Hemodynamic Stimulation Using the Biomimetic Cardiac Tissue Model (BCTM) Enhances Maturation of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Abstract

Human induced pluripotent stem cell (hiPSC)-derived cardio­myocytes (hiPSC-CMs) hold great promise for cardiovascular disease modeling and regenerative medicine. However, these cells are both structurally and functionally ­immature, primarily due to their differentiation into cardiomyocytes occurring under static culture which only reproduces biomolecular cues and ignores the dynamic hemo­dynamic cues that shape early and late heart development during cardiogenesis. To evaluate the effects of hemodynamic stimuli on hiPSC-CM maturation, we used the biomimetic cardiac tissue model to reproduce the hemodynamics and pressure/volume changes associated with heart development. Following 7 days of gradually increasing stimulation, we show that hemodynamic loading results in (a) enhanced alignment of the cells and extracellular matrix, (b) significant increases in genes associated with physiological hypertrophy, (c) noticeable changes in sarcomeric organization and potential changes to cellular metabolism, and (d) a significant increase in fractional shortening, suggestive of a positive force frequency response. These findings suggest that culture of hiPSC-CMs under conditions that accurately reproduce hemodynamic cues results in structural orga­nization and molecular signaling consistent with organ growth and functional maturation.

Biomimetic Cardiac Tissue Culture Model (CTCM) to Emulate Cardiac Physiology and Pathophysiology ex vivo

“…CTCM maintains heart tissue physiological stretch for 12 days in culture Hemodynamic mechanical cues play a critical role in preserving the functionality of cardiomyocytes (CM) in vitro [26][27][28] . In the current manuscript, we developed a CTCM (Fig.…”

Tissue Chips and Microphysiological Systems for Disease Modeling and Drug Testing

“…Using microfluidic approaches, several groups have developed both active and passive flow control valves that can be used to ensure pulsatile pumping and unidirectional flow, similar to that seen in the body [ 178 , 179 , 180 ]. Microfabrication techniques can also create alternatives to cardiac tissue via the development of pumps to generate pulsatile flow, similar to the heart [ 35 , 181 ]. In summary, fluidic circuits can be tailored via adjustments in geometry, perfusion rate, and organization, along with incorporating components, such as actuators and valves (both in tubing connecting different TCs and within the TC devices themselves), to meet perfusion and transport requirements.…”

Bioengineering approaches to mature induced pluripotent stem cell-derived atrial cardiomyocytes to model atrial fibrillation

“…35 , 95 , 105 , 106 Although the inherent polymeric structure of ECM hydrogels does not allow for uniaxiality and static tension, anisotropic ECM orientation can be generated by applying supportive structures such as post, pillars, pins, and clips during the hydrogel forming process, all of which can be engineered to also induce mechanical tension and synchronized contraction/stretching of the aligned iPSC-CMs. 107–111 The auxotonic contraction of CMs encapsulated in a hydrogel can be manipulated by adjusting the mechanical property of supportive structures.…”