Nanotechnology-Based Cardiac Targeting and Direct Cardiac Reprogramming: The Betrothed

Abstract

Cardiovascular diseases represent the first cause of morbidity in Western countries, and chronic heart failure features a significant health care burden in developed countries. Efforts in the attempt of finding new possible strategies for the treatment of CHF yielded several approaches based on the use of stem cells. The discovery of direct cardiac reprogramming has unveiled a new approach to heart regeneration, allowing, at least in principle, the conversion of one differentiated cell type into another without proceeding through a pluripotent intermediate. First developed for cancer treatment, nanotechnology-based approaches have opened new perspectives in many fields of medical research, including cardiovascular research. Nanotechnology could allow the delivery of molecules with specific biological activity at a sustained and controlled rate in heart tissue, in a cell-specific manner. Potentially, all the mediators and structural molecules involved in the fibrotic process could be selectively targeted by nanocarriers, but to date, only few experiences have been made in cardiac research. This review highlights the most prominent concepts that characterize both the field of cardiac reprogramming and a nanomedicine-based approach to cardiovascular diseases, hypothesizing a possible synergy between these two very promising fields of research in the treatment of heart failure.

Keeping heart homeostasis in check through the balance of iron metabolism

“…On the other hand, new chemical agents can be developed using our knowledge of the autonomous activity of cardiac iron proteins in preserving cardiac iron balance. These drugs can be delivered via new technologies which are able to restrict drug activity in specific cells …”

YAP and TAZ Mediators at the Crossroad between Metabolic and Cellular Reprogramming

“…Of note, not all reprogramming processes necessitate the activation of YAP/TAZ. Direct cardiac reprogramming generates cardiomyocytes from fibroblasts without passing through a stem cell state [ 109 ]. This transdifferentiation requires a massive epigenetic remodeling to allow the silencing of fibroblast gene programs and, in parallel, the upregulation of the transcriptional rate of genes in cardiogenic loci [ 110 ].…”

Strategies and Challenges to Improve Cellular Programming-Based Approaches for Heart Regeneration Therapy

“…Most iCM generation techniques employ the use of virus-based strategies to deliver reprogramming factors, which raises safety concerns including endogenous gene disruption and insertional mutagenesis [ 109 ]. Investigators have tried to avoid this pitfall via nongenetic strategies that employ the use of small molecules to induce reprogramming [ 110 ]. In 2014, Ding et al established their CASD (cell-activation and signaling-directed) approach and achieved successful reprogramming from MEFs and TTFs into iCMs by using a single TF-Oct4 and the four compounds SB431542 (AKT4/5/7 inhibitor), CHIR99021 (GSK-3 inhibitor), Parnate (LSD1/KDM1 inhibitor), and Forskolin (adenylyl cyclase activator) [ 111 ].…”