Since September 2003, when Prof. Anversa’s research group described rat cardiac stem cells for the first time,13
many research groups have claimed to have discovered new and important cardiac progenitor/stem cells in the adult heart.14
. Since 2005, the scientific community talked about adult c-Kit+ and/or Sca-1+ and/or MDR-1+ cells, and embryonic Isl1+ cells. These two populations have always been considered different entities and are described separately in many research papers and reviews,15-17
although expression of the Isl1 transcription factor by cardiac precursor cells has also been reported in adult hearts.
Our research group, in the same time as the research group of Prof. Di Nardo, described for the first time the concomitant expression of the three markers, i.e.
, c-Kit, Sca-1 and Isl1, in the same cardiac precursor cell. Prof. Di Nardo’s research group described the concomitant expression of the Isl1, c-Kit and Sca-1 markers in adult mouse cardiac progenitor cells in 2008,18
while in 2009 our research group confirmed the expression of the three markers in adult rat CPCs.19
In a systematic work published in 2011 about the identification of Isl1+ cells in the mouse heart from postnatal day 1 to young adulthood in different strains, the authors found clusters of positive cells in the cardiac ganglia of the studied strains, while found very a few clusters of Isl1+ cardiac precursors only in 129SvJ or Balb/C strains and in animals not older than 4 months.20
Recently Genead et al
demonstrated the contemporary expression of c-Kit and Isl1 markers in rat adult hearts in normal, pregnant and infarcted individuals. They reported the expression of both markers in the entire heart and in the right ventricle, the left ventricle, the outflow tract and the peri-infarct and peri-ischemia regions. Unfortunately, the study was based on real-time PCR analysis, and whenever immunocytochemistry was shown, no double staining for both markers had been performed. Other evidence supports the hypothesis that Isl1+ cells are not a different population from Sca-1+ CPCs. The contemporary expression of Sca-1 and Isl1 has been described both in a subpopulation of Sca-1+/c-Kit- cells identified and isolated from adult mouse hearts22
and in Sca-1+ cardiosphere-derived cells obtained from cardiac explants from normal, sham-operated or post-myocardial infarct hearts.23
In this study, only Sca-1+/CD45- cells were also positive for Isl1 and increased in number only after an acute myocardial infarct.23
Considering that other authors identified Isl1+ cells in adult murine and rat hearts, Weinberger et al.24
used heterozygous Isl1-LacZ mice, a more sensitive genetic approach, to investigate the presence and localisation of these precursor cells in 30 animals at different time points after birth (10 weeks to 18 months).
They found four different populations of Isl1+ cells: i) clusters of Isl1+ neurons were found in the cardiac parasympathetic ganglia of the posterior side of the heart and in the nervous plexus surrounding the pulmonary veins; ii) clusters of Isl1+ smooth muscle cells were found in the muscular layer above the aortic and pulmonary valve in the proximal part of the aorta and the trunk of the pulmonary artery (only a few positive cells were present in the aortic valve leaflets); iii) clusters of Isl1+ cardiomyocytes were found in the left ventricular outflow tract region; iv) clusters of Isl1+ sinoatrial node (SAN) cells were found in the muscular wall between right atrium and vena cava superior.
These results support the hypothesis that in the adult heart many cell populations may derive from Isl1+ embryonic precursors, as smooth muscle cells, parasympathetic neurons, SAN cells, but also that, even if reduced in number, Isl1+ cardiomyogenic progenitors, may be present in the adult myocardium.