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Global Translational Medicine Advancements in cardiac regenerative therapy

adhesion kinase and MAPK/ERK signaling, enhance of cell banks that provide access to high-quality, validated
cell adhesion, growth, and migration. Connexin-43 iPSC lines, serving as repositories to cater the various
gap junctions also form under ES, promoting requirements of clinical research communities. This would
electromechanical coupling and cell alignment for facilitate the widespread adoption of iPSCs in therapeutic
synchronized contraction, which is essential for mature research, ultimately advancing the regenerative medicine
cardiac tissue formation. 66,67 field. Clinical trials have begun utilizing human iPSCs to
In addition to promoting stem cell recruitment, address debilitating diseases. For instance, iPSC-derived
ES helps prevent atrophy caused by denervation, retinal-pigment epithelial cells have been transplanted
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which occurs when nerve supply to tissues is lost. By to tackle macular degeneration (MD), while β-like cells
maintaining heart contractility and enhancing cellular are being differentiated to overcome insulin dependence
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responsiveness to electrical signals, ES can counteract the in type 1 diabetes mellitus patients. These advancements
effects of denervation. ES activates pathways involved in highlight the need for large-scale, clinically compliant
muscle protein synthesis and cell survival, including the iPSC production to support these innovations. Several key
mechanistic target of rapamycin pathway, which is crucial factors must be optimized, including bioreactor design,
for maintaining muscle mass. 67,68 Furthermore, ES has culture conditions, and cell differentiation protocols. The
a neurogenic effect, influencing the autonomic nervous goal is to achieve rejection-free cell transplants without
system to regulate neurotransmitter release and modulate needing lifelong immunosuppressive therapy (that comes
cardiac function. 65,68 This interaction supports tissue repair with direct organ transplantation as earlier therapy finding).
by improving the heart’s electrical activity in response to From a bioprocess perspective, the autologous method
injury. Findings highlight the potential of ES in enhancing necessitates modestly sized, condition-targeted treatment
stem cell homing to cardiac injury sites, supporting tissue doses for each individual patient. This approach may also
repair, and preventing atrophy due to denervation. require extra cells for quality assurance, efficacy assays,
In large MIs with Q-waves and denervation, pulsed and reserved dosages for subsequent transplantation, if
electromagnetic fields (PEMF) simulate EM forces, applicable. For instance, estimates suggest that retinal-
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potentially aiding sympathetic re-innervation and pigment epithelium cells from approximately 50,000
autonomic regulation. PEMF has shown benefits in iPSCs would suffice to treat MD in one patient, as
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experimental studies, improving metrics such as ejection demonstrated in a successful case using human iPSCs.
fraction and supporting myocardial healing. At the To accommodate therapeutic cell production on such a
biomolecular level, PEMF promotes VEGFR-mediated limited scale, automation, facility space with minimal
angiogenesis, nerve GF for re-innervation, and IL-10 to good manufacturing practice (GMP) standards, and the
reduce chronic inflammation, all of which are essential simultaneous production of various patient samples in
for controlled tissue repair. In addition, piezoelectric single-use culture systems are crucial to the continuing of
materials are being investigated to localize electrical this production. 74
signals, improving stem cell migration to the infarct These facts collectively strongly advocate for an
site without invasive power sources. Further studies allogeneic approach, wherein a “universal cell source” is
employing 3D visualization methods, such as CUBIC and intended for transplantation into non-related recipients,
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CLARITY, have made strides in clarifying sympathetic likely requiring immunosuppressive therapy similar
nerve remodeling in post-MI contexts. This technology to traditional organ transplants. However, the degree
has enabled detailed mapping of cardiac sympathetic of immunosuppression needed will depend on human
networks, which could help in monitoring EM treatment leukocyte antigen compatibility, which can be achieved
effectiveness and improving nerve regeneration post-MI. through the strategic deployment of multiple iPSC lines to
Together, these biomolecular mechanisms position ES and cater to specific patient populations within a given region
EM therapies as potent tools for cardiac repair or country, as discussed in greater detail elsewhere. This
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allogeneic “off-the-shelf” strategy also ensures timely
3. Scalable production of iPSC-CMs cell availability to meet pressing clinical demands. This
The discovery of iPSCs has revolutionized the field of highlights the need for robust, cost-effective, and reliable
regenerative medicine, enabling the generation of diverse GMP-compliant protocols for scaling up iPSC cultivation
cell types for therapeutic applications. However, the high and differentiation into specialized cell types (including
costs associated with generating and validating iPSC lines iPSC-CMs), ensuring consistency and reproducibility in
pose a significant obstacle to their widespread adoption. research applications, without displaying heterogeneous
Consequently, there is an urgent need for the establishment behaviors.

Volume 4 Issue 1 (2025) 7 doi: 10.36922/gtm.5745