Cardiomyocyte renewal in the human heart: insights from the fall-out

Abstract

The capacity of the mammalian heart to regenerate cardiomyocytes has been debated over the last decades. However, limitations in existing techniques to track and identify nascent cardiomyocytes have often led to inconsistent results. Radiocarbon (14C) birth dating, in combination with other quantitative strategies, allows to establish the number and age of human cardiomyocytes, making it possible to describe their age distribution and turnover dynamics. Accurate estimates of cardiomyocyte generation in the adult heart can provide the foundation for novel regenerative strategies that aim to stimulate cardiomyocyte renewal in various cardiac pathologies.

Keywords: Cardiomyocyte proliferation; Dynamics of renewal; Retrospective radiocarbon dating.

Figure 1

Retrospective radiocarbon (¹⁴C) birth dating of human cells in the heart. Although ¹⁴C is naturally generated in the atmosphere by the action of cosmic rays on nitrogen, above-ground nuclear tests conducted during the Cold War significantly contributed to its environmental level. In the atmosphere, ¹⁴C reacts with oxygen to form CO₂, which then gets incorporated into plants through photosynthesis. The carbon content of plants is transferred into the human body via the food chain such that the ¹⁴C levels in tissues mirror the atmospheric ¹⁴C concentrations. With every cell division, ¹⁴C is integrated into newly synthetized DNA in amounts proportional to its atmospheric level at any given time. Due to the stability of nuclear DNA, the measured genomic ¹⁴C concentration can be used to establish the age of human cardiomyocytes.

Figure 2

Strategy for radiocarbon (¹⁴C) birth dating of distinct cell populations. (A–B) ¹⁴C content in the genomic DNA of the cell population of interest is compared with the recorded atmospheric ¹⁴C levels, as shown by the blue graph. The date of birth of the studied individual is indicated by a vertical dashed bar, while the horizontal dashed line corresponds to the ¹⁴C value measured in the DNA samples. The age of the sampled cell population can be inferred from the intersection of the horizontal line and the atmospheric ¹⁴C curve. (A) Genomic ¹⁴C values gained from individuals born before the nuclear bomb tests correspond to two distinct time points (Points 1 and 2). Since the incorporation of environmental ¹⁴C might have occurred during the rise and/or the fall of the curve, the precise age of the cell population cannot be determined with certainty based exclusively on these results. (B) However, in individuals born after the nuclear tests, the measured ¹⁴C levels unambiguously determine the age of the cell population (Point 1).

Figure 3

Retrospective radiocarbon (¹⁴C) birth dating and mathematical modelling of the turnover of different cell types in the heart. (A) Genomic ¹⁴C values of cardiomyocytes (blue dots), cardiac endothelial (light green dots), and cardiac mesenchymal cells (dark green dots) from different individuals are plotted against the person’s date of birth. Data points lying on the atmospheric ¹⁴C curve indicate no renewal of the cells after birth. The degree of deviation from the atmospheric ¹⁴C curve indicates the intensity of DNA synthesis and turnover in the post-natal period, childhood, and adulthood. (B) Applying mathematical modelling, the annual renewal rates of the investigated cell populations can be calculated. While endothelial (light green line) and mesenchymal cells (dark green line) are rapidly exchanged in young adults, with birth rates of 20% per year for the former and 5% per year for the latter, human cardiomyocytes (blue line) are replaced with annual rates of approximately 1% per year at the age of 20, declining to rates of < 0.5% per year in elderly individuals. This figure was adapted from Bergmann et al.

Figure 4

Cell generation and renewal dynamics in human cardiomyocytes. The number and cell turnover dynamics of human cardiomyocytes were established using a mathematical model combining results from radiocarbon (¹⁴C) birth dating and stereological strategies. (A) The number of human cardiomyocytes is already set during the perinatal period. Significant exchange of post-natal cardiomyocytes can mainly be observed during the first decades of life. Distinct shades of grey indicate cardiomyocyte subpopulations born during different decades of life. The black area shows cardiomyocytes that were already present at the time of birth. (B) Age distribution of post-natally generated cardiomyocytes in 25-, 50-, and 75-year-old individuals. This figure was adapted from Bergmann et al.

Figure 5

The human heart throughout life. Overview of age-related changes in cardiomyocyte number, multinucleation, polyploidy, and cardiomyocyte renewal in the human heart.