One Stride Forward
Maturation and Scalable Production of Engineered Human Myocardium
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Article, see p 1832
The capability of obtaining human cardiomyocytes from human pluripotent stem cells (hPSC-CM) opens up an array of medical possibilities from disease modeling, to drug screening, to heart regeneration. The hPSC-CM, however, are structurally and functionally immature relative to their adult counterparts.1 To achieve the full potential of hPSC-CM, one main challenge, and a field of intense research, is to drive the hPSC-CM into a phenotype reflecting the biology of the adult cardiomyocyte. Multiple approaches have been used, including long-term culture,2 electromechanical stimulation,3 hormonal treatment,4 microRNA,5 and tissue engineering.6 Although researchers are able to obtain hPSC-CM with increased cell size, decreased circularity index, increased contractile force, enhanced maximum mitochondrial respiratory capacity, and improved calcium dynamics, the achieved hPSC-CM maturation level, in every single aspect, is still far from complete. For example, the immature hPSC-CM typically has minimal phospholamban expression,7 which makes it impossible for hPSC-CM to respond to increased pacing frequency with enhanced contractile force or to inotropically and lusitropically respond to β-adrenergic stimulation (although the chronotropic response is present).
In a study published in this issue of Circulation, Tiburcy and colleagues8 studied the maturation status of cardiomyocytes in engineered human myocardium (EHM). This impressive international collaboration involved 31 researchers from Germany, Canada, Israel, the Netherlands, and the United States. The EHM was generated by casting cardiomyocytes and nonmyocytes in a hydrogel based on type I collagen as described earlier,9 but the authors painstakingly optimized the cellular and chemical components for EHM generation and EHM culture medium to make the conditions readily adaptable to current good manufacturing practice, a requirement for clinical translation.
Before this study, procedures to generate cardiac constructs had several aspects that needed refinement: (1) Although we know that …