Expression of Stem Cell Niche-Related Biomarkers at the Base of the Human Tricuspid Valve

Abstract

Stem cell niches have been thoroughly investigated in tissue with high regenerative capacity but not in tissues where cell turnover is slow, such as the human heart. The left AtrioVentricular junction (AVj), the base of the mitral valve, has previously been proposed as a niche region for cardiac progenitors in the adult human heart. In the present study, we explore the right side of the human heart, the base of the tricuspid valve, to investigate the potential of this region as a progenitor niche. Paired biopsies from explanted human hearts were collected from multi-organ donors ( N = 12). The lateral side of the AVj, right atria (RA), and right ventricle (RV) were compared for the expression of stem cell niche-related biomarkers using RNA sequencing. Gene expression data indicated upregulation of genes related to embryonic development and extracellular matrix (ECM) composition in the proposed niche region, that is, the AVj. In addition, immunohistochemistry showed high expression of the fetal cardiac markers MDR1, SSEA4, and WT1 within the same region. Nuclear expression of HIF1α was detected suggesting hypoxia. Rare cells were found with the co-staining of the proliferation marker PCNA and Ki67 with cardiomyocyte nuclei marker PCM1 and cardiac Troponin T (cTnT), indicating proliferation of small cardiomyocytes. WT1+/cTnT+ and SSEA4+/cTnT+ cells were also found, suggesting cardiomyocyte-specific progenitors. The expression of the stem cell markers gradually decreased with distance from the tricuspid valve. No expression of these markers was observed in the RV tissue. In summary, the base of the tricuspid valve is an ECM-rich region containing cells with expression of several stem cell niche-associated markers. Co-expression of stem cell markers with cTnT indicates cardiomyocyte-specific progenitors. We previously reported similar data from the base of the mitral valve and thus propose that human adult cardiomyocyte progenitors reside around both atrioventricular valves.

Global ischemia induces stemness and dedifferentiation in human adult cardiomyocytes after cardiac arrest

“…Beyond its function as a transcriptional regulator for the cellular response to hypoxia, Hif1α plays a role in the activation of genes related to tissue repair 28 . In contrast to the findings in LV, nuclear Hif1α expression was detected in non-cardiomyocytes in the AVj in both groups, as previously reported 4,5 . This indicates that the AVj region holds a lower oxygen level than other parts of the heart, strengthening the theory of hypoxic stem cell niche in adult human heart.…”

“…Previously, we reported increased numbers of BrdU+ proliferating cells in the AVj using physical exercise in the adult rats 3 . In addition we have shown expression of biomarkers related to hypoxia, cardiac stem cells, proliferation and migration in the left and right AVj 4,5 indicating that this region is of importance to cardiomyocyte cell renewal in human. I the current study, the increased expression of proliferation markers in the AVj after cardiac arrest suggests that more cardiomyocytes might had entered the cell cycle.…”

“…Thus, it is essential to assess regenerative processes in human heart when possible. In this study, we evaluated the expression of several early cardiac stem cell-and proliferation-associated biomarkers in adult human cardiac tissue from the left ventricle (LV) and the potential stem cell niche region the atrioventricular junction (AVj) [3][4][5] . Specifically, we sought to investigate whether global ischemia, caused by When damage occur in cardiac tissue, the result is often an increase in fibrosis, hypertrophy, adipose tissue infiltration, lipofuscin accumulation or nuclei fragmentation.…”

“…Biopsies were obtained from two different locations in each heart; 1. Left atrioventricular junction (AVj) located at the lateral base of mitral valve, between left atrium and ventricle that represents the previously proposed cardiac stem cell niche [3][4][5] , and 2. transmural left ventricular myocardium (LV) tissue from the lateral middle region.…”

“…A potential cardiac stem cell niche was identified in the atrioventricular junction (AVj) of adult rat heart by using physical exercise for activation of stem cells in combination with DNA labeling with BrdU 3 . In human hearts, the AVj, at the insertion point of the mitral and tricuspid valves contain cells expressing cardiac embryonic stem cell markers and cardiomyocytes at different stages of development, and also display markers of migration and proliferation 4 , 5 . Cells expressing stem cell markers in the AVj may thus be of importance for the tissue homeostasis of the valvular apparatus as well as ventricles and atria.…”