Human Umbilical Cord Blood-Derived CD133+CD34+ Cells Protect Retinal Endothelial Cells and Ganglion Cells in X-Irradiated Rats through Angioprotective and Neurotrophic Factors.

Siyu Chen,Haiwei Xu,Yuxiao Zeng,Xiaona Huang,Chuanhuang Weng,Minghui Li,Jianguo Sun,Shujia Huo,Shiying Li,Dan Wang,Yijian Li,Ting Zou

doi:10.3389/fcell.2022.801302

Abstract

Radiation retinopathy (RR) is a common complication following radiation therapy of globe, head, and neck malignancies, and is characterized by microangiopathy, neuroretinopathy, and the irreversible loss of visual function. To date, there is no effective treatment for RR. Stem cells have been clinically used to treat retinal degeneration. CD133+CD34+ cells from human umbilical cord blood (hUCB-CD133+CD34+ cells), a subpopulation of hematopoietic stem cells, were applied to determine their protective efficacy on irradiated rat retinas. After X-ray irradiation on the retinas, rats were intravitreally injected with hUCB-CD133+CD34+ cells. Transplantation of hUCB-CD133+CD34+ cells prevented retinal dysfunction 2 weeks post-operation and lasted at least 8 weeks. CD133+CD34+ cells were distributed along the retinal vessel and migrated to the ganglion cell layer. Moreover, grafted CD133+CD34+ cells reduced the apoptosis of endothelial and ganglion cells in irradiated rats and increased the number of survived CD31+ retinal endothelial cells and Brn3a+ ganglion cells at 2 and 4 weeks, respectively, post-operation. Co-culturing of CD133+CD34+ cells or supernatants with irradiated human retinal microvascular endothelial cells (hRECs) in vitro, confirmed that CD133+CD34+ cells ameliorated hREC apoptosis caused by irradiation. Mechanistically, we found that angioprotective mediators and neurotrophic factors were secreted by CD133+CD34+ cells, which might attenuate irradiation-induced injury of retinal endothelial cells and ganglion cells. hUCB-CD133+CD34+ cell transplantation, as a novel treatment, protects retinal endothelial and ganglion cells of X-irradiated rat retinas, possibly through angioprotective and neurotrophic factors.

Highlights

Radiotherapy has been used to treat malignancies involving the globe, orbit, head, and neck, and radiotherapy usually causes several secondary complications, including radiation keratopathy, radiation iris neovascularization, neovascular glaucoma, radiation cataracts, radiation optic neuropathy, and radiation retinopathy (RR) (Reichstein 2015; Rose et al, 2018; Ramos et al, 2019)
CD133+CD34+ cells expressed the endothelial marker CD31 and the neuronal marker βIII-tubulin (Tuj1) (Supplementary Figure S4C,D) after inducing differentiation, demonstrating the ability of CD133+CD34+ cells to differentiate into endothelial cells and neurons. hUCBCD133+CD34+ cells were intravitreally transplanted into irradiated rats at the day post-irradiation (Figure 3A), and we examined whether they could ameliorate retinal injury (Figure 3B)
We found the expression of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and neuronutrient 3 (NT3) in CD133+CD34+ cell supernatants (Figure 7D)

Summary

Introduction

Radiotherapy has been used to treat malignancies involving the globe, orbit, head, and neck, and radiotherapy usually causes several secondary complications, including radiation keratopathy, radiation iris neovascularization, neovascular glaucoma, radiation cataracts, radiation optic neuropathy, and radiation retinopathy (RR) (Reichstein 2015; Rose et al, 2018; Ramos et al, 2019). RR is characterized by progressive ischemic and proliferative changes that are similar to the development of diabetic retinopathy and can lead to irreversible loss of visual function (Rose et al, 2018). RR is a chronic and progressive condition that may result from microangiopathy of the retinal vasculature after radiation exposure (Spielberg et al, 2013; Wilkinson et al, 2017). Large retinal vessel occlusion, extensive ischemic retinopathy and maculopathy, and consequent retinal and ocular neovascularization can lead to retinal dysfunction and degeneration (Spielberg et al, 2013). The incidence rate of RR is based on the total dose of radiation, pre-existing comorbidities (e.g., diabetes mellitus, hypertension), and radiation sensitizer exposure (e.g., chemotherapy) (Horgan et al, 2010; Ferguson et al, 2017; Wilkinson et al, 2017). X-rays are the most common type of ionizing radiation that causes RR, which has an onset typically occurring between 6 months to 3 years after exposure

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