In
addition to their tumor suppression function, senescent cells also play a
beneficial role in non-cancer pathology
by limiting tissue fibrosis.
For instance, tissue damage
within the liver stimulates the activation of hepatic stellate cells (HSCs),
which hyper- proliferate and secrete
extracellular matrix components to form a fibrotic scar. Hyper- proliferation of HSCs induces
cell senescence leading to a reduction in the secretion of ECM proteins and
enhanced secretion of ECM degrading proteins, thereby limiting fibrosis. Senescent
HSCs are then eliminated in a timely
manner by immune cells such as natural killer (NK) cells. When
the mechanisms leading to NK cell mediated elimination are disabled,
fibrosis is increased. In mice lacking
molecular components required for induction of cell senescence, HSCs continue to proliferate,
depositing ECM components and elevating the fibrotic response. Therefore,
induction of senescence in HSCs prevents
short-term tissue damage by limiting
fibrosis. In addition to the liver, a
similar process occurs during tissue repair within the pancreas
by senescent pancreatic stellate cells. In this instance,
it was suggested that lymphocytes at the sites of
wounds might play a duel-specific role in pancreatic fibrogenesis by triggering
both the initiation of wound healing by activating stellate cells and its
completion by clearance of senescent stellate cells.
Cell
senescence also limits tissue damage at sites of cutaneous wound healing, where
secretion of CCN1 induces fibroblast senescence associated with an elevation in the DNA damage
response and the activation of p53 and RAC1-NOX1 complex. The
expression of anti-fibrotic genes by CCN1-induced senescent cells prevented
excess fibrosis, whereas mice that express a senescence-defective Ccn1 mutant resulted in elevated fibrosis.
CCN1 also appears to play a role in the regression of liver fibrosis through induction of cell
senescence in HSCs. Therefore, cell senescence is a
mechanism that limits
tissue damage in multiple tissues
and serves not only to restrain
the damage, but also to initiate the repair and return the tissue to the
pre-damaged state.
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