Ординатура / Офтальмология / Учебные материалы / Clinical Diagnosis and Management of ocular trauma

196

Clinical Diagnosis and Management of Ocular Trauma

blunt head trauma. This is in contrast to direct TON,

which results from an anatomical disruption of the optic

nerve fibers.

Patients can present with a variable degree of vision

loss (decreased visual acuity, visual field abnormalities,

or loss of color vision). Most cases (up to 60%) present

with severe vision loss of light perception (LP) or

worse.

In the acute phase, the optic nerve usually appears

normal on funduscopic examination, but optic nerve

atrophy is often seen 3-6 weeks after the injury; so

the clinical must be aware to perform periodical

revisions of the traumatized eye during a long period

of time.

Fig. 31.7: Optic nerve avulsion

Mechanisms of Injury

There are two known forms of optic nerve injury:

Indirect injury: In indirect TON cases, the injury to

the axons is thought to be induced by shearing forces

that are transmitted to the fibers or to the vascular

supply of the nerve. Studies have shown that forces

are transferred and concentrated in the area near

the optic canal. The tight adherence of the optic

nerve’s dural sheath to the periosteum within the optic

canal is also thought to contribute to this segment

of the nerve being extremely susceptible to the

deformative stresses of the skull bones. Such injury

leads to ischemic injury to the retinal ganglion

cells within the optic canal.

Direct injury: A secondary mechanism can result

in optic nerve swelling after the occurrence the acute

injury. The optic nerve swelling can exacerbate retinal

ganglion cell degeneration by further compromising

Fig. 31.8: Optic nerve atrophy

the vascular blood supply, either through a rise in

intraluminal pressure or reactive vasospasm. These

of a bilateral TON, both pupils may be dilated and

secondary mechanisms, in theory, form the rationale

nonreactive to light if the injury is profound.

for optic canal decompression via medical (e.g.steroids)

At the funduscopic, because the location of the

or surgical means (e.g. bony decompression).

injury in most of the cases is within the posterior orbit

Diagnosis

or the optic canal, the optic disc typically appears

normal on funduscopic examination on initial diagnosis.

Even in an acute trauma setting, patients should have

Optic nerve atrophy usually appears 3-4 weeks after

a visual acuity assessment as soon as possible. If the

the traumatic event, and the disc acquires a diffuse

patient cannot read the top letter on the eye chart,

pallor. Rarely, optic nerve changes can be seen with

the visual acuity may be recorded with the following

direct injuries to the retrobulbar section of the optic

nomenclature; counting fingers vision, hand motion

nerve, presenting as an avulsed optic nerve head or

perception, light perception (LP), or no light perception

optic disc swelling with surrounding hemorrhage

(NLP), sometimes are the obtained lectures.

(Figs 31.7 and 31.8).

The pupil examination assesses for a relative or

Computed Tomography of orbits, comparing both

complete afferent pupillary defect. An eye with a

optic nerves anatomy, are sometimes of great value,

unilateral optic nerve injury will demonstrate an

but even so, sometimes even in the presence of severe

afferent papillary defect, verifying the presence of TON,

optic nerve damage, the funduscopic and the radiologic

but not excluding other diagnosis. In the rare cases

findings can be normal.

Management of Blunt Retinal Trauma

197

Management

velocity missile; it is the result of traumatic chorioretinal

Steroids have been used in TON since the early 1980s;

rupture followed by marked fibrovascular proliferation

they are thought to provide neuroprotection in

with variable replacement of the choroid and retina

traumatic central nervous system injury through their

with no retinal detachment.

antioxidant properties and inhibition of free radical-

Contusion force may lead to choroidal ruptures

induced lipid peroxidation. Recent studies have

with hyperplasia and migration of the retinal pigment

demonstrated that the therapeutic role for cortico-

epithelium into the retina and choroid, epiretinal

steroids in the management of TON is unsubstantiated.

membrane formation, loss of photoreceptors and

If steroids are considered to be used in cases with

marked atrophy of the optic nerve.

concomitant traumatic brain injury, it must not be a

decision of the ophthalmologist by it self; dangerous

Diagnosis

circumstances involving the central nervous system can

The diagnosis should be established only based on

be mascared. The use high or lower doses of steroids

clear objective findings, a relative afferent pupillary

is also not clearly defined by the literature as useful

defect or an evoked visual response. The most

for optic nerve protection. May be, as has been seen

important factor in determining the force of injury is

in other sections of this chapter, they can provide a

the velocity. As higher the speed of the projectile object,

placebo effect in the patient, family, but also in the

the greater the tissue disruption at the impact zone

physician.

