Diabetic retinopathy is one of the early complications of diabetes. The disease is serious and can lead to blindness in its advanced stages. Currently, treatments for diabetic retinopathy are mainly limited to the advanced stages, with a single treatment mechanism. Stem cells hold the promise of regenerative therapy and have the potential to comprehensively improve diabetic retinopathy. However, direct stem cell therapy carries certain cancer risks. The overall disease-improving effect of exosomes secreted by stem cells is similar to that of stem cells. Exosomes can carry biologically active substances from donor cells to recipient cells or distant organs, regulating signaling between cells. Exosomes have shown significant efficacy in reducing oxidative stress, inhibiting inflammatory responses, inhibiting angiogenesis, reducing apoptosis, and protecting neural tissue.

Recently, a paper titled “Stem Cell-Derived Exosomes: Natural Intercellular Messengers with Versatile Mechanisms for the Treatment of Diabetic Retinopathy” was published in the International Journal of Nanomedicine. The paper mainly introduces the current experimental literature on the use of stem cell exosomes to treat diabetic retinopathy. The article elaborates in detail on the therapeutic effects of exosomes on diabetic retinopathy. Given that exosomes can improve lesions through multiple mechanisms, the paper recommends exosome therapy as a promising method for treating diabetic retinopathy.

First of all, the article shows that exosomes in mesenchymal stem cell culture medium have similar repair capabilities to mesenchymal stem cells and are not carcinogenic. Exosomes are widely distributed in body fluids, and almost all cells secrete exosomes. Exosomes can accurately transmit some signal molecules to specific organ cells through cell surface receptors for intercellular communication. Exosomes are particularly rich in non-coding RNA, including miRNA and transfer RNA. Exosomes can transfer specific RNA subsets from different subpopulations of donor cells to recipient cells. These RNAs maintain functional integrity in exosomes, and information is transmitted between cells through exosomes binding to cell surface receptors and membrane fusion. As key signaling molecules, miRNAs have a profound impact on cell function through two regulatory mechanisms: transcription and epigenetics.

Secondly, the article discusses the pathological characteristics and related molecular mechanisms of diabetic retinopathy based on the concept of the neurovascular unit (NVU). In a healthy retina, there is functional coupling and interdependence between NVU cells, and they work closely with each other to ensure the normal metabolic activity of retinal tissue. Continuous hyperglycemia (HG) disrupts the metabolic balance of the NVU, leading to excessive production of reactive oxygen species (ROS), inflammatory mediators, and various stressor levels, causing cell damage and ultimately leading to retinal dysfunction. Stressors include advanced glycation end products (AGE), inflammatory factors, ROS, polyol pathways, and protein kinase C (PKC). Elevated levels of these stressors can lead to vascular and neural damage, and may increase the expression of vascular endothelial growth factor (VEGF) in the fundus vessels. This ultimately destroys the retinal barrier. Throughout the process, the reduction of factors such as neurotrophic factors can also lead to neuronal degeneration and death, ultimately leading to vision loss.

Then the article discusses the relevant molecular mechanisms including microRNAs and Wnt signaling pathways. miRNA is a type of post-transcriptional inhibitory RNA with multiple biological functions. It has been shown to play a role in the development of many diseases and has therefore become a widely valued therapeutic target. A large amount of literature in ophthalmology and molecular biology has shown that miRNA plays a vital role in the development of diabetic retinopathy (DR), such as inducing oxidative stress, triggering inflammation, causing cell apoptosis, angiogenesis, and neurodegeneration. Many targeted therapies for DR, aimed at specific miRNAs, have emerged, all of which have achieved good results. The Wnt pathway is a signaling pathway that plays an important role in the development and homeostasis of organisms. It is conserved across different species, indicating its crucial role in intercellular communication. Dysregulation of Wnt signaling may be associated with oxidative stress imbalance, pathological angiogenesis, and inflammation in patients with diabetic retinopathy.

The article also reviews research from the past five years on the use of exosomes to treat retinal diseases. Numerous of studies have shown that delivering exosomes into the eye can significantly improve various retinal disease models. Stem cell-derived exosomes retain the therapeutic properties of stem cell regenerative therapy while reducing immunogenic responses. Compared with cells, exosomes are smaller and simpler in structure, making them easier to isolate and preserve. In addition, the nanoscale size of exosomes allows them to effectively target specific tissues after administration, showing excellent targeting capabilities without accumulating in pulmonary microvessels, thereby reducing the risk of pulmonary embolism. Studies have shown that stem cell-derived exosomes can protect molecules from degradation and enhance cellular uptake via endocytosis. As a non-invasive treatment method, exosomes have a strong ability to cross biological barriers. Currently, experimental literature on the use of stem cell exosomes to treat diabetic retinopathy has compiled similar experimental results. Exosomes have a wide range of therapeutic effects and can treat diabetic retinopathy through various mechanisms. They have significant effects in reducing oxidative stress, inhibiting the inflammatory response, anti-angiogenesis, reducing apoptosis and protecting neural tissue. After reviewing all experimental papers and sorting them into categories, the content shown in the chart was obtained.

Stem cell-derived exosomes are engulfed by retinal cells, leading to a series of changes in signaling molecules and repairing retinopathy caused by hyperglycemia. These exosomes contain miRNA, proteins, and other bioactive molecules. In related experiments, lesions in the retinal ganglion layer, inner plexiform layer, and outer nuclear layer of the subjects were alleviated.

Secondly, the article summarizes the problems that need to be overcome for exosomes to move from the experimental stage to clinical application. It describes various sources of exosomes and demonstrates various methods for isolating, purifying, and modifying exosomes. By selecting exosomes from different sources, and then isolating, purifying, and subsequently modifying them, exosomes that meet specific requirements can be obtained, providing a potential solution for the treatment of diabetic retinopathy.

Finally, the article concludes that the prospects for exosomes are undoubtedly broad because, from the perspective of multiple molecular mechanisms, it is difficult to find such a perfect method to comprehensively improve a disease, especially diabetic complications that are difficult to prevent and control. It is hoped that through improvements, the clinical application of exosomes can be truly realized.

 

Reference:

Song, Yameng et al. “Stem Cell-Derived Exosomes: Natural Intercellular Messengers with Versatile Mechanisms for the Treatment of Diabetic Retinopathy.” International Iournal of Nanomedicine vol. 19 10767-10784. 24 Oct. 2024, doi:10.2147/IJN.S475234

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