Abstract
Human pluripotent stem cell (hPSC)-derived cardiomyocytes have attracted attention as an unlimited source of cells for cardiac therapies. One of the factors to surmount to achieve this is the production of hPSC-derived cardiomyocytes at a commercial or clinical scale with economically and technically feasible platforms. Given the limited proliferation capacity of differentiated cardiomyocytes and the difficulties in isolating and culturing committed cardiac progenitors, the strategy for cardiomyocyte production would be biphasic, involving hPSC expansion to generate adequate cell numbers followed by differentiation to cardiomyocytes for specific applications. This review summarizes and discusses up-to-date two-dimensional cell culture, cell-aggregate and microcarrier-based platforms for hPSC expansion. Microcarrier-based platforms are shown to be the most suitable for up-scaled production of hPSCs. Subsequently, different platforms for directing hPSC differentiation to cardiomyocytes are discussed. Monolayer differentiation can be straightforward and highly efficient and embryoid body-based approaches are also yielding reasonable cardiomyocyte efficiencies, whereas microcarrier-based approaches are in their infancy but can also generate high cardiomyocyte yields. The optimal target is to establish an integrated scalable process that combines hPSC expansion and cardiomyocyte differentiation into a one unit operation. This review discuss key issues such as platform selection, bioprocess parameters, medium development, downstream processing and parameters that meet current good manufacturing practice standards.
Highlights
Cardiovascular disease is the leading cause of death globally, accounting for 244.8 per 100,000 deaths in 2008 [1]
Current platforms for Human pluripotent stem cell (hPSC) expansion have been reviewed for their propensity to be adapted into a scalable bioprocess and their efficiency in terms of cardiomyocyte differentiation
The different protocols developed over the past few years have focused on generation of high purity cardiomyocytes without considering issues involved in scaling up the processes
Summary
Cardiovascular disease is the leading cause of death globally, accounting for 244.8 per 100,000 deaths in 2008 [1]. The immense potential of hPSC-derived cardiomyocytes in regenerative medicine, cardiotoxicity pharmacology testing and drug discovery is tantalizing To effectively serve these applications, a reproducible, efficient and cost-effective platform for in vitro cardiomyocyte generation must be developed. It is possible to isolate and cultivate cardiac progenitors as shown in several studies using fluorescence-activated cell sorting of the KDR+/PDGFRA- population [23] or genetically modified NKX2-5 reporter cell line [24] Even though these progenitors have the potential to be used directly for cell therapy and as the source for cardiomyocyte generation [25], their isolation, maintenance requirements and expansion capacity provide several challenges. The technical issues involved in each and their implications on subsequent cardiomyocyte differentiation
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