due to the delivered kinetic energy. The shock wave

The indication for surgical therapy in indirect optic

energy released by the projectile object is considered

nerve trauma is to decompress it at the site of injury,

as the main cause of choroidal and subsequently retinal

which is often the intracanalicular segment. Surgical

injury (Fig. 31.9).

decompression is thought to help reduce optic nerve

compression and subsequent vascular compromise that

Treatment

may occur as a result of the indirect injury. Another

probably benefit of surgery that has been postulated,

Retained intraorbital metallic foreign bodies may

is to remove bone fragments that may be injuring on

accompany chorioretinitis scleopetaria, commotio

the optic nerve within the optic canal. However, no

retinae, vitreous hemorrhages, or some other times

randomized, controlled studies have been performed

this entity can be presented alone; treatment of

to evaluate the role of surgery in this disease.

concomitant damage should be done. In the case of

bullets, gun pellets, the usual management is

Conclusions

conservative due to the inert nature of this type of

Traumatic optic neuropathy (TON) can lead to pro-

metallic foreign bodies. There are considerable

found visual loss from either indirect or direct

reported cases with chorioretinitis sclopetaria due to

mechanisms. The diagnosis can be made with

bullet gun injuries; the characteristic pattern of

accurate history taking and clinical examination, based

choroidal and retinal changes caused by a high

on the presence of visual loss and an accompanying

velocity projectile object passing through the orbit,

relative afferent pupillary defect. The optimal treatment

in close proximity to the globe is usually seen in this

for TON, however, remains debated among physicians.

condition.

Corticosteroids should not be used in cases with

concomitant traumatic brain injury or in patients who

present 8 hours or more after initial injury. Based on

the available evidence, surgical decompression of the

optic canal is not routinely recommended. If treatment

with either steroids, surgical intervention or both is

considered, appropriate information and informed

consent should be given to the patient and their family;

they should know (and sign) the potential benefits and

the risks.

CHORIORETINITIS SCLOPETARIA

Definition

It is a proliferation of fibrous tissue in the choroid and

Fig. 31.9: Retinitis sclopetaria

retina as the result of contusion of the sclera by a high

Management of Blunt Retinal Trauma

199

3.

Barr CC. Prognosis factors in corneoscleral lacerations.

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Gass JDM. Stereoscopic Atlas of Macular Disease:

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Barr CC, Vine AK, Martonyi CL. Unexplained hetero-

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Goffstein R, Burton TC. Differentiating traumatic from

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Berlin R. Zur sogenannten commotio retinae. Klin

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Monatsbl Augenheilkd 1873;11:42.

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Hart JCD, Frank HJ. Retinal opacification after blunt

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Blight R, Hart JCD. Structural changes in the outer

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Hilton GF. Late serosanguineous detachment of the

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Brinton CS, Topping TM, Hyndiuk RA, et al. Post-

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Kaufer G, Zimmerman IE. Direct rupture of choroid.

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Chang S. Low viscosity liquid fluorochemicals in

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Kohno T, Ishibashi T, Inomata H, et al. Experimental

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Chang S, Reppucci V, Zimmerman NJ, et al. Perfluoro-

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Lewis H, Blumenkranz M, Chang S. Treatment of

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Coleman DJ. Early vitrectomy in the management of the

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Thompson JT. Traumatic retinal tears and detachments.

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Applications of Stem Cell Therapy in Ophthalmology

201

myocardium is not supported by experimental data

mammal does not show regenerative capacity after

by Murry CE et al. According to Balasam LB et al

damage, there is a possibility for the reinitiation of stem

hematopoietic stem cells adopt mature hematopoietc

cell potential at the peripheral retinal margin, from

fates in ischemic myocardium. According to Anderson

the RPE or from the Muller glial cells. The application

DJ, et al these clinical observations cannot be

of information derived from the studies of retinal

invalidated but raises many questions regarding

progenitor cells in developing organisms should soon

interpretation and emphasizes that there is a need to

provide a test of these possibilities.

establish rigorous standards by which such clinical

This regenerative capacity derives from quiescent

studies are evaluated.

stem cells that reside in the adult retina of these species.

