Intraocular Retinal Transplantation: A Review

Abstract

This review covers intraocular transplantation of retinal tissue. This has importance both for theoretical understanding of retinal and neural development and for possible future clinical application. Transplantation sites have ranged from the anterior chamber through the retina to the subretinal space.
Transplanted tissue has ranged from whole retina to specific retinal layers or specific types of retinal cells. Both within-species and inter-species transplants have been performed, and donor age has ranged from embryonic to adult. The ability of transplanted tissue to be accepted and to differentiate in host eyes has been studied. The conditions under which successful transplants are obtained, host-graft interactions, and transplantation methodologies have been explored. Morphological, and to a small extent, also functional characteristics of the transplants have been studied.

Full text

Intraocular
Retinal
Transplantation:
A
Review
R.M.
Hammer
and
U.
Yinon
Physiological
Laboratory,
Maurice
&
Gabriela
Goldsctzleger
Eye
Research
Institute
Tel
Aviv
University,
Sackler
Faculty
of
Medicine,
Chaim
Sheba
Medical
Center,
Tel
Hashomer
52621,
Israel
SUMMARY
KEY
WORDS
This
review
covers
intraocular
transplantation
of
retinal
tissue.
This
has
importance
both
for
theoretical
understanding
of
retinal
and
neural
development
and
for
possible
future
clinical
application.
Transplantation
sites
have
ranged
from
the
anterior
chamber
through
the
retina
to
the
subretinal
space.
Transplanted
tissue
has
ranged
from
whole
retina
to
specific
retinal
layers
or
specific
types
of
retinal
cells.
Both
within-species
and
inter-species
transplants
have
been
performed,
and
donor
age
has
ranged
from
embryonic
to
adult.
The
ability
of
transplanted
tissue
to
be
accepted
and
to
differentiate
in
host
eyes
has
been
studied.
The
conditions
under
which
successful
transplants
are
obtained,
host-graft
interactions,
and
transplantation
methodologies
have
been
explored.
Morphological,
and
to
a
small
extent,
also
functional
characteristics
of
the
transplants
have
been
studied.
Reprint
address:
U.
Yinon
Physiological
Laboratol7
Goldschleger
Eye
Research
Institute
Sheba
Medical
Center
Tel
Hashomer
52621
Israel
Retinal
transplant,
retinal
graft,
retinal
implant,
eye,
pigment
epithelium,
rods,
photoreceptors
INTRODUCTION
Studying
retinal
transplants
is
a
way
of
obtaining
insights
into
the
development
of
retinal
tissue
and
factors
which
influence
this,
the
formation
of
neural
connections,
and
interactions
between
transplanted
and
surrounding
tissue.
Additionally,
there
are
many
eye
diseases
which
due
to
their
effects
on
the
retina
cause
severe
visual
loss.
It
is
important
to
begin
to
preliminarily
explore
the
possibility
that
transplantation
techniques
may
be
a
means
of
replacing
irreversibly
damaged
retinal
tissue.
Studies
of
the
development
of
retinal
tissue
when
transplanted
into
host
brains
have
been
reported
for
some
time/38,40-43/.
Apart
from
one
pioneering
study/46/,
intraocular
retinal
transplants
have
been
carried
out
only
relatively
recently.
The
sparse
literature
regarding
retinal
transplants
up
to
mid-1986
has
been
reviewed
/60/
and
integrated
into
a
review
of
retinal
transplants
into
the
brain,
along
with
the
use
of
peripheral
nerve
grafts
VOL.
2,
NO.
2,
1991
81

82
R.M.
Hammer
and
U.
Yinon
as
bridges
for
the
growth
of
retinal
ganglion
cells.
A
further
review
of
retinal
transplantation/11/has
also
recently
come
to
our
attention.
The
present
review
emphasizes
recent
developments
in
the
transplantation
of
retinal
tissue
into
host
eyes.
TRANSPLANTS
OF
WHOLE
RETINA
Transplants
into
the
Anterior
Chamber
Del
Cerro
et
al.
grafted
retinas
from
Long-Evans
rat
embryos
aged
13
to
16
postconceptual
days
(E13-E16)
/14,15/
and
2
days
post-natal
(P2)
/15/,
to
the
anterior
chambers
of
adults,
both
of
the
same
species,
and
also
of
other
species,
namely
Lewis/14,
15/and
Fischer/14/.
The
transplanted
neural
retina
and
the
retinal
pigment
epithelium
(RPE)
grew
at
a
roughly
linear
rate
until
one
month
after
transplantation,
after
which
its
size
and
appearance
remained
unchanged.
