Thermosensitive and Highly Flexible Hydrogels Capable of Stimulating Cardiac Differentiation of Cardiosphere-Derived Cells under Static and Dynamic Mechanical Training Conditions

Abstract

Cardiac stem cell therapy has been considered as a promising strategy for heart tissue regeneration. Yet achieving cardiac differentiation after stem cell transplantation remains challenging. This compromises the efficacy of current stem cell therapy. Delivery of cells using matrices that stimulate the cardiac differentiation may improve the degree of cardiac differentiation in the heart tissue. In this report, we investigated whether elastic modulus of highly flexible poly(N-isopropylamide) (PNIPAAm)-based hydrogels can be modulated to stimulate the encapsulated cardiosphere derived cells (CDCs) to differentiate into cardiac lineage under static condition and dynamic stretching that mimics the heart beating condition. We have developed hydrogels whose moduli do not change under both dynamic stretching and static conditions for 14 days. The hydrogels had the same chemical structure but different elastic moduli (11, 21, and 40 kPa). CDCs were encapsulated into these hydrogels and cultured under either native heart-mimicking dynamic stretching environment (12% strain and 1 Hz frequency) or static culture condition. CDCs were able to grow in all three hydrogels. The greatest growth was found in the hydrogel with elastic modulus of 40 kPa. The dynamic stretching condition stimulated CDC growth. The CDCs demonstrated elastic modulus-dependent cardiac differentiation under both static and dynamic stretching conditions as evidenced by gene and protein expressions of cardiac markers such as MYH6, CACNA1c, cTnI, and Connexin 43. The highest differentiation was found in the 40 kPa hydrogel. These results suggest that delivery of CDCs with the 40 kPa hydrogel may enhance cardiac differentiation in the infarct hearts.

Poly(N-isopropylacrylamide) and Copolymers: A Review on Recent Progresses in Biomedical Applications

“…The same research group described most recent papers with chemically modified HEMA comonomers to modulate the LCST, stiffness properties, and CDC encapsulation of PNIPAAm copolymers [105,106].…”

Thermo-Sensitive Nanomaterials: Recent Advance in Synthesis and Biomedical Applications

“…Moreover, other thermo-sensitive hydrogels have been investigated as candidates for cardiac regeneration therapy [ 149 , 150 ]. A system based on thermo-sensitive hydrogel and oxygen releasing microspheres was developed for the delivery of oxygen to heart tissue [ 151 ].…”

Thermosensitive, fast gelling, photoluminescent, highly flexible, and degradable hydrogels for stem cell delivery

“…1 μg of RNA was utilized for cDNA synthesis using a high-capacity cDNA reverse transcription kit (Applied Biosystem). The primers used were listed in Table 1 [49, 54, 55]. Real-time RT-PCR was performed with Maxima SYBR Green/Fluorescein master mix on an Applied Biosystem 7900 system.…”