Enhanced therapeutic angiogenesis in mouse hindlimb ischemia model by electrical stimulation and extracellular matrix

Abstract

The present study is the report on the enhancing therapeutic angiogenesis in mouse hindlimb ischemia model by usage of electrical stimulation (ES) derived from solar cell and injectable decellularized extracellular matrix (IDM) for stem cell transplantation. In ischemic tissue, most of the transplanted cells and native cells undergo apoptosis and necrosis due to the low oxygen and nutrient delivery. Therefore, improved cell therapy method of acellular therapy method is required for enhancing or replacing previous therapy. In chapter 3, the solar-cell-based device was designed, which converts light energy to electrical energy, can generate an electrical stimulus that would control cell behavior and stimulate therapeutic angiogenesis in a mouse ischemic hindlimb. For easy utilization of the device in vivo, we designed a solar cell circuit that consisted of an implantable electrode and a solar panel that adhered to the skin. Conventional clinical ES usually involves a large electrical device, which may require patient hospitalization. By contrast, the solar-cell-based wearable device developed in this study overcomes the limitation. In an in vitro experiment, ES applied to various types of cells associated with angiogenesis significantly enhanced cell migration and secretion of angiogenic paracrine factors. To evaluate the therapeutic efficacy of the device in vivo, the electrode of the solar cell device was implanted into the ischemic region of a mouse hindlimb, and the solar panel part of the device was attached to the back of mouse for exposure to light. The device successfully converted light energy into electrical energy and generated ES. ES induced cell migration and promoted the secretion of angiogenic paracrine factors. Furthermore, use of the solar cell device led to significant increase in the number of capillaries and arterioles at the ischemic region, and prevented muscle necrosis and loss of the ischemic limb. In the chapter 4, IDM was investigated and examined whether the IDM can enhance transplanted cell grafting and therapeutic efficacy. In an in vitro experiment, IDM and ADSC complex (cell-IDM) enhanced cell viability and upregulation of angiogenic paracrine factors. To evaluate the therapeutic efficacy in vivo, cell-IDM was implanted into the ischemic region of a mouse hindlimb. Transplantation of cell-IDM induced significant increase in the number of capillaries and arterioles at the ischemic region, and prevented muscle necrosis. The result of this study may be applicable for the enhancing and optimizing therapeutic angiogenesis in both cell transplantation model and in vivo implantable device model. Moreover, this study provided a disposable and easily usable and implantable ES-generating solar cell device and easily applicable developed stem cell transplantation method to treat angiogenic disease.