Iridal
vessels
entered
the
implants
and
formed
branches
with
them.
The
capillaries
within
the
implant
formed
tufts
around
the
trunks
of
origin,
in
contrast
to
the
vascular
network
found
in
normal,rat
retinas.
Survival
times
(time
from
transplant
till
sacrifice)
allowed
in
the
study
ranged
from
0
to
90
days,
with
long-term
survival
rate
for
transplants
larger
than
1
mm
ranging
from
25%
to
80%.
Fifteen
days
proved
adequate
for
the
differentiation
of
a
rudimentary
layered
structure
/14,15/.
This
included
patches
of
outer
(ONL)
and
inner
(INL)
nuclear
layers
(the
INL
sometimes
forming
a
distinct
layer),
as
well
as
definite
inner
limiting
membranes
(ILM)
with
baskets
of
Muller
cell
processes
and
outer
limiting
membranes
(OLM)
and
outer
plexiform
layers
(OPL).
The
plexiform
layers
contained
numerous
synaptic
endings
and
both
ribbon
and
conventional
synaptic
contacts
/14,15/.
(A
ribbon
synapse
is
characterized
by
a
dense
ribbon
or
bar
seen
in
the
electron
micrograph
of
the
presynaptic
cytoplasm
and
always
has
multiple
post-synaptic
elements
/23/.
Conventional
synaptic
contacts
in
the
retina
are
similar
to
those
found
throughout
the
vertebrate
nervous
system/23/.
Both
types
of
synapses
would
be
expected
to
be
found
if
the
transplant
resembles
normal
adult
retinal
tissue.)
Photoreceptor
outer
segments,
which
were
all
stunted
/14,15/,
were
only
observed
to
develop
when
the
pigment
epithelium
was
present
near,
though
not
necessarily
in
contact
with,
the
rod
cells/14/.
Rod
cells
were
closely
packed,
and
in
some
cases
formed
rosettes
within
the
thickness
of
the
ONL
and
INL
/14,15/.
Ganglion
cells
were
present
in
transplants
from
embryonic
/14,15/,
but
not
from
post-natal/15/donors,
and
were
few
in
number.
Within-species
transplants
were
very
well tolerated
by
the
host,
even
3
months
post-transplantation
/14,15/.
Lewis
strain
hosts
usually
did
not
show
inflammation
/12,13/
while
Fischer
strain
hosts
showed
an
intense
reaction/14/.
This
began
in
the
form
of
vascular
congestion
of
the
iris,
which
could
progress
to
general
hyperemia
of
the
conjunctiva,
with
Clouding
of
the
media.
In
the
two
worst
cases,
such
alterations
as
anterior
chamber
hemorrhages,
cataractous
changes,
along
with
vascularization
and
opacification
of
the
cornea
occurred.
In
these
severe
cases,
the
transplants
were
surrounded
and
infiltrated
by
macrophages,
which
were
also
plentiful
in
the
host
retina
and
were
a
major
component
of
a
granulomatous
tissue
found
throughout
the
vitreal
cavity.
Ninomiya
/45/
transplanted
retina
from
E13-E20
Fischer
rats
to
the
anterior
chambers
of
adults,
with
survival
times
of
2-37
weeks.
The
transplanted
tissue
was
seen
as
an
irregular
translucent
whitish
mass
into
which
small
blood
vessels
entered.
Microscopically,
tubular
structures
of
varying
sizes
and
some
rosette-
likp
structures
were
seen.
Survival
rate
was
22%,
but
if
a
co-transplant
of
tectal
tissue
was
made,
then
it
was
74%.
The
retina-tectum
double
grafts
fused
about
2
weeks
after
transplantation.
Transplants
to
the
Host
Retina
Rat
to
rat
transplants.
Del
Cerro
et
al.
/12/
performed
transplants
from
both
embryonic
and
P1-P2
postnatal
outbred
Long-Evans
rats
into
the
retinas
of
adult
male
outbred
Long-Evans
rats
and
albino
Lewis
strain
rats.
The
host
retinas
were
either
damaged
prior
to
transplantation
by
light
or
by
kainic
acid
or
were
normal.
The
transplant
was
either
in
the
form
of
strips
of
retina
or
of
a
cell
suspension.
Survival
times
of
up
to
90
days
were
allowed.
A
mass
of
retinal
tissue
was
found
to
develop
on
the
host
retina,
and
the
nuclear
and
plexiform
layers
differentiated
and
were
populated
by
the
expected
neuronal
and
glial
types.
