Adenosine accelerates the healing of diabetic ischemic ulcers by improving autophagy of endothelial progenitor cells grown on a biomaterial.

Wen Chen,Wen Zeng,Chuhong Zhu,Lei Shen,Ju Tan,Mingcan Yang,Yangxiao Wu,Ge Liu,Li Li

doi:10.1038/srep11594

Abstract

Endothelial progenitor cells (EPCs) seeded on biomaterials can effectively promote diabetic ischemic wound healing. However, the function of transplanted EPCs is negatively affected by a high-glucose and ischemic microenvironment. Our experiments showed that EPC autophagy was inhibited and mitochondrial membrane potential (MMP) was increased in diabetic patients, while adenosine treatment decreased the energy requirements and increased the autophagy levels of EPCs. In animal experiments, we transplanted a biomaterial seeded with EPCs onto the surface of diabetic wounds and found that adenosine-stimulated EPCs effectively promoted wound healing. Increased microvascular genesis and survival of the transplanted cells were also observed in the adenosine-stimulated groups. Interestingly, our study showed that adenosine increased the autophagy of the transplanted EPCs seeded onto the biomaterial and maintained EPC survival at 48 and 96 hours. Moreover, we observed that adenosine induced EPC differentiation through increasing the level of autophagy. In conclusion, our study indicated that adenosine-stimulated EPCs seeded onto a biomaterial significantly improved wound healing in diabetic mice; mechanistically, adenosine might maintain EPC survival and differentiation by increasing high glucose-inhibited EPC autophagy and maintaining cellular energy metabolism.

Highlights

EPCs have been defined as a type of stem cell that can colonize an ischemic site and differentiate into endothelial cells to promote angiogenesis[5]
Researchers have transplanted EPCs to diabetic wounds after seeding the cells onto biomaterials; the results showed that this stem cell–biomaterial therapy considerably improved ischemic wound healing[6,7,8]
These results suggest that the imbalance between EPC autophagy and energy metabolism occurred in diabetic patients

Summary

Introduction

EPCs have been defined as a type of stem cell that can colonize an ischemic site and differentiate into endothelial cells to promote angiogenesis[5]. Researchers have transplanted EPCs to diabetic wounds after seeding the cells onto biomaterials; the results showed that this stem cell–biomaterial therapy considerably improved ischemic wound healing[6,7,8]. This effect was not significant when the transplantation was performed on diabetic ischemic wounds. Autophagy plays a crucial role in cell protection and in the control of energy balance, which is the same as the effect of adenosine. We investigated whether adenosine can promote diabetic ischemic wound healing by increasing autophagy in EPCs grown on biomaterials. We generated a degradable biomaterial with high biocompatibility and seeded this material with adenosine-stimulated EPCs and transplanted it onto diabetic ischemic wound surfaces to improve diabetic wound healing

Methods

Results

Conclusion