Myocardial Isl(+)land: a place with lots of rhythm, but no beat.

As you read these words, an intrinsic rhythm of life ripples through your heart. Your personal “metronome” is required to begin at the earliest stages of embryonic development and continues unceasingly as life unfolds. Understanding the genesis of our rhythm continues to be refined by intense investigation from developmental biologists who are unraveling the intertwined orchestration of myocardial organization, timing, and cardiac precursor cell incorporation. Almost a decade ago, a remarkable publication identified an embryonic stem cell subpopulation essential for cardiac formation expressing a LIM homeodomain transcription factor called Isl1.1 Isl1-null mice fail to develop major cardiac segments resulting in embryonic lethality, convincingly demonstrating an essential role of Isl1 stem cells in the initial stages of cardiogenesis. Potential significance of these cellular developmental biology observations did not go unnoticed by those committed to the comparatively nascent field of myocardial regeneration who long for a specific cardiac stem cell marker. Following closely on the heels of initial Isl1related revelations, a spate of high-impact publications touted the potential of Isl1 as a marker for pluripotent cardiac precursors capable of generating all cardiovascular lineages.2–5 Thereafter, as the proverbial saying goes, “then all hell broke loose” and researchers became embroiled in yet another controversy about cardiac stem cell biology.6–9 Fortunately, time discovers truth and a clearer vision emerges, as presented in this issue of Circulation Research by Weinberger et al10 that helps reconcile speculation with reality and dispels some of the hyperbole about Isl1 in the adult heart.