Differ-
entiation
included
the
appearance
of
numerous
rod
cells,
often
forming
rosettes,
and
a
few
cones.
The
JOURNAL
OF
NEURAL
TtLANSPLANTATION
&
PLASTICITY

RETINAL
TRANSPLANTATION
83
lumina
of
these
rosettes
were
limited
by
an
OLM
and
were
filled
by
cilia-bearing
inner
segments
and
contorted
outer
segments.
They
also
contained
some
macrophages
loaded
with
cytoplasmic
debris.
The
layers
of
the
transplant
came
to
blend
with
those of
the
host
as
they
grew
and
became
progressively
vascularized.
Synapses,
both
of
the
conventional
and
ribbon
types,
were
found
within
the
plexiform
layer
of
the
transplant/12/.
In
these
types
of
transplant,
and
with
survival
times
up
to
120
days,
no
evidence
of
immune
mediated
rejection
was
found/13/.
In
a
similar
study
/20/,
dissociated
retinal
cell
suspension,
in
some
cases
prestained
with
either
Fast
blue
or
Fluoro-gold,
was
obtained
from
P1-P2
Long-
Evans
and
Lewis
pups.
The
cells
were
injected
into
the
retinas
of
Long-Evans,
Lewis
and
Fisher
hosts
(some
phototoxically
damaged).
With
survival
times
of
10,
30,
and
100
days,
the
transplants
showed
excellent
integration
with
the
host
tissue,
without
any
glial
barrier.
In
those
cases
which
were
not
prelabelled,
it
was
difficult
to
define
precisely
the
distribution
of
the
transplant
in
the
normal
host
retinas.
Precise
transplant
survival
data
were
not
given,
but
it
was
mentioned
that
in
a
few
cases,
viable
grafts
failed
to
occur/20/.
Further
details
regarding
the
results
of
trans-
plantation
of
retinal
cell
suspensions
to
light-damaged
host
retinas
have
been
reported
for
adult
Fisher
rat
hosts
with
donors
of
the
same
species
/17,19/.
The
photodamage
had
been
achieved
by
4
weeks
of
12
hours
per
day
of
exposure
to
an
illuminance
of
3500
lux
from
fluorescent
lamps.
Transplants
were
from
P2
donors,
and
were
allowed
to
grow
3-100
days.
They
were
found
to
grow
well,
although
the
laminar
organization
was
less
regular
than
in
other
trans-
plantation
methods/17,19/.
Density
of
rod
cell
nuclei
in
the
transplant
was
high
(145
nuclei
per
250/m
of
retina),
as
compared
to
almost
zero
in
light-damaged
retinas
without
transplants
(2.8
nuclei
per
250/am
of
retina),
but
it
was
approximately
one-third
of
that
found
in
the
corresponding
area
of
normal
control
retinas
(415
nuclei
per
250/m
of
retina)/17/.
Rod
cells
were
usually
grouped
in
rosettes/17,19/.
Their
inner
segments
developed
consistently,
while
their
outer
segments
tended
to
be
defective,
containing
collections
of
irregular
cisternae.
Many
synapses,
both
of
the
conventional
and
ribbon
type,
occurred
within
patches
of
plexiform
layer
around
the
grafts.
Transplants
could
be
found
in
approximately
two-
thirds
of
transplanted
eyes.
Similar
results
were
also
obtained
when
transplants
to
photodamaged
albino
Lewis
rats
were
performed,
with
donor
material
from
P0
to
P2
Lewis
or
Long-
Evans
rats/18/.
Turner
and
Blair
obtained
donor
retinal
tissue
from
newborn
rat
pups
/56/.
The
retinas
of
the
adult
Sprague-Dawley
hosts
were
lesioned
by
means
of
a
razor
blade
that
was
passed
through
the
layers
of
the
eye
until
the
vitreous
was
exposed,
the
incision
being
subsequently
sutured
dosed.
Donor
retinas
were
cut
into
small
pieces
and
injected
into
a
host
lesion
site.
The
lesion
either
was
newly
prepared
or
5
weeks
old.
Within
1
week
post-transplantation,
a
distinct
ganglion
cell
layer
two
or
three
cells
thick
was
present,
but
without
an
optic
fiber
layer.
There
was
a
small
inner
plexiform
layer
(IPL)
between
the
ganglion
cell
layer
and
the
neuroblastic
layer.
At
four
weeks,
an
ILM
and
a
continuous
optic
fiber
layer
were
still
absent.
In
some
cases,
however,
fascicles
of
fibers
ran
from
the
graft
ganglion
cell
layer
and
joined
with
and
coursed
for
some
distance
along
the
host
ILM/optic
fiber
layer.
