radiotherapy
was given and the girl remains in continuous second
remission with a follow-up of more than 4 years.
Stem cells in ocular surface disease
The corneal epithelium is a highly
differentiated cell type with rapid self-renewal and
limbal stem cells are primarily responsible for epithelial
replacement and maturation. Any damage in limbus leads
to variety of seemingly unrelated disease process under
one heading of corneal stem cell disease.
The cornea is resurfaced by abnormal,
injured conjunctival epithelium, after severe chemical
or thermal injury to the eye. Such eyes are chronically
inflamed and irritated with persistent epithelial defects,
stromal scarring and neovascularization. Poor prognosis
after conventional therapies led to use of alternative
modalities.
Limbal stem cells under different
conditions are used for transplantation in patients
with grade III & IV chemical injury, recurrent pterygium
and other ocular surface diseases.
Server ocular surface disease (OSD)
with limbal stem cell deficiency is one of the most
challenging disease entities facing the clinician today.
Poor outcome with conventional treatment have been observed
in these patients. Limbal stem cell transplantation
has shown promising results in these types of cases.
A variety of limbal stem cell transplantation options
are available to replace defective limbal tissues.
Stem cell culture
There is ongoing research into the
benefits of directly transplanting healthy photoreceptors
taken from donor eyes. In fact, in animal models of
retinal degeneration, such transplants have been observed
to restore retinal structure somewhat. However, even
if this approach can be perfected and shown to significantly
restore vision in humans, there is one major problem.
Just as the number of people requiring donor hearts
far exceeds the number of organs available for transplantation,
it is likely that more patients would benefit from retinal
cell transplantation than available quantities of donor
eye tissue will support. Unlike photoreceptor cells,
stem cells can be helped to divide many times in the
laboratory, thereby expanding the number of cells available
for transplant and providing for the treatment of more
patients. Stem cells can often be kept expanding for
lengthy periods of time in the laboratory and they might,
therefore, represent a renewable source of replacement
cells.
Source: Invention
Intelligence, September - October 2006
