Thermosensitive and Highly Flexible Hydrogels Capable of stimulating cardiac differentiation

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 modulusdependent

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.