The
neuroblastic
layer
had
developed
into
an
INL
and
an
ONL
separated
by
an
OPL.
Both
ribbon
and
conventional
synapses
were
present.
Photoreceptor
cell
bodies
and
inner
segments,
but
not
outer
segments,
were
found.
The
photoreceptors
on
occasion
collected
to
form
rosettes,
with
the
cell
bodies
facing
an
inner
luminal
surface
filled
with
microvilli.
Merging
of
the
plexiform
layers
of
the
graft
and
the
host
was
observed.
A
clear
distinction
could
be
made
between
the
host
and
graft
tissue,
the
latter
being
located
mostly
within
the
cut
edges
of
the
lesion
in
the
host
retina.
The
transplants
were
successful
for
both
fresh
and
5-week-old
lesion
sites/56/and
also
for
8-week-
old
lesion
sites/59/.
This
last
point,
regarding
lack
of
influence
of
lesion
age
on
the
success
of
the
transplant,
was
also
confirmed
in
a
further
study/4/.
Retinal
transplants
were
performed
by
the
same
method,
both
from
P1
pups
and
from
El5
Sprague-
Dawley
embryos,
into
lesioned
retinas
of
young
adults
of
the
same
species
/2,61/.
Six
to
7
weeks
post-
transplant,
the
P1
transplants
had
fewer
laminae
(only
ganglion
cell
layer,
IPL,
INL
and
ONL)
than
the
El5
transplants
(OPL
and
OLM
also
present).
The
P1
transplants
also
integrated
more
poorly
within
the
host
retina
under
fresh
lesion
conditions,
but
equally
well
in
VOL.
2,
NO.
2,
1991

84
R.M.
Hammer
and
U.
Yinon
older
lesions.
For
both
donor
ages,
a
continuous
optic
fiber
layer
and
the
ILM
were
again
absent
/2,61/.
Glial
cells
from
within
embryonic
grafts
developed
normally,
while
host
glial
cells
also
migrated
into
the
grafts/49,61/.
Graft
filling
and
viability
did
not
differ
between
newborn
or
embryonic
donors/2,61/.
Retinal
graft
from
E15
donors
to
a
fresh
lesion
site
also
reduces
the
degeneration
in
the
host
retina
in
the
region
surrounding
the
lesion,
compared
to
that
which
occurs
with
the
lesion
alone
/32/.
This
effect
is
not
specific
for
retinal
grafts;
similar
results
are
obtained
if
sciatic
nerve
pieces
are
implanted,
but
not
with
implants
of
sheath
tissue
or
tendon/57,58/.
An
earlier
study
/4/
from
the
same
laboratory
involved
using
retinal
donor
material
from
P10
and
P1
pups
and
E14-E20
embryos.
The
grafts
were
histologically
examined
when
they
reached
the
equivalent
of
age
P28.
They
found
that
10-day-old
donor
material
resulted
in
a
lower
"evaluation
index"
(a
quantitative
measure
of
graft
survival,
lamination,
integration
with
host
retina,
absence
of
non-neuronal
barriers,
and
lesion
filling
and
repair
by
the
graft
tissue)
than
that
from
1-day-old
donors.
No
significant
difference
in
the
"evaluation
index"
was
found,
however,
between
transplants
from
P1
pups
and
the
embryos.
The
transplants
from
P10
donors
had
essentially
no
ganglion
cell
layer
or
IPL
present.
The
cells
from
the
INL
were
relatively
few
in
number
and
quite
disorganized.
Massive
fiber
outputs
which
did
leave
younger
grafts
were
absent
from
the
P10
graft
tissue.
Photoreceptor
cells
dominated
the
cyto-
architecture
of
these
grafts
in
the
absence
of
normal
populations
of other
cell
types.
The
average
survival
rate
was
over
90%/4/.
As
donor
age
increased
from
P2
to
P21,
the
success
of
the
transplant
progressively
declined.
For
P21
donors
the
transplant
completely
degenerated
within
2
days,
with
no
viable
grafted
tissue
found
in
the
lesion
site
/2,61/.
Daily
Cyclosporin
A
injections,
however,
allowed
healthy
retinal
donor
cells
from
21-day-old
donors
to
survive
for
at
least
6
days/3/.
If
given
only
for
the
first
24
hours,
only
a
remnant
of
the
graft
remained
at
6
days,
and
it
was
infiltrated
by
connective
tissue
and
some
macrophages/3/.
