Page 17 - GTM-4-1

Global Translational Medicine Advancements in cardiac regenerative therapy

help increase cell density in the bioreactor, enhancing development of more effective, scalable, and clinically
yield without significantly increasing reactor size, and relevant platforms for heart disease modeling, drug
(3) perfusion bioreactors: by continuously supplying fresh discovery, and regenerative medicine. The development
medium while removing waste, perfusion bioreactors of economically and methodologically efficient large-
maintain optimal conditions for cell growth, supporting scale iPSC-CM culture is closely tied to understanding
longer culture durations and higher cell densities, and and promoting cell maturation, whereas optimization of
(4) 3D suspension culture systems: enabling cells to grow rhythm control in CMs requires a comprehensive approach
as aggregates or spheroids, which can better mimic in vivo which incorporates advances in scalable production and
environments, potentially leading to more mature cell cellular maturation, underscoring the importance of these
phenotypes and scalable expansion. 111 three pillars. 112
3D suspension culture systems have emerged as a 4. Conclusion
powerful method for scalable iPSC-CM production,
offering significant advantages over traditional 2D culture Substantial advancements have been made in leveraging
systems by better mimicking the in vivo environment. In iPSC-CMs for cardiac regenerative medicine, with current
11
these systems, iPSCs aggregate into spheroids, fostering bioreactor systems capable of producing up to 10 cells
enhanced cell-cell and cell-matrix interactions and per batch. To enhance predictive power and recapitulate
creating a more uniformed cellular microenvironment, population-level cardiovascular risks, further refinements
promoting CPCs differentiation into functional CMs. are required, such as implementing robust quality
This setup supports key signaling pathways, such as gap control endpoints, scalable differentiation protocols with
junction maturation. 3D cultures generate CMs with better minimized variability, and nutrient-driven maturation
electrophysiological properties, contractile function, and strategies. Notably, 3D bioprinting and microphysiological
drug response, making them ideal for drug screening systems enable the replication of complex tissue
and regenerative medicine. In addition, 3D cultures are structures and interactions, facilitating more accurate
more likely to exhibit a mature phenotype, including disease modeling and drug screening. Such bidirectional
better synchronization of cell contractions and enhanced scalability is crucial for translating iPSC-CMs into large-
responses to pharmacological agents, making them more scale regenerative applications. Efforts to harmonize
suitable for drug screening and regenerative medicine patient iPSC banking and generation of cardiovascular cell
applications. Their scalability is crucial for therapeutic types with reduced batch-to-batch variability will support
applications, supporting heart disease modeling, personalized treatment approaches. These advancements
personalized medicine, and autologous therapies with set the foundation for population-based studies and
improved consistency. pharmacogenetic tools, and, importantly, potential
To optimize these systems for scalable production, autologous transplant therapies to address myocardial
bioreactor design plays a pivotal role. Maintaining repair in clinical settings. Continued progress on cost
continuous nutrient flow and removing waste through reduction, iPSC-CM maturation, and safety protocols will
continuous perfusion are crucial for supporting large-scale be pivotal for making iPSC-CM-based therapies a viable
cell cultures. For instance, spinner flasks, wave-induced option in clinical practice.
motion systems, and perfusion-based platforms have been Acknowledgments
used to maintain optimal cell health and growth while
ensuring uniform differentiation. These bioreactor systems None.
allow the maintenance of large volumes of spheroids,
streamlining the process of expanding iPSC-CMs. The Funding
success of these cultures also hinges on controlling key None.
parameters, such as shear forces, agitation speed, and
seeding density, all of which can influence cell viability and Conflict of interest
differentiation outcomes. Tadahisa Sugiura is the Editorial Board Member of this

While scalable production is crucial for iPSC-based journal and Guest Editor of this special issue, but was not in
therapies, it is equally important to ensure cell fate control any way involved in the editorial and peer-review process
of the mature cell phenotype and its functional rhythm conducted for this paper, directly or indirectly. Separately,
control. By combining optimized bioreactor conditions other authors declared that they have no known competing
with precise biochemical cues, these systems are advancing financial interests or personal relationships that could have
the field of iPSC-derived cardiac models, enabling the influenced the work reported in this paper.

Volume 4 Issue 1 (2025) 9 doi: 10.36922/gtm.5745