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Effect of mechanical stress o the integrity, signalling mechanisms and function of bovine mammary epithelial cells : a thesis submitted in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Animal Science at Massey University, Manawatū, Palmerston North, New Zealand
Mammary gland engorgement due to milk accumulation in late lactation leads to
changes in cell morphology and has been recognised as a potential key initiator
of involution and remodelling of the mammary gland. The physical distension of
mammary epithelial cells (MEC), due to udder filling, is likely to result in
mechanical tension on cell-cell and cell-matrix interactions. Cell-cell and cellmatrix
junctions provide tissue integrity, promote cell polarity, guarantee sufficient
communication between cells to ensure synchronised milk secretion and support
cell survival. Their disruption may be one of the early initiators of the mammary
gland remodelling process. As a consequence, the primary goal of this study was
to determine the potential effects of MEC stretch on changes in cell sensing
within the mechanical micro-environment in the initiation of bovine MEC
involution. During this investigation, particular emphasis was put on three
potential mechanosensors: tight junctions (TJ), focal adhesions (FA) and primary
cilia (PC), and their regulation in the early stages of involution using in vivo and in
vitro experimental approaches. Static, biaxial in vitro cell stretch and acute
physical distension in vivo resulted in changes in TJ protein expression levels
implying a potential disruption of cell-cell communication as well as
communication with the cell‟s cytoskeleton. Furthermore, down-regulation of Akt
and pAkt following different periods of mechanical strain applied in vitro and
decreased levels of pAkt following acute physical distension in vivo indicated a
disruption of β1-integrin-FAK survival signalling through the PI3K-Akt pathway
downstream of FA interactions. Increased numbers of ciliated MEC following
extended periods of non-milking indicated a dedifferentiation of MEC.
Furthermore, increased levels of STAT6 transcription (part of PC signalling
following mechanical stimulation) factor indicates the initiation of macrophage
accumulation and promotion of tissue remodelling of the bovine mammary gland.
In conclusion, this study supports the hypothesis that local factors play an
important role during bovine mammary gland involution and that mechanical
stimulation may play a part in the initiation of this process.