Very limited work has been done regarding retinal

Similar regenerative capacity has been demonstrated

stem cells.There has been extensive literature work

in mammalian retina. For a population of retinal stem

done an stem cells giving rise to vascular, muscle

cells to exist in the adult retina, it would have been

nervous hemopoietic tissue. Very limited work has

necessary for such a population of progenitor cells to

been done on the retinal stem cells.

remain quiescent after the retina has fully differentiated.

There are four basic population of cells that may

Livesey FJ et al has done large scale Genomic anlysis.

contain dormant progenitor cells.

Blackshaw S et al has done Genomic analysis of mouse

1. Retinal stem cells that can give rise to

retinal development.

photoreceptors

The work of livesey and Blackshaw can serve as

2.

Muller/glial stem cells

the starting point for the evaluation of numerous genes

3.

Retinal pigment epithelial [RPE]; and endothelial

and their potential role in the regulation of retinal cell

progenitor cells [EPC]

developmental determination. How genes are

Recently adult bone marrow-derived HSCs

progressively switched on and off in an orderly fashion

containing EPC is an intresting areas of research.

during the generation of specific retinal cell types, and

how this overlaps with gene sets utilized during the

Role of Retinal Stem Cells and

establishment of other, nonretinal neuronal cell types,

will contribute significantly to our understanding of

Muller Glial Cells

retinal progenitor biology. Dyer MA et al has done

study in regulation of cell proliferation in retinal

Reh TA et al. has shown that regenerative capacity

development. Das AV et al has done identification of

exists in retina of amphibians and chicken embryos

c-KIT receptor as a regulator of adult neural stem cells

after injury.The vertebrate retina is derived from paired

in the mammalian eye and the role of various

evaginations from the neural tube in embryonic

transcription factor and signaling molecules during this

development and is initially produced by progenitor

process have provided insight into putative

cells similar to those that generate the neurons and

mechanisms whereby the mammalian retina holds in

glia of other areas of the central nervous system. In

reserve a subset of progenitor cells that theoretically

some amphibians and fish, the retina continues to grow

could be used to regenerate damaged issued in the

along with the eye throughout the life of the animal.

in the adult. Clearly, James J et al has studied the the

The new retinal cells are added at the ciliary margin

development state of the retina and the context in

of the eye from the mitotic activity of neural/glial stem

which a specific cell finds itself will determine how a

cells in a region known as the germinal zone and are

particular retinal progenitor cell behaves: whether it

seamlessly incorporated into the existing retinal circuitry.

will terminally differentiate or maintain a quiescent state

Little is known about the cell or molecular biology of

from which it can letter emerge to give rise to cells

these stem cells; however, studies of retinal progenitor

useful in repair of a damaged retina will depend not

cells in chick and mammalian embryos have led to

only on its own developmental programme, but the

the identification of several factors that control their

microenmorvironment in which it finds it self.

proliferation. Moreover, studies of retinal regeneration

James J et al has done cellular and molecular

have shown that retinal stem cells can also be derived

characterization of early and late retinal stem cells/

from two or perhaps three additional sources after

progenitors: differential regulation of proliferation and

retinal damage: (a) the retinal pigmented epithelium

context dependent roll of notch signaling.

(RPE) in amphibians and embryonic chicks and

James J et al has done transcriptional profiling

mammals; (b) a specialized rod progenitor in fish; and

studies of retina at different states of development

(c) the Muller glial cells. While there is currently no

coupled with in vitro studies of progenitor cell

evidence for a neural/glial stem cell in the adult

populations should provide the information necessary

mammalian retina, and the retina of the mature

to begin such an analysis and determine what

202

Clinical Diagnosis and Management of Ocular Trauma

conditions help maintain quiescence and what

activation of intrinsic genes. These studies are most

conditions stimulate proliferation and subsequent

provocative, could provide additional insight into

differentiation of retinal progenitor cell populations.

retinal regeneration in mammals, and provide a

Konobu T et al have shown that cells with

rationale for the targeting of Muller glial in certain

characteristics of retinal neuron have been obtained

inherited and acquired retinal degenerative disorders.

from a number of embryonic tumor cell line, including

If we isolate retinal stem cells from the adult

neuroblastoma, gliaoblastoma, but because of the

mammalian eye and then using them to regenerate

malignant potential of these cells they are not likely

diseased retina then it will have a great therapeutic

to be useful.

