Role of the cytoskeleton in cellular reprogramming: effects of biophysical and biochemical factors

Abstract

The cytoskeleton plays a crucial role in regulating cellular behavior, acting as both a structural framework and a mediator of mechanical and biochemical signals that influence cell fate. In the context of cellular reprogramming, modifications to the cytoskeleton can have profound effects on lineage commitment and differentiation efficiency. This review explores the impact of mechanical forces such as substrate stiffness, topography, extracellular fluid viscosity, and cell seeding density on cytoskeletal organization and mechanotransduction pathways, including Rho/ROCK and YAP/TAZ signaling. Additionally, we examine the influence of biochemical agents that modulate cytoskeletal dynamics, such as actin and microtubule polymerization inhibitors, and their effects on stem cell differentiation. By understanding how cytoskeletal remodeling governs cellular identity, this review highlights potential strategies for improving reprogramming efficiency and directing cell fate by manipulating mechanical and biochemical cues.

Keywords: cell fate; cellular reprogramming; chromatin; cytoskeleton; mechanotransduction; regenerative medicine; signal pathways.

FIGURE 1

Cytoskeletal structures and their connections to nuclear and extracellular environment. The cytoskeleton is integral in maintaining cellular architecture and transmitting mechanical signals, impacting gene regulation and cell fate determination. Actin filaments maintain cellular shape, receive external mechanical signals by focal adhesions or adhesion junctions, and transmit them to the nucleus. The perinuclear actin cap encircles the nucleus, influencing the nuclear shape and gene expression. Microtubules extend from the microtubule organizing center (MTOC), maintain cell structure, and facilitate intracellular molecular transport. The nuclear lamina, along with lamina-associated domains (LADs), supports nuclear organization and chromatin positioning, while other intermediate filaments provide numerous different functions in the cytoplasm. Mechanical forces affect Rho/ROCK signaling which in turn affects YAP nuclear localization and further genomic events.

FIGURE 2

Role of the cytoskeleton and mechanotransduction in defining MSCs fate. Extrinsic biochemical agents and physical forces can affect MSCs differentiation. (A) Shows the chemical agents that promote adipogenic differentiation like Cytochalasin D, Lantrunculin A, Y-27632, Blebbistatin; and physical forces like soft matrix. (B) Shows the chemical agents that promote osteogenic differentiation including Paclitaxel, Nocodazole, and physical forces like stiff matrix, high viscosity media, and low-intensity vibrations.