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Global Translational Medicine

REVIEW ARTICLE
Advancements in cardiac regenerative

therapy: Scalable human iPSC-derived
cardiomyocyte differentiation and maturation

Tadahisa Sugiura * , Dhienda C. Shahannaz 1† , Brandon E. Ferrell ,
1
1†
and Taizo Yoshida 2
1 Department of Cardiothoracic and Vascular Surgery, Montefiore Medical Center/Albert Einstein
College of Medicine, New York, United States of America
2 Department of Surgery, Montefiore Medical Center/Albert Einstein College of Medicine, New York,
United States of America
(This article belongs to the Special Issue: Exploring Cardiovascular Regenerative Therapy Using
Induced Pluripotent Stem Cells)

Abstract
The demand for mass production of induced pluripotent stem cell-derived
cardiomyocytes (iPSC-CMs) is escalating, driven by their potential to revolutionize
cardiac regenerative therapies. The development of large-scale production
protocols for iPSC-CMs is crucial to attain their therapeutic potential, enabling the
† These authors contributed equally
to this work. treatment of millions of patients’ worldwide suffering from cardiovascular diseases.
However, the scalable production of iPSC-CMs hinges on overcoming several critical
*Corresponding author:
Tadahisa Sugiura challenges, including cellular differentiation and maturation. In pursue of tackling
(tsugiura@montefiore.org) these challenges, researchers are investigating novel strategies such as prolonged
culture periods, mechanical stimulation, and co-culture with supporting cell types.
Citation: Sugiura T, Shahannaz DC,
Ferrell BE, Yoshida T. Overcoming these challenges is essential for unlocking the full potential of iPSC-CMs
Advancements in cardiac and paving the way for a new era in cardiac regenerative medicine. In this review,
regenerative therapy: Scalable following topics are covered: (1) improvement of differentiation and maturation of
human iPSC-derived cardiomyocyte
differentiation and maturation. iPSC-CMs and (2) scalable production of iPSC-CMs.
Global Transl Med. 2025:4(1):1-15.
doi: 10.36922/gtm.5745
Keywords: Induced pluripotent stem cell; Cardiac regenerative therapy; Cardiomyocyte;
Received: November 1, 2024
Stem cell maturation; Clinical translation
Revised: November 20, 2024
Accepted: November 27, 2024
Published online: January 8, 2025 1. Introduction
Copyright: © 2025 Author(s).
This is an Open-Access article The human heart possesses a limited capacity for regeneration, characterized by a
distributed under the terms of the modest annual turnover rate of cardiomyocytes (CMs), which decreases with age, from
Creative Commons Attribution approximately 1% at 25 years to 0.45% by 75 years, indicating a decline in regenerative
License, permitting distribution, 1
and reproduction in any medium, potential over the lifespan. The remarkable longevity of adult human CMs results in
provided the original work is almost 50% being replaced over a 75-year lifespan, in stark contrast to the high mitotic
properly cited. and cytokinetic activity observed in infant CMs reaching 40%, which drives cardiac
1
Publisher’s Note: AccScience growth and development, indicating a pronounced regenerative capacity in pediatric
Publishing remains neutral with heart. Research investigations which incorporate findings based on animal model
regard to jurisdictional claims in
published maps and institutional findings have consistently demonstrated that CMs undergo a developmental shift
affiliations. from a mononucleate to a binucleate state, concomitant with cell cycle withdrawal and

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