Stem cells in the adult heart - 3D culture, isolation of side population cells and search for a stem cell niche

Abstract

Cardiac tissue shows a poor regenerative capacity. From 2003 reports, mostly based on animal models, have showed existence of stem cells also in the heart. Using 14C measurements, a slow but steady turnover of the cardiac cells was shown in humans, around 1%/year. As a source for this regeneration endogenous stem cells have been suggested. The aim of this thesis was to identify, isolate and characterize cardiac stem cells and to find their niche. Therefore, in Study I a new “High Density Sphere” 3D culture system was adopted where cardiac- and progenitor biomarker levels increased over time. In Study II Side Population progenitors were isolated from the left human atria. In Study III the distribution of label retaining cells was investigated, throughout the adult rat heart and a region in the Atrio Ventricular junction (AVj) was proposed as a potential stem cell niche. To assess translatability human AVj was explored in Study IV. The concomitant appearance of all of the selected stem cell biomarkers in the AVj indicated that the normal human heart also harbors a potential stem cell niche which to our knowledge has not been described previously. The location of these findings in the humans coincides with the same region in rat hearts. In conclusion we propose a new, 3D in vitro system for studies of cardiac cell phenotypes, identified Side Population cells and found an anatomic site, with features of a stem cell niche in rats and humans. The function of these potential niches is important to investigate in future. With these findings, we hope to contribute to better understanding of basic concepts of cardiac regeneration; an important step towards improved future therapies for patients.