Mechanically guided cell fate determination in early development

Abstract

Cell fate determination, a vital process in early development and adulthood, has been the focal point of intensive investigation over the past decades. Its importance lies in its critical role in shaping various and diverse cell types during embryonic development and beyond. Exploration of cell fate determination started with molecular and genetic investigations unveiling central signaling pathways and molecular regulatory networks. The molecular studies into cell fate determination yielded an overwhelming amount of information invoking the notion of the complexity of cell fate determination. However, recent advances in the framework of biomechanics have introduced a paradigm shift in our understanding of this intricate process. The physical forces and biochemical interplay, known as mechanotransduction, have been identified as a pivotal drive influencing cell fate decisions. Certainly, the integration of biomechanics into the process of cell fate pushed our understanding of the developmental process and potentially holds promise for therapeutic applications. This integration was achieved by identifying physical forces like hydrostatic pressure, fluid dynamics, tissue stiffness, and topography, among others, and examining their interplay with biochemical signals. This review focuses on recent advances investigating the relationship between physical cues and biochemical signals that control cell fate determination during early embryonic development.

Keywords: Cell fate; Cell signaling; Embryogenesis; Mechanobiology.

Fig. 1

Components of mechanotransduction pathway in cell fate determination. a, Mechano-inducer elements (in blue) that apply physical force. The physical source can be extrinsic (e.g., compressive force, fluidic pressure, among others) or intrinsic (e.g., change in cell membrane property/tension, nuclear to cytoplasm shuttling, among others). b, Mechano-sensing elements (in yellow) that respond to the physical force applied upstream (often) and initiate a cascade of biochemical reactions downstream. c, Mechano-transducer elements (in pink) are proteins or ions that are part of the signaling pathway and have the ability to respond to mechano-sensing elements. d, Mechano-response, a cellular response towards the activation of the mechanotransduction pathway that leads to change at the transcriptional level, ultimately, in this case, to fate regulation

Fig. 2

Mechnotransduction of physical force into biochemical signals. a, An upsurge of tension in mice trophectoderm is mediated by the increased hydrostatic pressure of the blastocoel cavity (BC) that leads to vinculin recruitment to tight junctions. b, Increase in Xenopus embryos blastocoel volume and hydrostatic pressure controls the ectoderm competence to respond to Wnt signaling mediated by mechanosensor Yap. c, Embryonic alveolar epithelial cell differentiation, controlled by both cellular protrusion and mechanical cues developing from amniotic fluid inhalation. At the distal airway tips, prior to the arrival of inhaled amniotic fluid, alveolar progenitor cells begin protruding, leading to reduced apical surface area and the accumulation of apical myosin (red). Nonprotruding cells are flattened and differentiate into AT1 cells by mechanical cues; in contrast, protruding cells maintain their cuboidal shape and differentiate into AT2 cells

Fig. 3

Convergence of physical cues into biochemical pathways. a, Extracellular Matrix (ECM) promotes activation of signaling pathways (WNT, ERK, and others) that regulate cell fate via mechanosensory such as vinculin. b, Membrane deformation (a change in cell surface mechanical property) leads to activation of mechanosensitive ion channels such as Piezo1 and controlling downstream effectors. c, Transducers of mechanical cues, such as Yap, translocated to the nucleus regulating transcriptional activity. d, Nucleus can act as a mechanotransducer of force by mediating protein translocation and as a mechanoinductive where it remodels cellular shape or elasticity to elicit a biological response