It
is
interesting
to
note
that
integration
even
of
donor
retina
frozen
for
several
months
to
the
temperature
of
liquid
nitrogen
is
possible,
although
over
a
narrower
range
of
donor
ages
/47/.
The
optimal
donor
age
for
transplants
of
strips
of
retina
into
lesioned
host
retinas
is
approximately
E16.
Donor
age
in
excess
of
E19
leads
to
poorer
success
and
differentiation,
while
E13
donor
tissue
rarely
survives.
Retinal
tissue
cryopreserved
for
8
months
survives
and
differentiates
just
as
well
as
tissue
cryopreserved
for
4
months/47/.
Xenografts
to
rat
hosts.
Retinas
transplanted
from
mouse
embryos
into
retinal
lesions
of
adult
Sprague-
Dawley
rats
required
that
the
hosts
be
treated
with
daily
Cyclosporin
A
(10
mg/kg)
in
order
for
the
.transplant
to
survive
30
days/3,61/.
At
8
to
9
days
post-transplantation,
the
grafts
were
still
mostly
undifferentiated
and
consisted
of
a
neuroepithelial
layer.
By
30
days,
the
ONL,
INL,
IPL
and
ganglion
cell
layers
were
all
identifiable
within
the
rosette
structures
of
the
graft/3,61/.
In
contrast
to
this
result,
strips
of
retina
from
newborn
C57BL/6J
mice
transplanted
into
the
posterior
poles
of
Fisher
344
albino
rats
were
still
well
accepted
17
days
post-transplant
without
any
immuno-
suppression/8-10/.
The
transplants
differentiated
into
ONL
cells
(with
inner
and
outer
segments
attached
to
them),
INL
cells,
and
a
plexiform
layer.
The
reaction
of
the
appearance
of
a
few
macrophages
around
the
transplant
was
reported
as
being
no
worse
than
that
found
in
corresponding
intraspecies
transplants/8-10/.
,Strips
of
retina
from
a
P60
and
a
P90
Cebus
Appella
monkey
fetus
transplanted
into
the
eyes
of
adult
Fisher
344
albino
rats
to
which
Cyclosporin
A
was
administered
were
still
not
rejected
33
days
post-
transplant/16,31/.
The
graft
differentiated
into
ONL
cells
with
inner
segments
attached
to
them,
INL
cells,
and
a
plexiform
layer.
It
integrated
well
with
the
host
retina
and
sometimes
also
expanded
into
the
vitreal
cavity/16,31/.
Non-rat
hosts.
The
rabbit
and
the
mouse
are
among
the
few
species
other
than
rats
to
have
been
utilized
as
intraocular
whole
retina
transplant
recipients.
Retinas
from
El5
albino
rabbits
have
been
transplanted
to
surgically
lesioned
retinas
of
4-
to
6-
week-old
albino
rabbits
/48/.
At
4
weeks
post-
transplant,
grafts
of
approximately
2
mm
in
diameter
were
found.
Rosettes
in
the
graft
contained
all
retinal
cell
layers,
with
the
exception
of
the
ILM/48/.
At
8
weeks
post-transplant,
the
grafts
appeared
to
be
smaller
and
with
fewer
rosettes
/1/.
Transplanted
JOURNAL
OF
NEURAL
TRANSPLANTATION
&
PLASTICITY

RETINAL
TRANSPLANTATION
whole
retina
which
included
the
RPE
led
to
a
higher
success
rate
and
usually
larger
graft
sizes
at
4
weeks
post-transplant
than
whole
retina
without
the
RPE
lid
Normal
retinas
from
P0
mice
were
transplanted
into
adult
mice
with
inherited
retinal
degeneration
(rd/rd)
/29/.
Three
days
after
the
transplant,
rosettes
of
grafted
tissue
showed
photoreceptor
differentiation.
The
survival
rate
for
the
transplants
was
high
at
3
days
post-transplant
but
dropped
dramatically
at
10-15
days,
with
a
regressive
change
in
the
photoreceptors.
Transplants
from
P0
(rd/rd)
mice
into
normal
mice,
on
the
other
hand,
still
had
a
good
survival
rate
10-15
days
post-transplant,
the
grafts
having
numerous
rosettes
and
some
photoreceptors
having
well
developed
outer
segments
/29/.
By
30
days
the
survival
rate
was
reduced,
but
photoreceptors
were
still
the
majority
of
surviving
cells
/30/.
The
authors
concluded
that
the
retina
or
the
intrinsic
cellular
defect
itself
may
not
be
the
only
factors
playing
a
role
in
this
type
of
retinal
degeneration/29,30/.
