Stem cell therapy is one of the promising regenerative strategies developed to improve cardiac function in patients with ischemic heart diseases (IHD). However, this approach is limited in IHD patients with diabetes due to a progressive decline in the regenerative capacity of stem cells. This decline is mainly attributed to the metabolic memory incurred by diabetes on stem cell niche and their systemic cues. Understanding the molecular pathways involved in the diabetes-induced deterioration of stem cell function will be critical for developing new cardiac regeneration therapies. In this review, we first discuss the most common molecular alterations occurring in the diabetic stem cells/progenitor cells. Next, we highlight the key signaling pathways that can be dysregulated in a diabetic environment and impair the mobilization of stem/progenitor cells, which is essential for the transplanted/endogenous stem cells to reach the site of injury. We further discuss the possible methods of preconditioning the diabetic cardiac progenitor cell (CPC) with an aim to enrich the availability of efficient stem cells to regenerate the diseased diabetic heart. Finally, we propose new modalities for enriching the diabetic CPC through genetic or tissue engineering that would aid in developing autologous therapeutic strategies, improving the proliferative, angiogenic, and cardiogenic properties of diabetic stem/progenitor cells. STEM CELLS 2017;35:2009-2026 SIGNIFICANCE STATEMENTStem cell therapy is gaining global interest as the next generation of drug treatment in patients with ischemic heart disease. However, this approach is limited in patients with diabetes, due to the reduction in the available pool and functional deficit of the diabetic stem/progenitor cells. To our knowledge, this is the first review summarizing the molecular alterations in the diabetic cardiac progenitor/stem cells, which reduce its functional efficacy. We believe this review will provide a strong foundation for several future studies aiming to regenerate the diabetic heart by restoring the dysregulated molecular signaling cascade in the diabetic stem/progenitor cells.

The above-named article by Manning PJ, Dixit P, Satthenapalli VR, Katare R, and Sutherland WHF (J Clin Endocrinol Metab. [published online ahead of print 21 May 2019]; doi: 10.1210/jc.2018-00197) has been withdrawn by the authors. The authors report, “The reason for this decision is that the statistical methodology we used did not adequately limit the impact of outlier data points on our findings. This was evident after reanalysis of the data using a different method.” doi: 10.1210/jc.2019-01393