effect. There have been some reports suggesting that

Martinez-Serrano A et al, have cultured virally

if multipotent progenitor cells isolated from retina of

transformed, immortalized neuronal precursors were

neonatal mice retina are used in the early, then some

evaluated for their ability to differentiate into retinal

level of visual function may be obtained in animal eyes

neurons after intraocular implantation.

with retinal degeneration. At cellular level it is very

Bain G et al have attempted at inducing in vitro

difficult to establish functional neuronal connection

differentiation of embryonic stem cells into retinal

between implanted progenitor cells or sheets of

neuronal phenotypes were done using a variety of

photoreceptor and the host’s nerve fiber layer prior

factors, including retinoic acid.

to reestablishing visual pathways that would lead to

Tropepe V, et al has identified Retinal progenitor

functional vision.

stem cells in the adult mammalian eye. Ahmad I, et al

have done Identification of neural progenitors in the

Role of Retinal Pigment

adult mammalian eye. Retinal progenitor cells have

been identified in ciliay margin. These cells were not

Epithelial Stem Cells

isolated from central or peripheral pigmented

epithelium. These cells are clonally expanded in culture

RPE cells and photoreceptors enjoy an close

to give rise to a variety of retinal cells types, including

relationship both anatomically and functionally. Where

rod photoreceptors, bipolar neurons, and muller glia.

is the principal underlying defect in many inherited

The differentiation of these cells from the ciliary margin

retinal degenerations is still a question: the

pigmented cell progenitors is not due to

photoreceptor or RPE cells ?. Although with the advent

transdifferentiation of the ciliary margin cells, but rather,

of molecular genetics this confusion has become less,

clonal proliferation and defferentiation as observed in

but the interdependency between these two cells types

a true stem cell.

remains and there is often concomitant degeneration

Fischer AJ et al have shown that in chicken an adult

of both cell types observed in a variety of inherited

differentiated muller gila can serve as a source of stem

and acquired degenerative disease of the retina. In

cells that will, in response to injury, or cytokinenes,

this regard—RPE cell transplantation has been

differentiate, proliferate and redifferentiate into

evaluated both for its potential to replace diseased RPE

additional glial cells or neurons.

as well as to provide a source of cells whose phenotypic

Turner DL, et al have identified common progenitor

differentiation may be manipulated by various

cells that gives rise to both Muller glia and retinal

cytokines and trophic substances. Thus, RPE cell lines

neurons.

have been developed for use as RPE cell transplants,

Thus, the concept that Muller glia of the adult retina

cell-based drug delivery platforms, and “photoreceptor

can serve as potential source of retinal stem cells is

stem cells”.

consistent with molecular profiling of developing

Transplantable RPE cell lines may serve as stem

mammalian retinas that shown a high degree of

cells of sorts to replenish diseased RPE cells themselves.

similarity between the gene expression profiles of Muller

In a number of macular and retinal degenerative

glia and mitotic retinal progenitor cells in the mouse.

disorders there is atrophy of the RPE and associated

Since the Muller glia are the cells that commonly

malfunctioning in the phototransducing cellular

proliferate in response to retinal injury, it would not

machinery. Damaged RPE cells and associated atrophy

be surprising that these cells also retain the potential

are hallmarks of age-related macular degeneration and

to defferentiate along a number of pathways, some

heroic surgical approaches have been considered to

of which may lead to retinal neuronal replacement.

provide photoreceptors in such individuals with

Ooto S et al have done a recent study significantly

healthier, RPE-rich regions of the retina through retinal

expanded this concept: amarcine, horizontal, and

translocation and the insertion of RPE sheets.

photoreceptor phenotypes were mammalian retina in

Human RPE cell lines enjoy an extended life span

the presence of extrinsic factors (e.g. retinoic acid) or

after being stably transfected with a plasmid encoding

Applications of Stem Cell Therapy in Ophthalmology

203

the simian virus 40 large T antigen and many of the

circumstances, provide a transplantable pool of cells

factors expressed by functional RPE cells in vivo are

to rescue diseased photoreceptors and, as such, have

observed to be expressed by these transformed cell

utility in the treatment of retinal degenerations.

lines. When these cells are transplanted subretinally

into a rat model of retinal degeneration (the RCS rat),

Role of Bone Marrow: Derived

loss of visual function is attenuated and cortically

dependent visual function is preserved long-term.

