Lamin B2 Levels Regulate Polyploidization of Cardiomyocyte Nuclei and Myocardial Regeneration

• Published in: Developmental cell Vol. 53; no. 1; pp. 42 - 59.e11
• Main Authors: Han, Lu, Choudhury, Sangita, Mich-Basso, Jocelyn D., Ammanamanchi, Niyatie, Ganapathy, Balakrishnan, Suresh, Sangita, Khaladkar, Mugdha, Singh, Jennifer, Maehr, Rene, Zuppo, Daniel A., Kim, Junhyong, Eberwine, James H., Wyman, Samuel K., Wu, Yijen L., Kühn, Bernhard
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.04.2020
• Subjects: Animals; cardiomyocytes; Cell Nucleus - metabolism; Cell Nucleus Division - physiology; Cell Proliferation - physiology; Cells, Cultured; Heart - physiology; heart injury; Induced Pluripotent Stem Cells - cytology; karyokinesis; Lamin B2; Lamin Type B - metabolism; Lmnb2; Mice; mitosis; myocardial regeneration; Myocytes, Cardiac - metabolism; polyploidy; Regeneration - physiology; terminal differentiation; Wound Healing - physiology; zebrafish; cardiomyocytes; Lamin B2; polyploidy; karyokinesis; zebrafish; mitosis; terminal differentiation; heart injury; myocardial regeneration; Lmnb2
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2020.01.030

Heart regeneration requires cardiomyocyte proliferation. It is thought that formation of polyploid nuclei establishes a barrier for cardiomyocyte proliferation, but the mechanisms are largely unknown. Here, we show that the nuclear lamina filament Lamin B2 (Lmnb2), whose expression decreases in mice after birth, is essential for nuclear envelope breakdown prior to progression to metaphase and subsequent division. Inactivating Lmnb2 decreased metaphase progression, which led to formation of polyploid cardiomyocyte nuclei in neonatal mice, which, in turn, decreased myocardial regeneration. Increasing Lmnb2 expression promoted cardiomyocyte M-phase progression and cytokinesis and improved indicators of myocardial regeneration in neonatal mice. Inactivating LMNB2 in human iPS cell-derived cardiomyocytes reduced karyokinesis and increased formation of polyploid nuclei. In primary cardiomyocytes from human infants with heart disease, modifying LMNB2 expression correspondingly altered metaphase progression and ploidy of daughter nuclei. In conclusion, Lmnb2 expression is essential for karyokinesis in mammalian cardiomyocytes and heart regeneration. [Display omitted] •Lamin B2 regulates nuclear envelope breakdown and M-phase progression•Decreased Lamin B2 levels lead to formation of polyploid nuclei•Increased prevalence of polyploid nuclei decreases myocardial regeneration in mice•Modifying LMNB2 expression in human cardiomyocytes alters ploidy of nuclei Polyploid nuclei in heart muscle cells are thought to be a barrier for heart regeneration, but how they are generated is unknown. Han et al. demonstrate that low Lamin B2 levels trigger formation of polyploid nuclei in mouse and human heart muscle cells, which decreases heart regeneration.