Interrogating functional integration between injected pluripotent stem cell-derived cells and surrogate cardiac tissue

Abstract

Myocardial infarction resulting in irreversible loss of cardiomyocytes (CMs) remains a leading cause of heart failure. Although cell transplantation has modestly improved cardiac function, major challenges including increasing cell survival, engraftment, and functional integration with host tissue, remain. Embryonic stem cells (ESCs), which can be differentiated into cardiac progenitors (CPs) and CMs, represent a candidate cell source for cardiac cell therapy. However, it is not known what specific cell type or condition is the most appropriate for transplantation. This problem is exasperated by the lack of efficient and predictive strategies to screen the large numbers of parameters that may impact cell transplantation. We used a cardiac tissue model, engineered heart tissue (EHT), and quantitative molecular and electrophysiological analyses, to test transplantation conditions and specific cell populations for their potential to functionally integrate with the host tissue. In this study, we validated our analytical platform using contractile mouse neonatal CMs (nCMs) and noncontractile cardiac fibroblasts (cFBs), and screened for the integration potential of ESC-derived CMs and CPs (ESC-CMs and -CPs). Consistent with previous in vivo studies, cFB injection interfered with electrical signal propagation, whereas injected nCMs improved tissue function. Purified bioreactor-generated ESC-CMs exhibited a diminished capacity for electrophysiological integration; a result correlated with lower (compared with nCMs) connexin 43 expression. ESC-CPs, however, appeared able to appropriately mature and integrate into EHT, enhancing the amplitude of tissue contraction. Our results support the use of EHT as a model system to accelerate development of cardiac cell therapy strategies.

Design and formulation of functional pluripotent stem cell-derived cardiac microtissues

“…Eschenhagen and coworkers have advanced the field by developing aligned tissue models suitable for some multiwell-plate analytics and that are capable of measuring forces of contraction (22). Together, these and other systems (23,24) have already proven their utility as models for cell transplantation (25) and drug candidate evaluation (12,26,27). We have recently used microfabrication to miniaturize such aligned tissue models into microscale tissues (11).…”

Evolutionarily conserved intercalated disc protein Tmem65 regulates cardiac conduction and connexin 43 function

“…A great effort is currently underway to promote the maturation of embryo-derived stem cells by a multitude of methods, including manipulation of growth factors 19 , electrical stimulation 20 and mechanical stretching 21 . To date, monitoring the developmental stages of human embryonic stem cell (hESC)-derived cardiomyocytes (hESC-CM) has been dependent on gene expression levels and morphological changes 22 .…”

Enabling stem cell therapies through synthetic stem cell–niche engineering

“…High-throughput approaches are also available to screen niche parameters in a combinatorial manner (32,33). Finally, stem cell-niche engineering may reveal novel strategies to modulate stem cell niches in vivo for clinical benefit; for example, it may be possible to specifically disrupt interactions between stem cells and their niche (See Future directions: clinical translation of engineered niches below) or develop a way to guide the integration and functional maturation of cells into injured tissue (34). In the following sections, we discuss how various microscale technologies will enable stem cell-niche engineering at the molecular and cellular scale.…”