TRANSPLANTS
OF
SPECIFIC
RETINAL
COMPONENTS
So
far
in
this
review,
whole
retinal
transplants
have
been
discussed.
Transplants
of
retinal
components
alone
will
now
be
considered.
Transplant
of
Separated
Retinal
Layers
Retinas
from
P4
Fisher
rat
donors
have
been
separated
into
an
outer
layer
consisting
mainly
of
neuroblasts
and
an
inner
layer
consisting
primarily
of
ganglion
cells,
displaced
amacrine
cells,
and
astroglial
elements/21,22,39/.
Both
layers
of
cells,
when
trans-
planted
into
both
normal
and
light-damaged
retinas
of
adult
Fisher
rats,
successfully
differentiated
into
photoreceptors,
a
plexiform
layer,
and
a
cell
layer
which
was
presumably
the
inner
nuclear
layer.
Inner
layer
transplants
survived
better
than
outer
layer
transplants.
The
intact
photoreceptor
matrix
separated
from
the
retinas
of
normal
7-day-old
Sprague-Dawley
rats
has
been
transplanted
to
the
subretinal
space
of
photo-
damaged
retinas
of
adult
albino
hosts
of
the
same
species/54/.
Transplanted
photoreceptors
were
found
at
survival
times
of
2,
4,
and
6
weeks,
with
an
overall
success
rate
of
67%.
The
transplant
remained
approximately
constant
in
size
with
survival
time,
and
consisted
of
columnar
stacks
of
about
12
cell
bodies,
which
is
characteristic
of
the
photoreceptor
layer,
as
well
as
some
rosette
formations.
The
number
and
length
of
photoreceptor
outer
segments
was
reduced,
however/54/.
Photoreceptor
layer
transplants
from
adult
human
eyebank
eyes
to
photodamaged
adult
host
retinas
were
also
successful,
but
only
if
the host
rats
were
immuno-
suppressed/52/.
Retinal
Pigment
Epithelium
(RPE)
Transplants
The
retinal
layer
which
has
most
frequently
been
transplanted
alone
is
the
RPE.
The
earliest
report
of
RPE
transplant
was
from
Gouras
et
al.
They
obtained
human
RPE
cells
from
donors
aged
65
to
85
years
within
12
to
24
hours
after
death
and
cultured
them
in
vivo
/27/.
Cells
from
the
primary
culture
were
subcultured
and
radiolabelled.
The
subcultured
cells
were
transplanted
to
an
area
of
Bruch’s
membrane
of
owl
monkeys
which
had
been
exposed
and
denuded
of
host
RPE
cells.
Survival
times
ranged
from
2
hours
to
7
days.
Transplanted
cells
had
already
attached
to
the
denuded
area
of
Bruch’s
membrane
at
2
hours
and
continued
to
divide
thereafter.
Leukocytes
were
observed
in
the
choriocapillaris
and
Bruch’s
membrane
at
times
as
early
as
2
hours.
Macrophages
appeared
in
the
choriocapillaris
and
Bruch’s
membrane
beginning
at
3
days
and
increasing
in
number
up
to
7
days
(immunosuppression
was
not
used).
Lopez
et
al.
performed
transplants
of
cultured
rabbit
RPE
cells
from
adult
albino
and
pigmented
rabbits
to
the
subretinal
space
of
normal
adult
pigmented
rabbits
/36/.
Within
an
hour,
cells
attached
to
Bruch’s
membrane,
and
at
24
hours
(the
longest
post-
transplant
time
reported),
some
cells
were
phagocytosing
receptor
outer
membranes.
The
success
rate
for
the
most
successful
method
attempted
was
approximately
25%.
The
main
problems
encountered
in
their
transplants
were
breaks
in
Bruch’s
membrane,
unsuccessful
denudation
of
the
host
pigment
epithelium,
and
failure
to
inject
a
sufficient
number
of
donor
cells/36/.
VOL.
2,
NO.
2,
1991

86
R.M.
Hammer
and
U.
Yinon
When
this
type
of
transplant
was
followed
for
6
months
in
non-irnmunosuppressed
rabbits,
there
were
granulomatous
reactions
with
damage
to
the
ehorio-
capillaris
and
overlying
photoreeeptors
/5/.
Inflammatory
cells
traversed
Brueh’s
membrane
and
entered
the
subretinal
space.
It
was
possible,
however,
to
prevent
these
reactions,
while
also
enabling
trans-
planted
RPE
to
survive
the
6-month
period
by
administering
Cyelosporin/5].