Stem Cells

These RPE cell lines can be transferred with plasmids

encoding a variety of trophic factors shown to have

BONE MARROW HEMATOPOIETIC

protective effects on photoreceptors and then

STEM CELLS

encapsulated into polymer devices that permit diffusion

In 1917, Pappenhein postulated the existensce of an

of cell products into the tissue into which they are

undifferentiated stem cell for blood cells. The hema-

transplanted. When transformed RPE cell lines are

topoietic or blood forming cells are located in the bone

transfected with a plasmid encoding one such factor,

marrow. The lineage of blood cells extends from a

ciliary neurotrophic factor (CNTF), and transplanted

resting stem cell, to transitamplifyilng precursor cells,

directly into the vitreous of dogs with retinal

to mature circulting blood cells. Untill recently, most

degeneration, photoreceptor degeneration is reduced.

primitive bone marrow progenitor cell was believed

Further more, production of this factor and

to be pluripotent, giving rise to stromal cells and

implantation of the encapsulation device into the

lymphocytic cells, as well as RBCs, WBCs. In addition

vitreous of normal rabbits did not lead to toxic effects

to hematopoietic precursor, bone marrow also

on either the electroretinogram or retinal histology in

contains a mesenchyamal progenitor cell can give rise

these animals at doses that protect photoreceptors in

to many other cell types such as muscle cells, astrocytes,

dogs with retinal degeneration. Such cell-based

and neurons,as well as stromal cells that support

delivery devices may be used to provide trophic factors

hematopoiesis. However, the accumulating evidence

for the treatment of a variety of retinal degenerative

is that, not only does the bone marrow contain a pluri/

diseases and, in fact have recently been used in a

multipotent blood forming stem cell, but it also contains

human clinical trial evaluating the efficacy of CNTF

a cell that has the capacity to circulate to other organs

in the treatment of retinal degeneration. In this respect,

and replace different nonhematopoietic tissues.

the implanted encapsulated cell devices function as a

Although these bone marrow-derived cells have

stem cell, providing factors critical to the prevention

markers of the hematopoietic stem cell [HSC], it has

of, or recovery from, retinal degenerative disease.

not been ruled out that this multipotent cell may be

Spontaneously differentiating human embryonic

of stromal origin. Serial transplantation indicates that

stem cell lines having many molecular and functional

a single bone marrow cell may give rise to many

characteristics of RPE cells have been touted as a

different tissue types and suggest that a common

potential source of transplantable RPE cells for

precursor must exist, not only for stromal and

hematopoietic lineages, but also other germ layer-

subretinal transplantation into human retinas. Large-

derived cell types. It is this putative totipotent bone

scale genomic analysis was used to compare these cells

marrow cell that has stimulated the great revival of

to primary human RPE cell lines and they were found

interest in adult stem cells in the last few years. There

to resemble more closely the molecular signature of

are still some caveats to the generally accepted

primary RPE cells than previously reported, established

assumption of pluripotentiality of tissue stem cells

human RPE cell lines. If these cell lines can be

including HSCs.

maintained in cell banks and altered so as to facilitate

immune acceptance, they may represent a source of

transplantable tissue.

Role of Adult Bone Marrow:

Studies done over a decade ago evaluated the

potential use of RPE cells as stem cells of sorts: when

Derived Endothelial Progenitor

RPE cells were injected subretinally into the eyes of

(Stem) Cells

mice with inherited retinal degeneration, rescue of

photoreceptors was observed. It was found that

Abnormalities in the retinal or choroidal vasculature:

exogenously injected basic fibroblast growth factor

macular edema, retinal and vitreous hemorrhage, and

could mimic this rescue. This led to the concept that

fibrovascular scarring commonly contribute to visual

RPE cells may, under appropriate conditions, serve

loss in diseases such as age retinal macular degene-

as a form of cell-based therapy and may, under certain

ration, diabetic retinopathy, retinopathy of prematurity,

204

Clinical Diagnosis and Management of Ocular Trauma

and neovascular glaucoma. Retinitis pigmentosa are

anywhere but in or near blood vessels since these cells

commonly thought of as neuronal degenerations, but

are derived from green fluorescent protein. How this

most also exhibit vascular abnormalities traditionally

is going to be used in human is still in question?

attributed to loss of neuronal elements and accompan-

ying decreased metabolic demand leading to vascular

Role of Bone Marrow: Derived

atrophy. Otoni A et al have describe a newly emerging

paradigms: the existence of trophic “cross-talk”

