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CUX1 belongs to the homeodomain transcription factor family and is evolutionarily and functionally conserved from Drosophila to humans. In addition to the involvement in various physiological events including tissue development, cell proliferation, differentiation and migration, and DNA damage response, CUX1 has been implicated in tumorigenesis. Interestingly, CUX1 has been recently recognized as a haploinsufficient tumor suppressor, which is paradoxically overexpressed in tumor cells. While loss of heterozygosity and/or mutations of CUX1 have been frequently detected in many types of cancers, genomic amplification, and overexpression of CUX1 have also been reported in cancer tissues and are correlated with higher tumor grade and poor prognosis. Therefore, deciphering the roles of different CUX1 isoforms and in different tumor stages is required to establish a CUX1-based therapeutic strategy for cancer treatment.

Cardiac tissue engineering using biomaterials with or without combination of stem cell therapy offers a new option for repairing infarcted heart. However, the bioactivity of biomaterials remains to be optimized because currently available biomaterials do not mimic the biochemical components as well as the structural properties of native myocardial extracellular matrix. Here we hypothesized that human heart valve-derived scaffold (hHVS), as a clinically relevant novel biomaterial, may provide the proper microenvironment of native myocardial extracellular matrix for cardiac repair. In this study, human heart valve tissue was sliced into 100 μm tissue sheet by frozen-sectioning and then decellularized to form the hHVS. Upon anchoring onto the hHVS, post-infarct murine BM c-kit+ cells exhibited an increased capacity for proliferation and cardiomyogenic differentiation in vitro. When used to patch infarcted heart in a murine model of myocardial infarction, either implantation of the hHVS alone or c-kit+ cell-seeded hHVS significantly improved cardiac function and reduced infarct size; while c-kit+ cell-seeded hHVS was even superior to the hHVS alone. Thus, we have successfully developed a hHVS for cardiac repair. Our in vitro and in vivo observations provide the first clinically relevant evidence for translating the hHVS-based biomaterials into clinical strategies to treat myocardial infarction.

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