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. 2024 Jun 20;14(1):14256.
doi: 10.1038/s41598-024-65212-z.

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

Helen Jinton  1 , Victoria Rotter Sopasakis  2 , Linnéa Sjölin  1 , Anders Oldfors  2   3 , Anders Jeppsson  4   5 , Jonatan Oras  6 , Mathias Wernbom  7 , Kristina Vukusic  8
Affiliations

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

Helen Jinton et al. Sci Rep. .

Abstract

Global ischemia has been shown to induce cardiac regenerative response in animal models. One of the suggested mechanisms behind cardiac regeneration is dedifferentiation of cardiomyocytes. How human adult cardiomyocytes respond to global ischemia is not fully known. In this study, biopsies from the left ventricle (LV) and the atrioventricular junction (AVj), a potential stem cell niche, were collected from multi-organ donors with cardiac arrest (N = 15) or without cardiac arrest (N = 6). Using immunohistochemistry, we investigated the expression of biomarkers associated with stem cells during cardiomyogenesis; MDR1, SSEA4, NKX2.5, and WT1, proliferation markers PCNA and Ki67, and hypoxia responsive factor HIF1α. The myocyte nuclei marker PCM1 and cardiac Troponin T were also included. We found expression of cardiac stem cell markers in a subpopulation of LV cardiomyocytes in the cardiac arrest group. The same cells showed a low expression of Troponin T indicating remodeling of cardiomyocytes. No such expression was found in cardiomyocytes from the control group. Stem cell biomarker expression in AVj was more pronounced in the cardiac arrest group. Furthermore, co-expression of PCNA and Ki67 with PCM1 was only found in the cardiac arrest group in the AVj. Our results indicate that a subpopulation of human cardiomyocytes in the LV undergo partial dedifferentiation upon global ischemia and may be involved in the cardiac regenerative response together with immature cardiomyocytes in the AVj.

Keywords: Atrioventricular junction; Cardiac arrest; Cardiomyocyte proliferation; Dedifferentiation; Heart; Hypoxia; Regeneration; Stem cells.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Histological overview of the human Atrioventricular junction (AVj) and left ventricle. Tissue sections were stained with Hematoxylin–Eosin. (a) AVj is located between the left ventricle and atrium near the mitral valve and consists of fibrotic tissue. Arrows point out the ventricular border, where islands of small cardiomyocytes reside. (b) and (c) showcase left ventricle tissue from two representative control donors. These biopsies were collected from the lateral side of mid-region of the muscular wall. (d) and (e) display the morphology of left ventricle tissue after cardiac arrest from two representative donors.
Figure 2
Figure 2
Immunohistochemistry showing expression of cardiac stem cell related markers SSEA4 (yellow), WT1 (red) and NKX2,5 (red) and hypoxia related marker Hif1α (red) in the atrioventricular junction (AVj) of cardiac arrest donors. Nuclei were stained blue with DAPI. (a) An overview of the AVj of a representative cardiac arrest donor, with the small cTnT+ cardiomyocytes that co-express SSEA4 and WT1. Larger cardiomyocytes further down into the myocardium express progressively less SSEA4 and WT1. (b1–b2) Close up of small cardiomyocytes in the AVj, expressing SSEA4 and WT1. (c1–c2) NKX2,5 expression in cells with and without cTnT expression. (d) Hif1α positive cell nuclei. Nuclei were stained blue with DAPI. The number of WT1+/cTnT+ cells were counted in 5.8 mm2 large images for each donor. (e) Number of WT1+/cTnT+ cells for each donor in AVj tissue, control group N = 4 and cardiac arrest N = 12. (f) Mean value number of WT1+/cTnT+ cells in both groups and locations.
Figure 3
Figure 3
Immunohistochemistry of left ventricular (LV) tissue showing reduced expression of the sarcomeric protein cardiac Troponin T, cTnT (green) in single cardiomyocytes and upregulation of cardiac stem cell related markers; MDR1, NKX2,5 (red) and SSEA4 (yellow) in the cardiac arrest group. (a) LV from a representative control, with equal expression of cTnT in all cardiomyocytes. (b1–3) LV from a representative cardiac arrest donor with a subpopulation of cardiomyocytes (arrows) showing a decreased expression of cTnT and expression of MDR1. (c1–4) Reduced cTnT expression (arrows) in cardiomyocytes overlapped with the expression of NKX2.5 and SSEA4 in single cardiomyocytes in the cardiac arrest group. Nuclei were stained blue with DAPI.
Figure 4
Figure 4
Expression of proliferation related markers PCNA and Ki67 (yellow), together with cardiomyocyte nuclei marker PCM1 (red) in cardiac arrest group. (a1–3) Cell nuclei with expression of both PCNA and PCM1 in the atrioventricular junction (AVj). (b) Many PCNA + nuclei in the AVj from a representative donor after cardiac arrest (c1–4) Cell nuclei in the AVj where one of the two Ki67+ nuclei co-expresses cardiomyocyte nuclei marker PCM1 indicating asymmetric cell division.
Figure 5
Figure 5
Detection and quantification of rare cardiomyocytes with PCM1+ twin nuclei (red) after cardiac arrest. (a) Overview of a binuclear cardiomyocyte with parted nuclei in left ventricle. (b,c) Cell nuclei with and without PCM1 expression from the ventricular myocardium in cardiac arrest group. PCM1 expression pattern showed a split between two nuclei, close together that was not observed with DAPI. (d) cTnT+/PCM1+ cardiomyocyte from the cardiac arrest group with twin nuclei. (e1–2) Bar graphs displaying the higher mean value of PCM1+ twin nuclei/donor, in cardiac arrest group compared to controls in both left ventricles and the atrioventricular junction. Twin nuclei were counted in 5.8 mm2 large images of 49 photos of fields with a 20 × objective/tissue section. 2–4 tissue sections were stained and counted per donor.
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