Lamin B2 controls nuclear envelope permeability and regulates cardiomyocyte regeneration

Heart muscle cells, cardiomyocytes, are highly differentiated cells that usually do not proliferate . During the non-proliferative state, extracellular signals control cardiomyocyte contractile function. However, during development and regeneration, cardiomyocytes enter the cell cycle and divide. It is unknown how cardiomyocytes modify their intracellular signaling to direct the cell cycle program. Here, we show that the nuclear lamina protein Lamin B2 (Lmnb2) regulates cardiomyocyte cell cycle activity using a gatekeeper mechanism. We identified Lmnb2 as a candidate for regulating intracellular signaling with deep transcriptional profiling of single cardiomyocytes. Lmnb2 was sufficient and necessary for cardiomyocyte cycling in the presence of serum. Lmnb2 increased the nucleoporin NUP98 and permeability of the nuclear membrane for phosphorylated ERK1/2. In vivo, the Lmnb2 gene was required for cardiomyocyte cell cycle activity during development. Increasing the expression of Lmnb2 in neonatal mice promoted cardiomyocyte M-phase and cytokinesis. LmnB2 gene transfer in neonatal mice that received a myocardial injury increased cardiomyocyte division and myocardial function in the injury border zone, indicating that the regenerated cardiomyocytes were functionally integrated. We propose a gatekeeper function of Lmnb2 that can be targeted to increase cardiomyocyte regeneration without the administration of exogenous growth factors.

心肌细胞（cardiomyocytes）是高度分化的细胞，通常不具备增殖能力。在非增殖状态下，细胞外信号调控心肌细胞的收缩功能。但在发育与再生过程中，心肌细胞会进入细胞周期并发生分裂。目前尚不明确心肌细胞如何调控胞内信号通路以启动细胞周期程序。本研究发现，核纤层蛋白Lamin B2（Lmnb2）通过闸控机制调控心肌细胞的细胞周期活性。我们通过对单个心肌细胞开展深度转录谱分析，将Lmnb2鉴定为调控胞内信号通路的候选靶点。在血清存在的条件下，Lmnb2对于心肌细胞的细胞周期运转既是充分条件也是必要条件。Lmnb2可上调核孔蛋白NUP98（nucleoporin 98）的表达，并提升核膜对磷酸化ERK1/2的通透性。在活体实验中，Lmnb2基因对于发育过程中心肌细胞的细胞周期活性是必需的。在新生小鼠体内提高Lmnb2的表达水平，可促进心肌细胞进入M期并完成胞质分裂。对遭受心肌损伤的新生小鼠实施Lmnb2基因转染，可提升损伤边界区域的心肌细胞分裂能力与心肌功能，表明再生的心肌细胞已实现功能整合。我们提出Lmnb2具有闸控功能，可通过靶向调控该蛋白来提升心肌细胞再生能力，无需外源性生长因子的施用。