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Wnt/β-catenin signalling controls adult heart remodelling in part via regulation of cardiac progenitor cell (CPC) differentiation. An enhanced understanding of mechanisms controlling CPC biology might facilitate the development of new therapeutic strategies in heart failure. We identified and characterized a novel cardiac interaction between Krueppel-like factor 15 and components of the Wnt/β-catenin pathway leading to inhibition of transcription. In vitro mutation, reporter assays and co-localization analyses revealed that KLF15 requires both the C-terminus, necessary for nuclear localization, and a minimal N-terminal regulatory region to inhibit transcription. In line with this, functional Klf15 knock-out mice exhibited cardiac β-catenin transcriptional activation along with functional cardiac deterioration in normal homeostasis and upon hypertrophy. We further provide in vivo and in vitro evidences for preferential endothelial lineage differentiation of CPCs upon KLF15 deletion. Via inhibition of β-catenin transcription, KLF15 controls CPC homeostasis in the adult heart similar to embryonic cardiogenesis. This knowledge may provide a tool for reactivation of this apparently dormant CPC population in the adult heart and thus be an attractive approach to enhance endogenous cardiac repair. peerReviewed