Role of membrane potential in the regulation of cell proliferation and differentiation

Abstract

Biophysical signaling, an integral regulator of long-term cell behavior in both excitable and non-excitable cell types, offers enormous potential for modulation of important cell functions. Of particular interest to current regenerative medicine efforts, we review several examples that support the functional role of transmembrane potential (V(mem)) in the regulation of proliferation and differentiation. Interestingly, distinct V(mem) controls are found in many cancer cell and precursor cell systems, which are known for their proliferative and differentiation capacities, respectively. Collectively, the data demonstrate that bioelectric properties can serve as markers for cell characterization and can control cell mitotic activity, cell cycle progression, and differentiation. The ability to control cell functions by modulating bioelectric properties such as V(mem) would be an invaluable tool for directing stem cell behavior toward therapeutic goals. Biophysical properties of stem cells have only recently begun to be studied and are thus in need of further characterization. Understanding the molecular and mechanistic basis of biophysical regulation will point the way toward novel ways to rationally direct cell functions, allowing us to capitalize upon the potential of biophysical signaling for regenerative medicine and tissue engineering.

Fig. 1

Integration of bioelectric events with canonical biochemical and genetic pathways occurs through a number of sequential phases. Such signals can be initiated at the cell membrane of individual cells (function of ion transporters), can arrive through gap junctional connections to their neighbors, or be imposed through breaks in an epithelium that carries a transepithelial potential. Physically, such signals are carried by changes in transmembrane potential, pH gradients, flows of specific ions, or long-range electric fields. A number of mechanisms serve as biophysical receptors for these signals, including voltage-sensing domains within proteins, changes of intracellular ion content, electro-osmosis, changes in the gating of transorters for signaling molecules, calcium influx, and electrophoresis of morphogens through gap junctional paths between cells. A number of early response genes have been identified immediately downstream, including integrins, Slug/Sox10, Notch, NF-kB, and PTEN. Because these transcriptional cascades can control all aspects of cell behavior, including proliferation, differentiation, and migration, transduction into these secondary pathways allow bioelectrical signals to control cell number and type during complex morphogenetic events such as tissue regeneration