The Atrioventricular Junction: A Potential Niche Region for Progenitor Cells in the Adult Human Heart

Abstract

A stem cell niche is a microenvironment where stem cells reside in a quiescent state, until activated. In a previous rat model, we combined 5-bromo-2-deoxy-uridine labeling with activation of endogenous stem cells by physical exercise and revealed a distinct region, in the atrioventricular junction (AVj), with features of a stem cell niche. In this study, we aim to investigate whether a similar niche exists in the human heart. Paired biopsies from AVj and left ventricle (LV) were collected both from explanted hearts of organ donors, not used for transplantation ( N = 7) and from severely failing hearts from patients undergoing heart transplantation ( N = 7). Using antibodies, we investigated the expression of stem cell, hypoxia, proliferation and migration biomarkers. In the collagen-dense region of the AVj in donor hearts, progenitor markers, MDR1, SSEA4, ISL1, WT1, and hypoxia marker, HIF1-α, were clearly detected. The expression gradually decreased with distance from the valve. At the myocardium border in the AVj costaining of the proliferation marker Ki67 with cardiomyocyte nuclei marker PCM1 and cardiac Troponin-T (cTnT) indicated proliferation of small cardiomyocytes. In the same site we also detected ISL1 + /WT1 + /cTnT cells. In addition, heterogeneity in cardiomyocyte sizes was noted. Altogether, these findings indicate different developmental stages of cardiomyocytes below the region dense in stem cell marker expression. In patients suffering from heart failure the AVj region showed signs of impairment generally displaying much weaker or no expression of progenitor markers. We describe an anatomic structure in the human hearts, with features of a progenitor niche that coincided with the same region previously identified in rats with densely packed cells expressing progenitor and hypoxia markers. The data provided in this study indicate that the adult heart contains progenitor cells and that AVj might be a specific niche region from which the progenitors migrate at the time of regeneration.

Human intracardiac SSEA4+CD34 cells show features of cycling, immature cardiomyocytes and are distinct from Side Population and C-kit+CD45- cells

“…The study was approved by the local ethics committee at the University of Gothenburg (#436–15, #596–11) and carried out in accordance with the Helsinki Declaration as revised 2013. Biopsy material from some of the patients were also used in other previously published studies or unpublished studies due to the limited supply of biopsy material [ 24 – 26 ]. No organs/tissues were procured from prisoners.…”

Adult stem cell niches for tissue homeostasis

“…Subepicardial regions have been indicated as preferential locations for CSC niches in the adult heart (Di Meglio et al, 2010;Limana et al, 2010). However, they can also be found scattered throughout the myocardium, particularly in the atria and apex, cardiac regions characterized by low hemodynamic stress (Vukusic et al, 2019). Experiments on CSC localization have been mostly carried out in rodents (Barreto et al, 2019).…”

“…In addition, SCA1‐expressing CSCs were only demonstrated in mice, whereas no human homolog has yet been identified (Holmes & Stanford, 2007 ). According to Vukusic et al (Vukusic et al, 2019 ), the atrio‐ventricular junction at the insertion point of the mitral valve may represent a crucial niche region, from which CSCs would promote regeneration processes for both the valve, atria, and ventricles.…”

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

“…In addition, we found expression of the stem cell markers MDR1 and Sca1. In a follow-up study on the human left AVj, the base of the mitral valve, we observed expression of biomarkers associated with hypoxia, stem cells, proliferation, and migration, showing features of a progenitor niche [ 18 ].…”