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

Journal article
Authors Kristina Vukusic
Mikael Sandstedt
Marianne Jonsson
Märta Jansson
Anders Oldfors
Anders Jeppsson
Göran Dellgren
Anders Lindahl
Joakim Sandstedt
Published in Stem Cells and Development
Volume 28
Issue 16
Pages 1078-1088
ISSN 1547-3287
Publication year 2019
Published at Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine
Institute of Biomedicine, Department of Pathology
Institute of Medicine, Department of Molecular and Clinical Medicine
Pages 1078-1088
Language en
Links dx.doi.org/10.1089/scd.2019.0075
Keywords heart, stem cell niche, atrioventricular junction, hypoxia, cardiomyocyte proliferation, hematopoietic stem-cells, cd117-positive cells, identification, population, expression, renewal, origin, life, Cell Biology, Hematology, Research & Experimental Medicine, Transplantation
Subject categories Cardiac and Cardiovascular Systems

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-alpha, 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.

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