Genetic Modification of Stem Cells in Diabetes and Obesity

Abstract

Genetic modification, or gene transfer, represents a method of treatment for several diseases. It has been used extensively in the context of cardiovascular diseases; however, its role in the context of metabolic diseases, such as diabetes and obesity, has remained largely unexplored. In this chapter, we will review the use of adult stem cells, focusing on endothelial progenitor cells (EPCs) and mesenchymal stromal cells (MSCs), in the context of diabetes. We have highlighted the use of viral vectors, particularly DNA viruses, as a tool for genetic modification to help stem cells survive and resist apoptosis in a hyperglycemic environment. We then discuss genetic modification of EPCs and MSCs to treat complications of diabetes and obesity. Although there are several unanswered questions in the field of metabolic diseases, the future application of gene transfer technology along with genetic modification of stem cells prior to the therapy holds significant therapeutic promise.

Use of p53‐Silenced Endothelial Progenitor Cells to Treat Ischemia in Diabetic Peripheral Vascular Disease

“…To solve this problem, we used short‐term silencing of p53 where the viral construct would not be viable beyond 28 days. Effects of adenoviral silencing usually persist ≈28 days . This time span is perfect because the time required by EPCs to transform to a mature endothelium is also ≈28 days.…”

“…This time span is perfect because the time required by EPCs to transform to a mature endothelium is also ≈28 days. Simultaneously, we did not want to use a turn‐on, turn‐off gene promoter, with another DNA virus like adeno‐associated virus, as the effect of silencing could be considered as “leaky.” Thus, the use of an adenovirus as a gene modification vector was the best selection, with a transduction efficacy profile better than liposomes …”

“…Adenovirus, unlike lentivirus, is a DNA virus and does not integrate with the host genome . It can also provide gene expression or a silencing effect for up to 4 weeks which should be enough for EPCs transition to mature endothelium. In our experience, efficacy with adenovirus is about 30% to 40% compared with lentivirus, where the efficacy is about 70% to 80%.…”

Reassessing the effects of continuous positive airway pressure (CPAP) on arterial stiffness and peripheral blood derived CD34+ progenitor cells in subjects with sleep apnea

“…Although there have been many different markers of inflammation used to look at endothelial dysfunction, cell-based biomarker such as hematopoietic progenitor cells CD34+ cells to assess endothelial function and treat cardiovascular diseases [8–12] has been widely used in various clinical scenarios [10]. Peripheral blood- and bone marrow-derived hematopoietic CD34+ cells are deemed to be premature or progenitor cells where CD34 is a progenitor marker.…”

“…Most studies have described a reduction in EPCs in that population, whereas others have shown an increase or no changes in the number of EPCs in OSA [18]. Despite the fact that many studies on EPCs in OSA have been reported, results are still controversial as definition of EPCs without a cell surface marker can be confusing [10]. In OSA patients, a reduction in circulating CD34+ cells can occur, where CD34+ cells may succumb to apoptosis secondary to increased level of reactive oxygen species (ROS) presence.…”