Challenges and innovation: Disease modeling using human-induced pluripotent stem cell-derived cardiomyocytes

Abstract

Disease modeling using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) has both challenges and promise. While patient-derived iPSC-CMs provide a unique opportunity for disease modeling with isogenic cells, the challenge is that these cells still demonstrate distinct properties which make it functionally less akin to adult cardiomyocytes. In response to this challenge, numerous innovations in differentiation and modification of hiPSC-CMs and culture techniques have been developed. Here, we provide a focused commentary on hiPSC-CMs for use in disease modeling, the progress made in generating electrically and metabolically mature hiPSC-CMs and enabling investigative platforms. The solutions are bringing us closer to the promise of modeling heart disease using human cells in vitro.

Keywords: arrhythmia modeling; biotechnology; cardiac metabolism; channelopathies; genomics; ion channel; regeneration; stem cell.

Figure 1

IK1 enhancement of iPS-CMs results in improved action potential (AP) characteristics. (A) Representative AP from IK1-enhanced iPS-CMs, paced at 0.5-3Hz at physiological temperature. (B) Resting membrane potential from IK1-enhanced iPS-CMs at different pacing frequencies. (C) dV/dTmax of iPS-CMs at different pacing frequencies. (D) Action potential duration (APD) at 10% (APD10), 50% (APD50), 70% (APD70) and 90% (APD90) at pacing frequencies 0.5Hz (black), 1Hz (dark grey), 2Hz (light grey), and 3Hz (white). (E) APD at APD10, APD50, APD70 and APD90 at 0.5Hz pacing from IK1 -enhanced iPS-CMs infected with WT Cav3 or LQT9-associated Cav3 mutation, F97C. (F) APD from IK1 -enhanced iPS-CMs expressing WT-Cav3 or F97C-Cav3 at 1Hz pacing. (G) Bradycardic pacing induced EADs in IK1-enhanced iPS-CMs expressing F97C-Cav3. Modified from (55).

Figure 2

Micropattern culture of iPS-CMs results in anisotropic conduction and improved myofibril alignment, which is maintained in coculture with CFs. (A) Percent of myofibrils aligned within 10 degrees of the primary axis significantly different in monolayers vs micropatterned. (B,C) Optical mapping of (B) monolayer and (C) micropatterned iPS-CMs. Ansiotropic conduction in patterned determined by comparison of the longitudinal (CVL) and transverse (CVT) conduction velocities. (D) iPS-CMs cultured on micropattern alone. Scale bar 200μM. (E) Aligned myofibrils of iPS-CMs seeded on micropatterned substrate maintained in co-culture with CFs at 18 days. Inset shows myofibrils with 79% of sarcomeres within 10 degrees of the superior angle. Scale bar 200μM. (F) Quantification of the percent of myofibrils aligned within 10 degrees of the superior angle at 18 days for the three conditions: iPS-CMs cultured alone, iPS-CMs co-cultured with CFs from Day 0 seeding, iPS-CMs co-cultured with CFs from Day 4 of seeding. (A–C) modified from (97), (D,E) unpublished data, and (F) modified from (99).