A novel dressing seeded with embryonic artery CD133+ cells and loaded with the Sirt1 agonist SRT1720 accelerates the healing of diabetic ischemic ulcers

Abstract

Refractory ischemic ulcers that occur in patients with diabetes present a major clinical challenge. Embryonic artery cluster of differentiation 133+ cells (EACCs) may promote the healing of diabetic ulcers; however, the high glucose environment in the diabetic ulcers decreases the survival rate of transplanted EACCs and inhibit their biological function. Furthermore, microcirculation in diabetic ischemic ulcers is impaired, which inhibits the beneficial effect of EACCs. In the current study, the Sirt1 agonist SRT1720 was selected as a therapeutic drug and loaded into a dressing composed of PLGA, collagen and silk (PCSS) formed using electrospinning technology. EACCs were seeded onto the PCSS dressing and this was used to treat diabetic ulcers. The results indicated that SRT1720 promotes the proliferation of EACCs, enhances the secretion of vascular endothelial growth factor A, interluekin 8 and basic fibroblast growth factor, and inhibits the secretion of tumor necrosis factor α. Furthermore, SRT1720 promoted the paracrine function of EACCs and promoted the proliferation and migration of human umbilical vein endothelial cells. PCSS induced the steady release of SRT1720 over a 15-day period and PCSS seeded with EACCs (PCSS-EACCs) were transplanted into the diabetic ischemic ulcers of mice with diabetes. The results of these experiments indicated that angiogenesis and the healing of diabetic ischemic ulcers was significantly improved following the transplantation of PCSS-EACCs. Therefore, PCSS-EACCs may be a novel and effective treatment for diabetic ischemic ulcers.

The Emerging role of HDACs: Pathology and Therapeutic targets in Diabetes Mellitus

“…Among class IIb HDACs, HDAC6 has been revealed to be an agonist of glucocorticoids and endorse glucocorticoid-induced hepatic gluconeogenesis [45]. Also, HDAC6 can endorse glucoseprovoked ROS (reactive oxygen species) generation by regulating acetylation of peroxiredoxin-1 (Pdrx1) and thioredoxin-1 (Trx-1) [46].…”

“…Deletion of HDAC9 in a hyperglycemic state has been reported to improve glucose tolerance in mice [123]. HDAC6 has been regarded as an essential modifier of glucocorticoid-induced hepatic gluconeogenesis and impair glucose metabolism by regulating nuclear translocation of the glucocorticoid receptor [45]. Thus, inhibition of class II HDACs has been shown to ameliorate insulin resistance and glucose intolerance.…”

Animal models of ischemic limb ulcers: a systematic review and meta-analysis

“…Of 5844 screened studies, a total of 7 were included (online supplementary figure 1). [14][15][16][17][18][19][20]…”

“…Diabetes was present as a comorbidity in 322 wounds (Ischemia=161; Non-ischemia=161) during assessments performed at days 7 (n=144), 14 (n=136) and 21 (n=42). All included studies reported wound area at days 7 and 14, [14][15][16][17][18][19][20] whereas four studies reported wound area at day 21. 14 16-18 All time-points were eligible for meta-analysis.…”

“…Five of the included studies investigated the effect of different interventions on wound healing and reported significant improvement in healing under both diabetic and non-diabetic conditions (table 3). These interventions included hyperbaric oxygen therapy, 18 angiogenic self-assembling nanofiber hydrogel scaffold seeded with Akkermansia muciniphila, 19 bone marrow aspirate and peripheral blood derived platelet-rich plasma, 16 embryonic artery CD133+ cells loaded with the Sirt1 agonist SRT1720 20 and knockout of Redox Enzyme p66Shc. 15 The interventions were reported to improve wound healing via multiple different mechanisms including increased collagen content, granulation tissue thickness, myofibroblast differentiation and capillary density in addition to increased expression levels of vascular endothelial growth factor (VEGF-A), interleukin-8 and basic fibroblast growth factor.…”