An oxygen release system to augment cardiac progenitor cell survival and differentiation under hypoxic condition

Stem cell therapy has the potential to regenerate heart tissue damaged by myocardial infarction (MI), but it experiences extremely low efficacy. One of the major causes is the inferior cell survival under hypoxic condition of the infarcted hearts. We examined whether an oxygen-releasing system capable of sustainedly supplying oxygen to stem cells would augment cell survival and cardiac differentiation under hypoxic condition mimicking that of the infarcted hearts. The oxygen-releasing system consisted of hydrogen peroxide (H₂O₂)-releasing microspheres, catalase and an injectable, thermosensitive hydrogel. The microspheres were based on poly(lactide-co-glycolide) (PLGA) and a complex of H₂O₂ and poly(2-vinlypyrridione) (PVP). The oxygen was generated after the released H₂O₂ was decomposed by catalase. The hydrogel was designed to improve the retention of microspheres and stem cells in the beating heart tissue during myocardial injection. The oxygen-releasing system was capable of sustainedly releasing oxygen for at least two weeks. The release kinetics was dependent on the ratio of H₂O₂/VP. The hydrogel was based on N-isopropylacrylamide (NIPAAm), acrylic acid (AAc), and a macromer hydroxyethyl methacrylate-oligo(hydroxybutyrate) (HEMA-oHB). The hydrogel had a stiffness matching that of the heart tissue and was able to stimulate the cardiosphere-derived cells (CDCs) to differentiate into cardiomyocytes. Under hypoxic condition mimicking that of the infarcted hearts (1% O₂), CDCs encapsulated in the hydrogel experienced massive cell death. Introduction of oxygen release in the hydrogel significantly augmented cell survival; no cell death was found after seven days of culture, and cells even grew after seven days. Under hypoxic condition, cardiac differentiation of CDCs was completely silenced in the hydrogel, as confirmed at both mRNA and protein levels. However, introduction of oxygen release restored the differentiation. These results demonstrate that the developed oxygen-releasing system has great potential to improve the efficacy of cardiac stem cell therapy.