Making human cardiomyocytes up to date: Derivation, maturation state and perspectives  Tomasz J. Kolanowski, Christopher L. Antos, Kaomei Guan  International Journal of Cardiology  Volume 241, Pages 379-386 (August 2017) DOI: 10.1016/j.ijcard.2017.03.099 Copyright © 2017 The Authors Terms and Conditions

Fig. 1 Derivation of cardiomyocytes (CMs) from somatic cells by in vitro culture. CMs can be obtained from somatic cells using at least three different approaches: (1) induction of pluripotency by establishing iPSCs and subsequent differentiation to CMs (green), (2) direct reprogramming (violet), or manipulating these two pathways and performing (3) combinatory approach (dark red). In each approach, significant changes could be evoked by a set of transcription factors, small molecules or miRNAs, and some reported factors were mentioned. The second stage is maturation of derived CMs towards chamber-specific cells including ventricular-, atrial- and sino-atrial nodal-like cells (blue). International Journal of Cardiology 2017 241, 379-386DOI: (10.1016/j.ijcard.2017.03.099) Copyright © 2017 The Authors Terms and Conditions

Fig. 2 Criteria of cardiomyocyte (CM) maturation and stimuli used for inducing maturity. (A) Many properties used for estimation of CM maturation progress, which could be divided into four main groups with increasing stringency: expression of molecular markers (red), structural changes (green), metabolic changes (blue) and specific physiological features (violet). (B) The maturation process (red axis) involves numerous stimuli. Various biochemical signaling pathways (VEGF, FGF, IGF, Redox signaling, Akt, β-adrenergic and T3 stimulation, yellow) are required for specific stages of CM maturation. Biochemical signaling spans whole process of maturation and these factors although essential are not sufficient for completion of the process. Physical stimulation (mechanical load, substrate patterning, electric and magnetic field stimulation and forced medium flow, green) becomes more important after first signs of cardiac differentiation. This corresponds to in vivo maturation, where contractions are present after initial differentiation and stiffness increases after birth. The later stages of differentiation match the postnatal heart development and demand more holistic and organized stimulation that should be additionally supported by engineered heart tissues (EHTs), microfluidics, cell sheets or decellularized hearts (blue). International Journal of Cardiology 2017 241, 379-386DOI: (10.1016/j.ijcard.2017.03.099) Copyright © 2017 The Authors Terms and Conditions