Identification of a tsRNA Contributor to Impaired Diabetic Wound Healing via High Glucose-Induced Endothelial Dysfunction

Abstract

Purpose Delayed skin healing in diabetic wounds is a major clinical problem. The tRNA-derived small RNAs (tsRNAs) were reported to be associated with diabetes. However, the role of tsRNAs in diabetic wound healing is unclear. Our study was designed to explore the tsRNA expression profile and mine key potential tsRNAs and their mechanism in diabetic wounds. Methods Skin tissues of patients with diabetic foot ulcers and healthy controls were subjected to small RNA sequencing. The role of candidate tsRNA was explored by loss- and gain-of-function experiments in HUVECs. Results A total of 55 differentially expressed tsRNAs were identified, including 12 upregulated and 43 downregulated in the diabetes group compared with the control group. These tsRNAs were mainly concentrated in intercellular interactions and neural function regulation in GO terms and enriched in MAPK, insulin, FoxO, calcium, Ras, ErbB, Wnt, T cell receptor, and cGMP-PKG signaling pathways. tRF-Gly-CCC-039 expression was upregulated in vivo and in vitro in the diabetic model. High glucose disturbed endothelial function in HUVECs, and tRF-Gly-CCC-039 mimics further harmed HUVECs function, characterized by the suppression of proliferation, migration, tube formation, and the expression of Coll1a1, Coll4a2, and MMP9. Conversely, the tRF-Gly-CCC-039 inhibitor could attenuate high-glucose-induced endothelial injury to HUVECs. Conclusion We investigated the tsRNAs expression profile in diabetic foot ulcers and defined the impairment role of tRF-Gly-CCC-039 in endothelial function in HUVECs. This study may provide novel insights into accelerating diabetic skin wound healing.

Identification of tRNA-derived RNAs in adipose tissue from overweight type 2 diabetes mellitus patients and their potential biological functions

“…Nonetheless, a strong association between being overweight or obese and T2DM persists, with statistics from a UK study showing that over 80% of people with T2DM have a BMI ≥25 (23),and that in overweight individuals, a sustained increase in BMI leads to increased mortality from T2DM (24). Regrettably, there has been no progress in controlling overweight prevalence in the population over the last decade or so, even as the number of overweight individuals continues to rise and being overweight becomes nearly the population norm (8). In patients with T2DM with a BMI ≥15, appropriate weight loss significantly improves abnormally elevated blood glucose, lipids and blood pressure, enabling patients to minimize exposure to cardiovascular disease risk factors (25).…”

“…Some tsRNAs have been found to be involved in adipose differentiation, promoting the proliferation of preadipocytes or enhancing adipogenesis to mediate obesity (6,7). Other studies have identified tsRNA as a key factor in the pathogenesis of diabetes and its related diseases (8), and suggested that alterations in tsRNA may be closely related to the mechanism of pancreatic b-cell death (9). Yan et al also discovered that tsRNA may act as a new target in the treatment of diabetic foot ulcers by regulating Wnt signaling (10).…”

Unveiling the role of tRNA-derived small RNAs in MAPK signaling pathway: implications for cancer and beyond

“…Figure 3 depicts aberrant tsRNA expression patterns across ten different diseases, Figure 3 illustrates aberrant tsRNA expression patterns across ten distinct diseases, encompassing one cancer and nine non-cancerous conditions. These tsRNAs encompass a range of variants, including tRF-03357 in HGSOC, tRF-36-F900BY4D84KRIME, tRF-23-87R8WP9IY, and tRF-40-86J8WPMN1E8Y7Z2R in VV, tRF-Gly-CCC-039 in diabetic foot, tRF-Arg-ACG-007 and tRF-Ser-GCT-008 in diabetes, tRF-5014a in DCM, tsRNA-14783 in Keloid, tsRNA-04002 in IDD, tsRNA-21109 in SLE, tiRNA-Gly-GCC-002, tRF-Ala-AGC-010, tRF-Gln-CTG-005, and tRF-Leu-AAG-001 in LN, as well as tsRNA-1018, tsRNA-3045b, tsRNA-5021a, and tsRNA-1020 in ALI ( Yu et al, 2019 ; Zhang et al, 2019 ; Zhao Y. et al, 2022 ; Wang and Hu, 2022 ; Zhang et al, 2023 )[37373469][37287061][34464838][34923866][34811808][37259935].…”

“…A total of 55 differentially expressed tsRNAs emerged from diabetic foot ulcer tissues, with tRF-Gly-CCC-039 showing high expression and correlation with the MAPK pathway through KEGG analysis. Elevated tRF-Gly-CCC-039 hindered proliferation, motility, angiogenic capacity, and expression of specific genes in human umbilical vein endothelial cells (HUVECs) ( Zhang et al, 2023 ). In diabetes, there is an upregulation in the expression of tRF-Arg-ACG-007, whereas the expression of tRF-Ser-GCT-008 is downregulated.…”

“…Notably, elevated levels of tiRNA-Gly-GCC-001, tRF-Gly-GCC-012, tRF-Gly-GCC-013, and tRF-Gly-GCC-016 have been implicated in modulating the MAPK pathway via BDNF targeting in spinal cord injury ( Qin et al, 2019 ). Furthermore, heightened expression of tRF-Gly-CCC-039 is associated with sustained healing in Diabetic foot cases ( Zhang et al, 2023 ), while tRF-5014a exerts negative regulation on autophagy-related protein ATG5 in DCM ( Zhao et al, 2022 ). The multifaceted roles of tsRNA-14783 in Keloid formation, by steering M2 macrophage polarization, are also being unveiled ( Wang and Hu, 2022 ).…”