In situ Reprogramming as a Pro-Angiogenic Inducer to Rescue Ischemic Tissues

Abstract

<b><i>Background:</i></b> Enhanced regenerative therapeutic strategies are required to treat intractable ischemic heart disease. <b><i>Summary:</i></b> Since the discovery of putative endothelial progenitor cells (EPCs) in 1997, many studies have focused on their extraction, ex vivo processing, and autotransplantation under ischemic conditions. Nonetheless, numerous randomized clinical trials involving thousands of patients have yielded only marginal treatment effects, highlighting the need for advances regarding insufficient dosage and complex ex vivo processing. The prevailing paradigm of cellular differentiation highlights the potential of direct cellular reprogramming, which paves the way for in situ reprogramming. In situ reprogramming holds the promise of significantly enhancing current therapeutic strategies, yet its success hinges on the precise targeting of candidate cells for reprogramming. In this context, the spleen emerges as a pivotal “in situ reprogramming hub,” owing to its dual function as both a principal site for nanoparticle distribution and a significant reservoir of putative EPCs. The in situ reprogramming of splenic EPCs offers a potential solution to overcome critical challenges, including the aforementioned insufficient dosage and complex ex vivo processing. <b><i>Key Messages:</i></b> This review explores the latest advancements in EPC therapy and in situ reprogramming, spotlighting a pioneering study that integrates those two strategies with a specific focus on the spleen. Such an innovative approach will potentially herald a new era of regenerative therapy for ischemic heart disease.