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

Kristina Vukusic,Marianne Jonsson,Mikael Sandstedt,Göran Dellgren,Anders Lindahl,Anders Oldfors,Märta Jansson,Joakim Sandstedt,Anders Jeppsson

doi:10.1089/scd.2019.0075

Kristina Vukusic, Marianne Jonsson + Show 7 more

Open Access

https://doi.org/10.1089/scd.2019.0075

Copy DOI

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.

Highlights

There is a growing body of evidence supporting renewal of all cell types in the heart, including cardiomyocytes [1,2]
We wanted to investigate whether the human adult heart contains a stem cell niche region in the atrioventricular junction (AVj), similar to what we previously described in the rat heart
Sections from AVj and left ventricle (LV), from both the donors and the failing explanted hearts, were stained with Hematoxylin–Eosin and Picrosirius Red staining for histology examination (Fig. 1)

Summary

Introduction

There is a growing body of evidence supporting renewal of all cell types in the heart, including cardiomyocytes [1,2]. Several adult cardiac stem/progenitor cell populations have been described as a potential source for this regeneration, including ISL1+ [3], SSEA4+ [4,5], NKX2.5+ [3], WT1+ [6], Sca1 [7,8,9], MDR1+, and Side Population cells [10,11,12]. The niche is a reservoir of stem cells that can self-renew, divide, and give rise to new daughter cells These daughter cells will eventually migrate out of the niche and differentiate into tissue-specific cell types needed for the normal homeostasis or as a response to injury. This migration process has been associated with the expression of Snai-1 [21]

Objectives

Methods

Results

Conclusion