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Global Translational Medicine Advancements in cardiac regenerative therapy

the loss of postnatal proliferative capacity. In the context substantiating the concept of lifelong CM repopulation
2
of prevalent cardiovascular diseases, such in myocardial and overturning the previous understanding of CMs as a
infarction (MI), which results in the sudden loss of static cell population. 4
approximately one billion CMs, the inherent regenerative Cardiac development is a complex, multidimensional
capacity is markedly insufficient. This limitation leads process orchestrated by the sophisticated interplay of
to structural repair through scar formation rather signaling pathways and gene transcriptional regulation.
than functional repair through contractile restoration, The quest for generating CMs has undergone a significant
potentially culminating in adverse ventricular remodeling transformation. Formerly, embryonic stem cells were
and heart failure post-MI. Nevertheless, the discovery employed, but this approach was beset by ethical concerns.
of adult CM repopulation suggests that native cell However, in 2006, Yamanaka pioneered an innovative
populations, both cardiac progenitor cells (CPCs) and method, harnessing iPSCs to reprogram terminally
existing CMs, may serve as viable sources for myocardial differentiated human fibroblasts, obtained from skin
5,6
regeneration following injuries. 1 or connective tissue biopsies, or human hair follicle
Regenerative medicine requires a constant supply keratinocyte, using four transcription factors (OSKM).
7-9
of cell sources, such as induced pluripotent stem cells This reprogramming process yields iPSCs that can be
(iPSCs), including those differentiated into CMs and further directed toward a cardiac fate through cardiac
other functional progenies. First founded in 2006 differentiation/induction, involving the activation of
through reprogramming through the “Yamanaka cardiac-specific transcription factors (T-box transcription
Factors” (octamer-binding transcription factor 4 [OCT factor 5 [TBX , heart and neural crest derivatives expressed
5]
4]
4] , sex-determining region Y-box 2 [Sox , Kruppel- 1 [HAND1), GATA binding protein 4 [GATA , and
2]
like factor 4 [KLF , and c-Myc protein; all abbreviated NK2 homeobox 5 [NKX2- ). This process generates
5] 10,11
4]
as OSKM), these somatic cells are collectively referred reprogrammed cardiac precursors, including CPCs, which
to as iPSCs, which can differentiate into all three have the ability to differentiate into multiple cardiac cell
embryonic germ layers. As the research has been relying types, such as CMs, smooth muscle cells, and endothelial
3
on the advancement of these iPSCs, their production cells.
should be resilient, financially feasible, and ultimately In iPSC-CM development, differentiation and
standardized by lab-scale protocols for iPSC expansion maturation are two distinct processes that occur
and cardiomyogenic differentiation toward more sequentially: (1) the process of differentiation refers to
controlled processing in industry-compatible culture the process by which iPSCs are coaxed to undergo a series
platforms. Here, advanced strategies for the cultivation of molecular and cellular changes, acquiring a CM-like
and differentiation of iPSC will be reviewed by focusing phenotype and expressing cardiac-specific markers and
on stirred bioreactor-based techniques for process- genes. This process is characterized by the activation
upscaling. The generation of CM mass from iPSCs of cardiac-specific transcriptional programs and the
could be enhanced by cardiovascular progenitor state, suppression of pluripotency genes. 12,13 It results in the
with equally important processes of cell fate control formation of immature CMs with primitive structural and
(differentiation and maturation). Finally, remaining functional properties, which then will need to undergo
challenges will be highlighted specifically regarding the (2) maturation process to acquire advanced structural
adoption of three-dimensional (3D) iPSC suspension and functional properties. This second process is
culture techniques for process-upscaling and critical characterized by the further development of sarcomeres,
safety issues ahead of clinical translation. contractile apparatus, and mitochondrial density, leading

2. Differentiation and maturation of to enhanced contractility and electrophysiological
iPSC-CMs function. This results in the formation of mature CMs
with improved functionality and resemblance to native
2.1. Cardiac differentiation of iPSCs adult CMs.
The long-held notion that CMs are terminally The capacity of allowing stem cells to differentiate into
differentiated, post-mitotic cells with negligible specific human cell types of interest facilitates the discovery
regenerative capacity after birth has recently been of compounds that selectively influence the activity of
challenged. Bergmann et al. have provided evidence that these cells while exhibiting minimal effects on alternative
CMs do indeed undergo renewal, although at a remarkably cell types, thereby facilitating elucidation of cell-type-
low rate. Their findings suggest that approximately 50% specific responses. The differentiation process involves
14
of CMs are replaced throughout an individual’s lifetime, the orchestrated activation of transcriptional programs,

Volume 4 Issue 1 (2025) 2 doi: 10.36922/gtm.5745