Li
and
Turner/34/have
transplanted
cultured
RPE
cells
from
P6-P8
Long-Evans
rat
pups
to
Sprague-
Dawley
rat
hosts
of
ages
ranging
from
P10
to
adult.
Approach
to
the
subretinal
space
was
through
the
dorsal
surface
of
the
eye,
without
passing
through
the
vitreous.
Using
survival
times
ranging
from
2
hours
to
3
months,
the
grafts
were
successful
for
all
host
ages
attempted,
with
an
overall
success
rate
of
95%.
The
photoreeeptors
underlying
the
grafts
remained
normal.
An
additional
study
describes
pigment
epithelium
taken
from
the
peripheral
retina
of
12-
to
20-week-old
Gottingen
miniature
pigs
and
transplanted
to
the
subretinal
space
at
the
posterior
pole
of
the
same
eye
(autologous
transplant)
/33].
Cell
attachment
to
Brueh’s
membrane
was
demonstrated
1
hour
post-
transplant.
Effiux
of
cells
to
the
vitreous
and
significant
subretinal
hemorrhage
occurred
in
40%
of
cases.
At
least
two
laboratories
have
attempted
to
apply
RPE
transplantation
to
the
prevention
of
the
hereditary
photoreceptor
degeneration
in
the
Royal
College
of
Surgeons
(RCS)
rat,
as
will
be
discussed
in
the
paragraphs
which
immediately
follow.
There
is
evidence
that
the
gene
for
the
retinal
dystrophy
in
the
RCS
rat
acts
on
the
RPE
cells/44/.
Phagocytosis
by
RPE
cells
of
photoreceptor
outer
segments,
which
is
an
important
function
of
normal
RPE
cells,
is
deficient
in
the
RCS
rat
/6/.
Photoreceptor
outer
segments
differentiate
and
elongate
in
a
normal
fashion
until
age
P18;
by
P22,
degeneration
of
photoreceptor
cell
nuclei
is
well
underway,
and
photoreceptor
degeneration
is
almost
complete
by
P60/24/.
The
implication
of
the
RPE
in
this
process
(and
the
possibility
that
this
may
be
a
model
for
certain
human
retinal
degenerations)
has
spurred
the
following
studies.
Lopez
et
al.
transplanted
freshly
harvested
dissociated
RPE
cells
from
pigmented
normal
rats
(of
unspecified
age;
presumably
adults)
to
the
subretinal
space
of
congenic
RCS
rats
of
age
P15-P22/37/.
As
long
as
4
months
post-transplant,
areas
in
which
trans-
planted
RPE
cells
were
present
also
had
photo-
receptor
cells.
The
more
donor
RPE
cells
present
in
a
region,
the
thicker
was
the
host’s
photoreceptor
cell
layer
in
that
region.
Transplanted
pigment
epithelial
cells
contained
many
more
phagosomes
than
normal
]37/,
while
older
cells
]28/had
a
higher
content
of
older
phagosomes
than
younger
ones.
Receptors
survived
even
at
a
distance
from
transplants/28/.
Li
and
Turner
transplanted
RPE
cells
from
black-
eyed
Long-Evans
P6-P8
rats
to
the
subretinal
space
of
P26
non-pigmented
RCS
hosts
with
a
100%
success
rate/35/.
When
the
hosts
reached
age
60
days,
there
was
a
retinal
area
of
approximately
4.2
mm
2
where
degeneration
of
host
photoreceptors
was
prevented.
Distinct
zones
of
photoreceptor
outer
and
inner
segments
were
found,
and
the
OPL
was
not
reduced
in
thickness
compared
to
its
thickness
at
P26.
In
P60
nongrafted
controls,
however,
the
receptor
outer
segment
membranes
formed
only
a
debris
zone,
while
the
inner
segments
had
disappeared.
The
OPL
was
one-third
of
the
thickness
it
had
at
26
days
/35/.
Sheedlo
et
al.
further
found
that
the
thickness
of
the
ONL
varied
little
in
the
region
beneath
a
graft,
even
though
the
distribution
of
donor
cells
within
the
region
of
the
transplant
was
typically
random/50/.
Starting
at
the
transition
zone
between
the
graft
and
the
host
RPE,
the
ONL
began
to
decrease
in
thickness.
The
distribution
in
retinal
regions
where
photoreceptor
degeneration
was
prevented
of
the
membrane
protein
Na/,
K/-ATPase
and
of
the
photoprotein
Opsin
was
not
different
from
that
found
in
normal
control
Long-
Evans
rats.
