183the layered structure (Sato et al. 2001b, 2016b). The results of our studies (morpho-
logic differences are detected between adult vocal fold mucosae that have been
phonated and those that have remained unphonated since birth (Sato et al. 2008 ,
2012 , 2015 )) are consistent with this hypothesis.
We also hypothesize that after the layered structure of the adult vocal fold is
completed, the tensions caused by phonation (vocal fold vibration) stimulate cells
in the anterior and posterior maculae flavae to accelerate production of extracellular
matrices and maintain the layered structure of the human adult vocal fold mucosa as
a vibrating tissue. The results of our study (morphologic differences are detected
between the adult vocal fold mucosae that have remained phonated and those that
have been unphonated for a long period (Sato et al. 2011 )) are consistent with this
hypothesis.
The bending stresses on the vocal fold associated with phonation (vocal fold
vibration) are greatest in the region of the maculae flavae located at both ends of the
vocal fold mucosa (Titze and Hunter 2004 ). Tension caused by phonation seems to
regulate the behavior of the cells (mechanical regulation) in the maculae flavae of
the human vocal fold. It is of interest whether the mechanical forces caused by vocal
fold vibration from outside the cells in the maculae flavae contacts influence intra-
cellular signaling cascades through cell-matrix that ultimately alter many cellular
behaviors.
“Mechanotransduction” is the term for the ability of living tissues to sense
mechanical stress and respond by tissue remodeling. Cellular mechanotransduction
is the mechanism by which cells convert mechanical stimuli into biomechanical
responses. More recently, mechanotransduction has expanded to include the sensa-
tion of stress, its translation into a biochemical signal and the sequence of biological
responses it produces. Mechanical stress has become increasingly recognized as
one of the primary and essential factors controlling biological functions, ultimately
affecting the functions of the cells, tissue, and organs (Mofrad and Kamm 2010 ). It
is very likely that the mechanical stress caused by phonation (vocal fold vibration)
is one of the primary and essential factors controlling biological functions,
ultimately affecting the function of the cells in the macula flava of the human vocal
fold mucosa. However, the role of mechanotransduction in the vibrating vocal fold
mucosa remains unclear.
It is readily apparent that tensile and compressive strains can have direct effects
on cell morphology and structure, including changes in the cell membrane, shape,
and volume as well as cytoskeletal structure and organization (Kurpinski et al.
2010 ). These physical changes can be converted into changes in cell signaling and
transcriptional activities in the nucleus to cause alterations in cellular differentia-
tion, proliferation, and migration (Kurpinski et al. 2010 ).
The function and fate of stem cells are regulated by various microenvironmental
factors (Kurpinski et al. 2010 ). In addition to chemical factors, mechanical factors
can also modulate stem cell survival, organization, migration, proliferation, and dif-
ferentiation (Kurpinski et al. 2010 ). Stem cells are potentially one of the main play-
ers in the phenotype determination of a tissue in response to mechanical loading
(Kurpinski et al. 2010 ).
9 The Macula Flava of the Human Vocal Fold as a Stem Cell Microenvironment