Page 38 - Physico-Chemical Niche Conditions for Bone Cells

Physicochemical niche conditions and mechanosensing
which enables a biochemical event to occur in the cytoplasm. All the substances involved in the process of mechanotransduction are termed mechanotransducers, including focal adhesions, dystroglycan, glycocalyx, primary cilium, ion channels, integrins, etc. [79,80]. There are two pathways of the mechanotransduction process: 1) indirect mechanotransduction, which implies that the mechanical signal is transduced into a biochemical signal, and 2) direct mechanotransduction, which occurs via deformation of the cytoskeleton and nucleus. Mechanotransducers linking the ECM to the cytoskeleton are crucial for direct mechanotransduction [63].
Matrix stiffness
The importance of cell-ECM interactions in relaying mechanical signals has been well known for two decades [77]. Stiffness is the mechanical property of ECM that cells can sense by so- called stiffness sensing or rigidity sensing. The mechanism of stiffness sensing involves the contraction of myosin in the cell, and is regulated by the mechanical properties of the ECM. Stiffness sensing occurs by myosin-dependent traction forces of cells, and is likely affected by the number of focal adhesions and cell attachment to the ECM via high affinity integrin. Then actin stress fibers increase force transduction across the ECM-integrin-cytoskeleton connection [81]. Stiffness sensing also involves intracellular signaling. For example, Ca2+ concentration, which is regulated by mechanosensitive channels involved in stiffness sensing, as well as mechanosensitive adaptor proteins, may contribute not only to regulation of cell migration but also to substrate stiffness sensing [82]. Osteocyte-specific protein and osteoblast-specific gene expression has been investigated on substrates with different chemical composition and stiffness, as well as identical chemical composition but different stiffness. Osteocyte differentiation is highly increased on soft stiffness substrate at low seeding cell density [83].
MuSCs exhibit a strong regenerative ability in vivo, but this capacity is rapidly lost in vitro. The matrix or substrate stiffness is a potent regulator for MuSC behavior and fate in vitro [84]. MuSCs cultured on extremely thin hydrogel substrates of 2, 12, or 42 kPa stiffness mimics muscle elastic properties in vivo [84,85]. Interestingly, MuSCs exhibit extensively muscle regeneration on a 12 kPa hydrogel substrate, but they do not spread and tend to differentiate on rigid matrix stiffness [85]. A cell sensing mechanical stimulus provides feedback and adjusts its adhesion strength and force accordingly via modifying cytoskeletal support and cell deformation, which enables constant communication between the microenvironment and the cell [86].
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