Stem Cells in Retinal and

between local vascular networks and the tissues they

Choroidal Neovascularization

supply and such interactions almost certainly help to

maintain a functional differentiated state in a variety

It was Grant and colleague who has first directly

of organ systems. Shen Q et al have shown that,

demonstrated that systemically administered HSC

endothelial cells are also now known to provide trophic

(Hematic stem cell can function as Hemangioblast

substance that greatly stimulate self-renewal and

during hypoxia stimulated retinal neovascularization).

expand neural differentiation of neural stem cells.Given

Hematopoetic stem cells contains a pool of EPCs

such interdependency of vascular endothelial cells and

(endothelial progenitor cells) capable of incorporating

surrounding tissues, it may be possible to use one cell

into retinal vasculature has recently been demonstrated

type to rescue the other in the face of severe stress

by several groups. Grant and colleague have

such as hypoxia or genetically encoded cell-specific

demonstrated that circulating, undifferentiated

degenerations. Under such conditions it would be

precursor cells can be recruited to sites of retinal

desirable to have available populations of progenitor

neovascularization and, along with proliferation of local

cells useful for such protection.

endothelial cells, can contribute to new blood vessel

BONE MARROW: DERIVED STEM CELLS

growth and development. The relative contribution

of circulating precursor cells and endogenous retinal

CAN EXERT A NEUROTROPHIC RESCUE IN

vascular endothelial cells to newly forming vasculature

RETINAL DEGENERATION

in human disease remains unknown; the experiments

Humphries P et al has done molecular genetics of

of Grant and colleagues demonstrate that circulating

retinitis pigmentos and has identified mutations in over

cells can incorporate into laser-stimulated retinal

110 different genes, accounting for only a relatively

neovascularization, but the role of these cells in

small percentage of the known affected individuals

nonirradiated hosts where the proliferation of local

many of these mutations are associated with enzymatic

inflammatory, precursor, and endothelial cells is not

and structural components of the phototransduction

impaired by lethal irradiation remains unclear. Studies

machinery, including rhodopsin. Most inherited human

from several groups have demonstrated, using the

retinal digenerations

same irradiation/bone marrow reconstitution model

Otoni A et al have shown that bone marrow –

that circulating stem cells can also contribute to laser-

derived stem cells exert vasculotrophic properties.

stimulated choroidal neovascularization.

These cells have also recently been reported to

Dorrell MI, et al have demonstrated a role for the

completely prevent retinal vascular degeneration

adhesion molecule, R-Cadherin, in the targeting of

ordinarily observed in mouse models of retinal

HSC to the retinal vasculature when small molecule

degeneration, and the vascular rescue correlates with

antagonizes or function blocking antibodies to

neuronal rescue. The inner nuclear layer remains nearly

R-Cadherin are used to pretreat Lin-HSC prior to

normal and the outer nuclear layer containing

intravitreal injection, the cells no longer target sites of

photoreceptors is significantly preserved, with the

angiogensis and participate in the formation of new

rescued mice being predominantly cones. Detectable,

retinal blood vessels. Integrin alpha 4 beta 1, a

albeit severely abnormal electroretinogram recordings

adhesion molecules may play a role in targeting

are observed in rescued mice at time when they are

circulating EPCs to sites of abnormal angiogenesis

never observed in control treated, or untreated, rd/

during vascularization of tumor, and that these integrin

rd eyes. This rescue effect is also observed when human

may be potential therapeutic target if, indeed circulating

bone marrow-derived LinHSCs are used to treat

EPCs contribute to pathological ocular angiogenesis.

severe combined imnunodeficient mice with retinal

Interfering with the function of such targeting molecule

degeneration. Large-scale genomic analysis of rescued

used by EPCs to target sites of pathological

eyes revealed significant upregulation of antiapoptotic

neovascularization in combination with cell based

gene. It is important to note that the injected bone

therapies to produce angiostatic molecues locally could

marow-derived progenitor cells are never observed

significantly reduced abnormal angiogenesis.

