Engineering the maturation of stem cell-derived cardiomyocytes

Abstract

The maturation of human stem cell-derived cardiomyocytes (hSC-CMs) has been a major challenge to further expand the scope of their application. Over the past years, several strategies have been proven to facilitate the structural and functional maturation of hSC-CMs, which include but are not limited to engineering the geometry or stiffness of substrates, providing favorable extracellular matrices, applying mechanical stretch, fluidic or electrical stimulation, co-culturing with niche cells, regulating biochemical cues such as hormones and transcription factors, engineering and redirecting metabolic patterns, developing 3D cardiac constructs such as cardiac organoid or engineered heart tissue, or culturing under in vivo implantation. In this review, we summarize these maturation strategies, especially the recent advancements, and discussed their advantages as well as the pressing problems that need to be addressed in future studies.

Maturation of human cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs) on polycaprolactone and polyurethane nanofibrous mats

“…In addition, the cells grown on PCL and PU nanofibrous mats seeded at densities of 2.0 × 10 5 cells/cm 2 and 2.5 × 10 5 cells/cm 2 showed the most elongated and rod-like shape compared to the control and cultures at other densities. Literature sources show that mature cardiomyocytes have large, anisotropic, and rod-like, elongated shapes (high length/width ratio and less roundness) 10 , while fetal cardiomyocytes are rounder and smaller than adult CMs 31 . iPSC-CMs cultured on nanofibrous mats do not show the significant parallel alignment characteristic of mature cardiomyocytes compared to controls, regardless of seeding density.…”

Adult Human Heart ECM Improves Human iPSC-CM Function via Mitochondrial and Metabolic Maturation

“…Human iCMs provide an attractive cell source for heart regeneration, along with disease modeling, drug screening, and toxicity testing. Despite an extensive effort to enhance cardiac maturity [9,29],…”

“…Human iCMs provide an attractive cell source for heart regeneration, along with disease modeling, drug screening, and toxicity testing. Despite an extensive effort to enhance cardiac maturity[9,29], the achieved CM maturity has been limited mainly to structural aspects, leaving functional and metabolic maturation as attractive targets. Here, we conditioned iPSCs with adult human heart derived ECM at the pre-differentiation stage to generate functionally and metabolically mature iCMs.…”

“…Various approaches have been proposed to promote the maturation of iCM cultures [4][5][6][7][8][9]. As one of the early strategies, prolonged culture of iCMs for up to 120 days led to structural changes such as increased cell size and increased myofibrillar density and alignment, as well as improvements in contractile performance, calcium handling, and electrophysiological properties [2,10,11].…”

Advances in the Generation of Constructed Cardiac Tissue Derived from Induced Pluripotent Stem Cells for Disease Modeling and Therapeutic Discovery

“…Recapitulating native heart tissue in vitro is challenging because of the crosstalk between different cell types and the heart's unique architecture [7,57]. The heart has three layers (internal to external: endocardium, myocardium, and epicardium) that are responsible for the continuous nourishment, contraction, and maintenance of cardiac structure (Figure 1B) [31,46,58]. CMs compose heart muscle and represent 70%/30% of fetal/adult heart cells, respectively, while occupying 70% of its volume [7,25,36,37,54].…”