Both
those
transplanted
RPE
cells
attached
to
Bruch’s
membrane
and
those
on
the
apical
surface
of
other
RPE
cells
appeared
to
be
able
to
ingest
shed
rod
outer
segments
and
membrane
debris
/50/.
RPE
transplants
are
able
to
prevent
photoreceptor
degeneration
only
if
performed
prior
to
the
host
age
of
approximately
30
days/51/.
For
trans-
plants
performed
at
P39,
there
was
no
significant
photoreceptor
cell
rescue
3
months
after
grafting/51/.
While
transplant
of
RPE
alone
does
not
effect
photoreceptor
rescue
for
RCS
rat
hosts
older
than
P39
/51/,
transplant
of
RPE
together
with
dissociated
photoreceptors
to
the
subretinal
space
of
4-
to
6-
month-old
hosts
has
been
attempted/25,26/.
Survival
time
of
only
24
hours
was
reported,
and
photo-
receptors
were
found
in
the
subretinal
space/25,26/.
JOURNAL
OF
NEURAL
TRANSPLANTATION
&
PLASTICITY

RETINAL
TRANSPLANTATION
87
While
RPE
transplants
have
been
found
to
prevent
photoreceptor
degeneration
in
RCS
rats,
a
third
laboratory
has
found
that
surgical
manipulation
alone
in
P25
and
P36
RCS
rats,
including
injection
of
saline
or
implantation
of
a
gelatin
carrier
without
trans-
planted
cells,
is
sufficient
to
prevent
photoreceptor
degeneration
in
the
region
of
the
surgery
just
as
effectively/55/.
Survival
times
of
up
to
2
months
post-
surgically
were
utilized
/55/.
The
only
one
of
the
above-cited
studies
of
RPE
transplantation
to
RCS
rats
which
included
a
sham
control
group
/51/
(vehicle
injected
at
17
days)
found
only
a
partial
and
short-lived
photoreceptor
cell
rescue.
At
age
2
months,
the
ONL
was
much
thinner
than
with
RPE
transplant,
and
in
a
much
smaller
area,
while
at
3
months
the
rescue
effect
was
no
longer
seen.
TRANSPLANT
FUNCTION
In
addition
to
observing
the
structural
characteristics
of
transplanted
retinal
tissue,
it
is
important
to
assess
the
extent
to
which
the
transplant
functions
like
normal
retina,
and
whether
it
successfully
conveys
visual
information
to
higher
centers.
The
sparse
information
on
this
subject
which
is
available
at
the
present
early
stage
in
the
history
and
development
of
intraocular
retinal
transplantation
is
presented
in
this
concluding
section.
One
study
reports
on
the
2-deoxyglucose
uptake
in
photoreceptors
transplanted
from
P8
donors
to
adults
with
light-damaged
retinas
(they
do
not
mention
which
animal)
/53/.
The
uptake
patterns
in
transplanted
photoreceptor
regions
and
underlying
host
INL,
both
under
dark
conditions
and
under
10
Hz
flicker
stimulus,
were
similar
to
that
of
normal
retina.
Another
study
has
been
carried
out
on
trans-
plantation
of
retina
from
pigmented
Westenberg
Long-
Evans
rats
to
the
anterior
chamber
of
albino
rats
of
the
same
species/7/.
The
response
of
the
host
retina
to
light,
as
measured
by
the
electroretinogram
(ERG),
had
been
eliminated
by
poisoning
with
6-hydroxy-
dopamine.
The
ERG
was
detected
in
rats
which
received
retinal
transplants,
while
it
was
absent
in
those
which
received
no
transplant
or
a
sham
transplant
of
medium
only.
ACKNOWLEDGEMENT
R.M.
Hammer
is
grateful
to
the
University
of
New
South
Wales,
Australia,
for
granting
him
permission
to
perform
work
towards
his
MSc(Optom)
degree
at
the
Physiological
Laboratory,
Goldschleger
Eye
Research
Institute,
Tel
Aviv
University,
Israel,
where
this
work
was
carried
out.
REFERENCES
1..Aramant
R,
Seiler
M,
Bergstrom
A,
Adolph
AR.
Cografts
of
retina
and
retinal
pigment
epithelium
to
adult
rabbit
retina.
Soc
Neurosci
Abstr
1989;
15:1367.
2.
Aramant
R,
Seller
M,
Turner
JE.
Donor
age
influences
on
the
success
of
retinal
grafts
to
adult
rat
retina.
Invest
Ophthalmol
Vis
Sci
[988;
29:498-503.
3.
Aramant
R,
Turner
JE.
Cross-species
grafting
of
embryonic
mouse
and
grafting
of
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