Stem Cell Therapy for Retinopathy of Prematurity

Retinopathy of Prematurity (ROP) is a leading cause of childhood blindness that severely affecting the quality of life of these children. Few treatment options are available but without favorable outcomes. Stem cell therapy, through its proven potential in tissue regeneration, provides an attractive therapeutic approach in treating ROP and thereby restoring vision.published_or_final_versio

The Neurovascular Relation in Oxygen-induced Retinopathy

Purpose: Longitudinal studies in rat models of retinopathy of prematurity (ROP) have demonstrated that abnormalities of retinal vasculature and function change hand-in-hand. In the developing retina, vascular and neural structures are under cooperative molecular control. In this study of rats with oxygen-induced retinopathy (OIR) models of ROP, mRNA expression of vascular endothelial growth factor (VEGF), semaphorin (Sema), and their neuropilin receptor (NRP) were examined during the course of retinopathy to evaluate their roles in the observed neurovascular congruency. Methods: Oxygen exposures designed to induce retinopathy were delivered to Sprague-Dawley rat pups (n=36) from postnatal day (P) 0 to P14 or from P7 to P14. Room-air-reared controls (n=18) were also studied. Sensitivities of the rod photoreceptors ($S_{rod}$) and the postreceptor cells (Sm) were derived from electroretinographic (ERG) records. Arteriolar tortuosity, $T_A$, was derived from digital fundus images using Retinal Image multi-Scale Analysis (RISA) image analysis software. mRNA expression of $VEGF_{164}$, semaphorin IIIA (Sema3A), and neuropilin-1 (NRP-1) was evaluated by RT–PCR of retinal extracts. Tests were performed at P15–P16, P18–P19, and P25–P26. Relations among ERG, RISA, and PCR parameters were evaluated using linear regression on log transformed data. Results: Sm was low and $T_A$ was high at young ages, then both resolved by P25–P26. $VEGF_{164}$ and Sema3A mRNA expression were also elevated early and decreased with age. Low Sm was significantly associated with high $VEGF_{164}$ and Sema3A expression. Low Srod was also significantly associated with high VEGF164. $S_{rod}$ and Sm were both correlated with $T_A$. NRP-1 expression was little affected by OIR. Conclusions: The postreceptor retina appears to mediate the vascular abnormalities that characterize OIR. Because of the relationships revealed by these data, early treatment that targets the neural retina may mitigate the effects of ROP

670nm Photobiomodulation as a Novel Protection against Retinopathy of Prematurity: Evidence from Oxygen Induced Retinopathy Models

INTRODUCTION To investigate the validity of using 670nm red light as a preventative treatment for Retinopathy of Prematurity in two animal models of oxygen-induced retinopathy (OIR). MATERIALS AND METHODS During and post exposure to hyperoxia, C57BL/6J mice or Sprague-Dawley rats were exposed to 670 nm light for 3 minutes a day (9J/cm²). Whole mounted retinas were investigated for evidence of vascular abnormalities, while sections of neural retina were used to quantify levels of cell death using the TUNEL technique. Organs were removed, weighed and independent histopathology examination performed. RESULTS 670 nm light reduced neovascularisation, vaso-obliteration and abnormal peripheral branching patterns of retinal vessels in OIR. The neural retina was also protected against OIR by 670 nm light exposure. OIR-exposed animals had severe lung pathology, including haemorrhage and oedema, that was significantly reduced in 670 nm+OIR light-exposed animals. There were no significance differences in the organ weights of animals in the 670 nm light-exposed animals, and no adverse effects of exposure to 670 nm light were detected. DISCUSSION Low levels of exposure to 670 nm light protects against OIR and lung damage associated with exposure to high levels of oxygen, and may prove to be a non-invasive and inexpensive preventative treatment for ROP and chronic lung disease associated with prematurity.Australian Research Council Centres of Excellence Program Grant (CE0561903); Canberra Hospital Private Practice Fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Morphological and Functional Changes in the Retina after Chronic Oxygen-Induced Retinopathy

The mouse model of oxygen-induced retinopathy (OIR) has been widely used for studies of retinopathy of prematurity (ROP). This disorder, characterized by abnormal vascularization of the retina, tends to occur in low birth weight neonates after exposure to high supplemental oxygen. Currently, the incidence of ROP is increasing because of increased survival of these infants due to medical progress. However, little is known about changes in the chronic phase after ROP. Therefore, in this study, we examined morphological and functional changes in the retina using a chronic OIR model. Both the a- and b-waves in the OIR model recovered in a time-dependent manner at 4 weeks (w), 6 w, and 8 w, but the oscillatory potential (OP) amplitudes remained depressed following a return to normoxic conditions. Furthermore, decrease in the thicknesses of the inner plexiform layer (IPL) and inner nuclear layer (INL) at postnatal day (P) 17, 4 w, and 8 w and hyperpermeability of blood vessels were observed in conjunction with the decrease in the expression of claudin-5 and occludin at 8 w. The chronic OIR model revealed the following: (1) a decrease in OP amplitudes, (2) morphological abnormalities in the retinal cells (limited to the IPL and INL) and blood vessels, and (3) an increase in retinal vascular permeability via the impairment of the tight junction proteins. These findings suggest that the experimental animal model used in this study is suitable for elucidating the pathogenesis of ROP and may lead to the development of potential therapeutic agents for ROP treatment

Promoting vascular repair in the retina: can stem/progenitor cells help?

