Abigail Hawkins

 Background: Diabetic retinopathy is the primary ocular complication of uncontrolled diabetes mellitus and a chief cause of visual loss in the elderly.¹ Pathogenesis is characterized by pro-inflammatory signaling, via markers such as high mobility group box 1 (HMGB1), and oxidative stress, resulting in breakdown of the blood-retinal barrier and neovascularization.² With a prevalence rate of 28.5% in diabetic adults above age 40 in the US, diabetic retinopathy prevention and treatment is critical.³ A leading treatment option is anti-VEGF therapy, and some cases necessitate laser therapy or  vitrectomy.⁴ However, some criticisms of anti-VEGF therapy include its short half life and associated issues regarding patient compliance, leading to further investigation into potential new treatment strategies.⁵

 Objective: In this narrative review, I explored the role of HMGB1 and miRNA-126 in proinflammatory signaling in diabetic retinopathy pathogenesis and a potential therapeutic avenue, the usage of mesenchymal stem cell derived-exosomes.

 Search Methods: An online search in PubMed was conducted from 2017 to 2023 using the following keywords: “diabetic retinopathy”, “stem cells”, “miR-126”, and “HMGB1.”

 Results: HMGB1 is a damage-associated molecular pattern protein whose release by necrotic cells and granulocytes can be triggered by cellular stress.⁶ Downstream, HMGB1 activates macrophages and neutrophils, promoting inflammation.⁶  A study examining the vitreous of patients with proliferative diabetic retinopathy (PDR) found that HMGB1 levels were elevated in comparison to controls.⁷ Upon administration of HMGB1 inhibitor, glycyrrhizin, to rat subjects, more sirtuin-1, a protective agent against oxidative stress and inflammation, was observed.⁷ Further studies sought to establish the relationship between miRNA-126 and HMGB1. A transient transfection of miR-126 mimics suppressed pro-inflammatory HMGB1, TNF-α, and reactive oxygen species in human umbilical cord vein endothelial cells.⁸ A transient transfection of miR-126 decreased HMGB1 protein more than HMGB1 mRNA, indicating post-translational regulation.⁸ Levels of miR-126 were significantly depleted in the vitreous of those with non-proliferative diabetic retinopathy (NPDR), confirming a negative correlation between HMGB1 and miR-126.⁹ Administration of HMGB1 siRNA to rat models with diabetic retinopathy led to restored degradative activity of the autophagy-lysosome pathway, reduction of pro-inflammatory factor synthesis, and decreased apoptosis in retinal pigment epithelial cells.¹⁰  To target this pathway, exosomes derived from mesenchymal-stem cells (MSCs), obtained from human umbilical cord blood, were utilized as they can transport needed protein, nucleic acid, and miRNA.^11,12 Upon transfection of miR-126 into cells, results indicated decreased levels of HMGB1 protein and downstream targets, the NLRP3 inflammasome and NF-κB/P65, in the miR-126-Exo treatment group of rats compared to controls.¹¹

Conclusions: Studies suggest that miR-126 downregulation leads to HMGB1 protein upregulation in diabetic retinopathy, catalyzing inflammation, breakdown of the blood-retinal barrier, and impaired autophagic mechanisms. By specific targeting of HMGB1 via MSC-derived exosomes in rat models of DR, miR-126 transfection successfully reduced HMGB1 protein in retinal pigment epithelial cells. Further study is needed to determine applicability to humans, but stem cells could aid future prevention and treatment of diabetic retinopathy.

 Works Cited:

1. Lin KY, Hsih WH, Lin YB, Wen CY, Chang TJ. Update in the epidemiology, risk factors, screening, and treatment of diabetic retinopathy. J Diabetes Investig. 2021;12(8):1322-1325. doi:10.1111/jdi.13480
2. Kusuhara S, Fukushima Y, Ogura S, Inoue N, Uemura A. Pathophysiology of Diabetic Retinopathy: The Old and the New. Diabetes Metab J. 2018;42(5):364-376. doi:10.4093/dmj.2018.0182
3. Rübsam A, Parikh S, Fort PE. Role of Inflammation in Diabetic Retinopathy. Int J Mol Sci. 2018;19(4):942. Published 2018 Mar 22. doi:10.3390/ijms19040942
4. Mansour SE, Browning DJ, Wong K, Flynn HW Jr, Bhavsar AR. The Evolving Treatment of Diabetic Retinopathy. Clin Ophthalmol. 2020;14:653-678. Published 2020 Mar 4. doi:10.2147/OPTH.S236637
5. Wang W, Lo ACY. Diabetic Retinopathy: Pathophysiology and Treatments. Int J Mol Sci. 2018;19(6):1816. Published 2018 Jun 20. doi:10.3390/ijms19061816
6. Xue J, Suarez JS, Minaai M, et al. HMGB1 as a therapeutic target in disease. J Cell Physiol. 2021;236(5):3406-3419. doi:10.1002/jcp.30125
7. Mohammad G, Abdelaziz GM, Siddiquei MM, Ahmad A, De Hertogh G, Abu El-Asrar AM. Cross-Talk between Sirtuin 1 and the Proinflammatory Mediator High-Mobility Group Box-1 in the Regulation of Blood-Retinal Barrier Breakdown in Diabetic Retinopathy. Curr Eye Res. 2019;44(10):1133-1143. doi:10.1080/02713683.2019.1625406
8. Tang ST, Wang F, Shao M, Wang Y, Zhu HQ. MicroRNA-126 suppresses inflammation in endothelial cells under hyperglycemic condition by targeting HMGB1. Vascul Pharmacol. 2017;88:48-55. doi:10.1016/j.vph.2016.12.002
9. Pramanik S, Saha C, Chowdhury S, Bose C, Bhattacharyya NP, Mondal LK. Decreased Levels of miR-126 and miR-132 in Plasma and Vitreous Humor of Non-Proliferative Diabetic Retinopathy Among Subjects with Type-2 Diabetes Mellitus. Diabetes Metab Syndr Obes. 2022;15:345-358. Published 2022 Feb 4. doi:10.2147/DMSO.S346097
10. Feng L, Liang L, Zhang S, Yang J, Yue Y, Zhang X. HMGB1 downregulation in retinal pigment epithelial cells protects against diabetic retinopathy through the autophagy-lysosome pathway. Autophagy. 2022;18(2):320-339. doi:10.1080/15548627.2021.1926655
11. Zhang W, Wang Y, Kong Y. Exosomes Derived From Mesenchymal Stem Cells Modulate miR-126 to Ameliorate Hyperglycemia-Induced Retinal Inflammation Via Targeting HMGB1. Invest Ophthalmol Vis Sci. 2019;60(1):294-303. doi:10.1167/iovs.18-25617
12. Elahi FM, Farwell DG, Nolta JA, Anderson JD. Preclinical translation of exosomes derived from mesenchymal stem/stromal cells. Stem Cells. 2020;38(1):15-21. doi:10.1002/stem.3061