Introduction

• This paper reviews how bioelectric signals, especially the membrane voltage (Vmem) controlled by ion channels, regulate cell proliferation.
• It emphasizes the importance of proper cell cycle regulation during development, wound healing, and in the context of diseases such as cancer.
• Early studies noted that cells with a high resting potential (like neurons and muscle cells) tend to have low proliferative activity.

Key Concepts and Terms

• Membrane Voltage (Vmem): The electrical potential difference across the cell membrane that influences cell behavior. Think of it as the cell’s “battery” level.
• Ion Channels: Protein structures that allow ions (like potassium, sodium, and chloride) to pass through the cell membrane. They act like doors that open or close to regulate the cell’s charge.
• Cell Cycle: The series of phases (including G1, S, G2, and M) through which a cell grows and divides. Transitions between these phases are tightly controlled.

Main Findings

• A clear correlation exists between membrane potential and cell proliferation.
• Historical experiments, notably by Cone and colleagues, demonstrated that changing Vmem can directly affect cell cycle progression.
• Key observations include:
  • Hyperpolarization (a more negative Vmem) is often required to initiate DNA synthesis.
  • Depolarization (a less negative Vmem) is needed for cells to enter mitosis (cell division).

Mechanisms of Bioelectric Control

• Different ion channels (potassium, sodium, and chloride) contribute to the regulation of Vmem throughout the cell cycle.
• Pharmacological studies show that blocking specific ion channels can arrest cell division by altering the normal Vmem oscillations.
• Feedback loops exist where the cell cycle stage influences ion channel expression, and changes in Vmem in turn affect cell cycle regulators.

Implications for Cancer and Regenerative Medicine

• Cancer cells are often found to be depolarized compared to normal cells, indicating altered bioelectric states.
• Targeting specific ion channels could provide novel approaches for cancer treatment by restoring normal cell cycle control.
• Manipulating Vmem is also promising for regenerative medicine, as it can help guide tissue repair and wound healing.

Experimental Approaches and Evidence

• Researchers have used pharmacological blockers, genetic tools (like RNAi), and electroporation to manipulate ion channel function and Vmem.
• Studies across various cell types—including neurons, muscle cells, stem cells, and cancer cells—demonstrate that Vmem oscillates during cell cycle transitions.
• These experiments provide evidence that controlled changes in Vmem can either promote or inhibit cell proliferation.

Challenges and Future Directions

• The complex interplay of multiple ion channels and their feedback mechanisms makes it challenging to pinpoint exact regulatory pathways.
• There is a need for quantitative models that integrate the temporal dynamics of ion fluxes and membrane potential changes.
• Future research may lead to improved diagnostic tools and targeted therapies based on the bioelectric properties of cells.

Summary

• The paper demonstrates that bioelectric signals, particularly the modulation of membrane voltage by ion channels, play a crucial role in controlling the cell cycle and cell proliferation.
• This integration of bioelectric control with molecular and genetic pathways bridges multiple disciplines and opens up new avenues for cancer treatment and regenerative medicine.
• Understanding these mechanisms provides valuable insights into both normal development and disease processes.

引言

• 本文综述了生物电信号，特别是由离子通道调控的细胞膜电位(Vmem)，如何在细胞增殖中发挥关键作用。
• 强调了细胞周期在发育、创伤修复以及癌症等疾病背景下精确调控的重要性。
• 早期研究发现，静息电位较高的细胞（如神经元和肌肉细胞）通常增殖活性较低。

关键概念和术语

• 细胞膜电位 (Vmem)：细胞膜两侧的电压差，影响细胞行为，可视为细胞的“电池电量”。
• 离子通道：允许钾、钠、氯等离子通过细胞膜的蛋白质结构，类似于开关门，调节细胞的电荷状态。
• 细胞周期：细胞生长和分裂的连续过程，包括G1、S、G2和M各阶段，其转换受到严格控制。

主要发现

• 膜电位与细胞增殖之间存在明显的相关性。
• 历史性实验（例如Cone的研究）证明了改变Vmem可以直接影响细胞周期的进程。
• 主要观察结果包括：
  • 超极化（膜电位变得更负）通常有助于启动DNA合成。
  • 去极化（膜电位变得不那么负）则有助于细胞进入有丝分裂。

生物电控制机制

• 不同的离子通道（如钾通道、钠通道和氯通道）在细胞周期的不同时期调节Vmem。
• 药理学研究表明，阻断特定离子通道可通过改变正常的Vmem振荡而使细胞周期停滞。
• 存在反馈回路：细胞周期阶段影响离子通道的表达，而Vmem的变化又会调控细胞周期调控因子。

对癌症和再生医学的启示

• 癌细胞通常表现为比正常细胞更为去极化，显示出异常的生物电状态。
• 针对特定离子通道的治疗有望成为恢复正常细胞周期控制的新策略。
• 调控膜电位也为组织再生和伤口愈合提供了新的方法和机遇。

实验方法和证据

• 研究者使用药理阻断剂、基因工具（如RNAi）和电穿孔技术来操控离子通道功能和Vmem。
• 在神经元、肌肉细胞、干细胞及癌细胞等多种细胞类型中，均观察到了细胞周期各阶段中Vmem的周期性变化。
• 这些实验证据表明，通过控制Vmem的变化可以促进或抑制细胞增殖。

挑战与未来方向

• 多种离子通道及其复杂的反馈机制增加了明确调控路径的难度。
• 需要构建定量模型来整合离子流和膜电位随时间变化的动态过程。
• 未来研究可能会开发出基于细胞生物电特性的诊断工具和精准治疗方法。

总结

• 本文证明了生物电信号，尤其是由离子通道调控的膜电位，在调控细胞周期和细胞增殖中起着至关重要的作用。
• 这一领域融合了分子生物学、生理学和生物工程学，为癌症治疗和再生医学带来了新的前景。
• 深入理解这些机制有助于揭示正常发育和疾病过程中重要的生理调控网络。