Applications of Stem Cell Therapy in Ophthalmology

205

BONE MARROW—DERIVED STEM CELLS CAN

derived cells, placenta-derived cells, and mesenchymal

EXERT A VASCULOTROPHIC RESCUE EFFECT

stem cells were studied; dermal fibroblasts served as

Otoni A at al have injected LinHSCs directly into

cell controls. At various ages up to 100 days,

electroretinogram responses, spatial acuity and

the eyes of newborn mice while they were forming

luminance threshold were measured. Both umbilical-

their retinal vasculature; in this environment, these cells

derived and mesenchymal cells significantly reduced

can target activated astrocytes, a hallmark of many

the degree of functional deterioration in each test. The

ocular vascular and degenerative diseases. Once

effect of placental cells was little better than controls.

targeted to this template of activated astrocytes, the

Umbilical tissue-derived cells gave large areas of

Lin HsCs participate in normal developmental

photoreceptor rescue; mesenchymal stem cells gave

angiogenesis in both neonatal mice or injury-induced

neovascularization in the adult.

only localized rescue. Fibroblasts gave sham levels of

The HSC fraction used in these studies not only

rescue. Donor cells were confined to the subretinal

inhibited angiogenesis when engineered to express an

space. There was no evidence of cell differentiation

antiangiogenic, but also resued and stabilized

into neurons, of tumor formation or other untoward

(e.g. matured) degenerating vessels. More surprisingly,

pathology. Since the umbilical tissue-derived cells

it was also observed that by preventing vascular

demonstrated the best photoreceptor rescue and

degenertion there is a trophic rescue effect on the

unlike mesenchymal stem cells were capable of

photoreceptors themselves, suggesting that autologuous

sustained population doublings without karyotypic

bone marrow grafts of HSC fractions containing EPC

changes, it is proposed that they may provide utility

may provide trophic effects on associated neural tissue

as a cell source for the treatment of retinal degenerative

that goes beyond simple nutrition. Such observations

diseases such as retinitis pigmentosa.

could provide a rationale for the use of HSC in the

treatment of a variety of inherited retinal degenerations

Recent Advances

such as retinitis pigmentosa.

The use of stem cells are difficult and it is also very

Atmaca-Sonmez P et al have investigated whether

difficult to transfer and, it will be necessary to improve

hematopoietic stem cells (HSC) given systemically can

transfection efficiency. The use of human stem cell for

home to the damaged subretinal space and express

cell base therapy in the eye present a technical

markers of RPE lineage. They have shown that

challenge.

systemically injected HSC homed to the subretinal

Another enigma in the circulating stem cell filled

space in the presence of RPE damage and that FC

is the issue of HSC “Homing”, R-Cadherin is clearly

promoted survival of these cells. Furthermore, the RPE-

involved, but all of the molecular signals have not yet

specific marker RPE-65 was expressed on adoptively

been identified. Identification of these signals would

transferred HSC in the denuded areas.

be of immense benefit in terms of exploiting the

Harris JR et al have shown that HSCs/HPCs can

potential use of HSC in therapeutic angiogenesis as

migrate to the RPE layer after physical or chemical

well as directed cell therapy. Finally, which shall type

injury and regenerate a portion of the damaged cell

in adult bone marrow actually adheres to astrocytes

layer. Bone marrow-derived cells home to and

and incorporate into the developing vasculature.

regenerate retinal pigment epithelium after injury.

Lund RD et al have shown cells isolated from

The wet form of ARMD is characterized by

umbilical cord tissue rescue photoreceptors and visual

choroidal neovascularization (CNV). A prior study has

functions in a rodent model of retinal disease.

shown that adult hematopoietic stem cells (HSCs)

Progressive photoreceptor degeneration resulting from

contribute to approximately 50% of newly formed

genetic and other factors is a leading and largely

vasculature in CN. Sengupta N et al have shown that

untreatable cause of blindness worldwide. The object

stromal-derived factor (SDF)-1 is involved with homing

of this study was to find a cell type that is effective

of HSCs from bone marrow to target tissue. Vascular

in slowing the progress of such degeneration in an

endothelial cadherin (VE-cadherin, or CD144) is

animal model of human retinal disease, is safe and

involved in endothelial cell adhesion. Preventing

could be generated in sufficient numbers for clinical

homing and/or adhesion of progenitor cells to

application. We have compared efficacy of four

damaged choroid could reduce CNV.

human-derived cell types in preserving photoreceptor

METHODS: Adult C57BL/6J mice.

integrity and visual functions after injection into the

subretinal space of the Royal College of Surgeons rat

RESULTS: CNV lesions from eyes treated with anti-

early in the progress of degeneration. Umbilical tissue-

CD144 showed significantly less incorporation of gfp+