Specific Cell (Re-)Programming: Approaches and Perspectives

Abstract

Many disorders are manifested by dysfunction of key cell types or their disturbed integration in complex organs. Thereby, adult organ systems often bear restricted self-renewal potential and are incapable of achieving functional regeneration. This underlies the need for novel strategies in the field of cell (re-)programming-based regenerative medicine as well as for drug development in vitro. The regenerative field has been hampered by restricted availability of adult stem cells and the potentially hazardous features of pluripotent embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). Moreover, ethical concerns and legal restrictions regarding the generation and use of ESCs still exist. The establishment of direct reprogramming protocols for various therapeutically valuable somatic cell types has overcome some of these limitations. Meanwhile, new perspectives for safe and efficient generation of different specified somatic cell types have emerged from numerous approaches relying on exogenous expression of lineage-specific transcription factors, coding and noncoding RNAs, and chemical compounds.It should be of highest priority to develop protocols for the production of mature and physiologically functional cells with properties ideally matching those of their endogenous counterparts. Their availability can bring together basic research, drug screening, safety testing, and ultimately clinical trials. Here, we highlight the remarkable successes in cellular (re-)programming, which have greatly advanced the field of regenerative medicine in recent years. In particular, we review recent progress on the generation of cardiomyocyte subtypes, with a focus on cardiac pacemaker cells. Graphical Abstract.

Nkx2.5 Based Ventricular Programming of Murine ESC-Derived Cardiomyocytes

“…Ultimately, avoidance of any stably integrating programming as well as selection cassettes is of course highly desirable. In this regard, multiple cardiac differentiation protocols have meanwhile been published [72][73][74]. It remains to be seen whether an ultimate protocol fully reproducible between labs in the field as well as between different cell lines will emerge.…”

“…It remains to be seen whether an ultimate protocol fully reproducible between labs in the field as well as between different cell lines will emerge. On the other hand, avoidance of stable introduction of programming factor DNA constructs could be achieved via use of modified mRNA or non-integrating viral vectors [72][73][74].…”

hiPSCs Derived Cardiac Cells for Drug and Toxicity Screening and Disease Modeling: What Micro- Electrode-Array Analyses Can Tell Us

“…In drug development, pharmacological compounds are classified in respect to their cardiotoxic effects based on the AP or/and FP pattern in iPSC-derived CMs [34]. In addition, electrophysiology is used to identify and characterize the different cardiac subtypes in iPSC derived CM populations, which is crucial for specific cell programming strategies [20,66,67].…”

“…Moreover, it has largely been shown that iPSC-CMs represent a heterogeneous population of electrophysiological phenotypes, i.e., atrial, ventricular and nodal-like cells [19], each characterized by a specific electrical profile. Therefore, it is important to obtain electrophysiological data for detailed characterization of iPSC-CMs, in particular when differentiation into a certain cardiac subtype is desired [20,21].…”