Bone Marrow CD133⁺ Stem Cells Ameliorate Visual Dysfunction in Streptozotocin-induced Diabetic Mice with Early Diabetic Retinopathy

Abstract

Diabetic retinopathy (DR), one of the leading causes of vision loss worldwide, is characterized by neurovascular disorders. Emerging evidence has demonstrated retinal neurodegeneration in the early pathogenesis of DR, and no treatment has been developed to prevent the early neurodegenerative changes that precede detectable microvascular disorders. Bone marrow CD133+ stem cells with revascularization properties exhibit neuroregenerative potential. However, whether CD133+ cells can ameliorate the neurodegeneration at the early stage of DR remains unclear. In this study, mouse bone marrow CD133+ stem cells were immunomagnetically isolated and analyzed for the phenotypic characteristics, capacity for neural differentiation, and gene expression of neurotrophic factors. After being labeled with enhanced green fluorescent protein, CD133+ cells were intravitreally transplanted into streptozotocin (STZ)-induced diabetic mice to assess the outcomes of visual function and retina structure and the mechanism underlying the therapeutic effect. We found that CD133+ cells co-expressed typical hematopoietic/endothelial stem/progenitor phenotypes, could differentiate to neural lineage cells, and expressed genes of robust neurotrophic factors in vitro. Functional analysis demonstrated that the transplantation of CD133+ cells prevented visual dysfunction for 56 days. Histological analysis confirmed such a functional improvement and showed that transplanted CD133+ cells survived, migrated into the inner retina (IR) over time and preserved IR degeneration, including retina ganglion cells (RGCs) and rod-on bipolar cells. In addition, a subset of transplanted CD133+ cells in the ganglion cell layer differentiated to express RGC markers in STZ-induced diabetic retina. Moreover, transplanted CD133+ cells expressed brain-derived neurotrophic factors (BDNFs) in vivo and increased the BDNF level in STZ-induced diabetic retina to support the survival of retinal cells. Based on these findings, we suggest that transplantation of bone marrow CD133+ stem cells represents a novel approach to ameliorate visual dysfunction and the underlying IR neurodegeneration at the early stage of DR.

Mechanisms behind Retinal Ganglion Cell Loss in Diabetes and Therapeutic Approach

“…Other treatments involving transplanted CD133+ cells (where CD133 is a pentaspan membrane glycoprotein used as a stem cell biomarker [39]) in STZ-induced diabetic mice retina preserved the histological structure of inner retina, RGCs and rod-on bipolar cells. In addition, CD133+ cells differentiated to RGCs and expressed BDNF promoting the survival of RGCs and other retinal cells [40], Figure 1.…”

Recent Developments in Diabetic Retinal Neurodegeneration: A Literature Review

“…Of the neurotrophic and neuroprotective substances, CNTF [ 48 , 111 ], Sig1R [ 54 , 59 , 112 , 113 ], and synthetic microneurotrophin BNN27 [ 114 , 115 ], were shown to have neuroprotective properties and ability to reduce neurodegeneration in diabetic animals. Several studies have targeted BDNF reduction via intraocular BDNF administration [ 116 ], oral intake of eicosapentaenoic acid ethyl ester [ 116 ], and intravitreal bone marrow CD133+ stem cells transplantation, leading to improved retinal cell survival [ 118 ]. Topical administration of SST was tested in a randomized, placebo-controlled, phases II–III trial and could inhibit the neurodegenerative process in early DR with preexisting retinal neuro-dysfunction [ 109 ].…”

“…An EPA metabolite, 18-HEPE, induced BDNF upregulation in Müller glia cells and recovery of ERG results [ 117 ]. In a separate study, bone marrow CD133+ stem cells were intravitreally transplanted into STZ-induced diabetic mice and caused retinal BDNF levels to increase, with consequent retinal cell survival [ 118 ].…”

“…As mentioned previously, the antioxidative effect of notoginsenoside R1 [ 98 ] and the neurotrophic effect of EPA-A [ 117 , 118 ] are also the subject of recent research, as are other nutraceuticals and nutritional supplements [ 138 – 140 ].…”

Glucocorticoids Promote Extracellular Matrix Component Remodeling by Activating YAP in Human Retinal Capillary Endothelial Cells

“…A diabetes mellitus (DM) mouse model was established as previously described ( Rong et al, 2018 ). The C57BL/6 mice used in the present study were housed according to the Third Military Medical University (Army Medical University) guidelines.…”