Since its first epidemic in the 1940s, retinopathy of prematurity (ROP) has been a challenging illness in neonatology. Higher than physiological oxygen levels impede the development of the immature retinal neuropil and vasculature. Current treatment regimens include cryotherapy, laser photocoagulation, and anti-VEGF agents. Unfortunately, none of these approaches can rescue the normal retinal vasculature, and each has significant safety concerns. The limitations of these approaches have led to new efforts to understand the pathological characteristics in each phase of ROP and to find a safer and more effective therapeutic approach. In the era of stem cell biology and with the need for new treatments for ROP, this review discusses the possible future use of unique populations of proangiogenic cells for therapeutic revascularization of the preterm retina

Development of astrocytes in the vertebrate eye

Astrocytes represent the earliest glial population in the embryonic optic nerve, contributing critically to retinal angiogenesis and formation of brain-retinal-barrier. Despite of many developmental and clinical implications of astrocytes, answers to some of the most fundamental questions of this unique type of glial cells remain elusive. This review provides an overview of the current knowledge about the origination, proliferation, and differentiation of astrocytes, their journey from the optic nerve toward the neuroretina, and their involvement in physiological and pathological development of the visual system

Histopathology of human ischemic retinopathies

Retinal ischemia is a key feature in sight threatening eye diseases such as retinopathy of prematurity (ROP) or diabetic retinopathy (DR). Whilst the longterm consequences of ROP and DR are well described, our understanding of the early pathobiological events is much less clear. In particular cellular changes during the early stages of these disease are poorly studied so far. Most of our current insights about the pathobiological events are derived from animal models, with little confirmation in humans. The aim of this thesis is therefore to fill this gap by carefully characterizing vascular features and cellular damage in post-mortem tissue from patients with early stages of ROP and DR. To better understand the early cellular events in ROP, post-mortem eyes from postnatal, premature infants were collected. Different vascular phenotypes could be distinguished in whole mount retinal vasculature stains. Differences in branching profiles and capillary free zone morphology implicated different levels of oxygen exposure in the infants studied. Furthermore, characterizing a hyperplastic ridge, distal to the edge of the growing vascular plexus, revealed a correlation between the retinal astrocyte marker PAX2 and increased expression of vascular endothelial growth factor (VEGF). This suggests that retinal astrocytes make an important, but so far overlooked, contribution to the pathology in ROP. To better understand early stages of DR, eyes from diabetic donors without diagnosed DR were collected. Whole mount imaging revealed an indistinguishable retinal vasculature phenotype compared to controls, confirming the absence of DR. However, detailed quantification of vessel profiles on retinal cross sections demonstrated a 5-fold increase in acellular (and presumed non-perfused) capillaries (7-fold in the deeper plexuses) in retinas from diabetics without DR. Interestingly, localized capillary dropout of individual capillaries in the deeper plexuses did not correlated with a reduction of cells in the vicinity of the non-perfused capillaries. Instead, there was a panretinal loss of cells in the inner nuclear layer (INL) in diabetic retina, suggesting an ischemia independent mechanism for INL cell loss in diabetic retina

Vascular endothelial growth factor in eye disease

Collectively, angiogenic ocular conditions represent the leading cause of irreversible vision loss in developed countries. In the U.S., for example, retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration are the principal causes of blindness in the infant, working age and elderly populations, respectively. Evidence suggests that vascular endothelial growth factor (VEGF), a 40 kDa dimeric glycoprotein, promotes angiogenesis in each of these conditions, making it a highly significant therapeutic target. However, VEGF is pleiotropic, affecting a broad spectrum of endothelial, neuronal and glial behaviors, and confounding the validity of anti-VEGF strategies, particularly under chronic disease conditions. In fact, among other functions VEGF can influence cell proliferation, cell migration, proteolysis, cell survival and vessel permeability in a wide variety of biological contexts. This article will describe the roles played by VEGF in the pathogenesis of retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration. The potential disadvantages of inhibiting VEGF will be discussed, as will the rationales for targeting other VEGF-related modulators of angiogenesis

670nm Photobiomodulation as a Novel Protection against Retinopathy of Prematurity:Evidence from Oxygen Induced Retinopathy Models

Introduction:To investigate the validity of using 670nm red light as a preventative treatment for Retinopathy of Prematurity in two animal models of oxygen-induced retinopathy (OIR).Materials and Methods:During and post exposure to hyperoxia, C57BL/6J mice or Sprague-Dawley rats were exposed to 670nm light for 3 minutes a day (9J/cm2). Whole mounted retinas were investigated for evidence of vascular abnormalities, while sections of neural retina were used to quantify levels of cell death using the TUNEL technique. Organs were removed, weighed and independent histopathology examination performed.Results:670nm light reduced neovascularisation, vaso-obliteration and abnormal peripheral branching patterns of retinal vessels in OIR. The neural retina was also protected against OIR by 670nm light exposure. OIR-exposed animals had severe lung pathology, including haemorrhage and oedema, that was significantly reduced in 670nm+OIR light-exposed animals. There were no significance differences in the organ weights of animals in the 670nm light-exposed animals, and no adverse effects of exposure to 670nm light were detected. Discussion: Low levels of exposure to 670nm light protects against OIR and lung damage associated with exposure to high levels of oxygen, and may prove to be a non-invasive and inexpensive preventative treatment for ROP and chronic lung disease associated with prematurity.</p