�Although post-reproductive life in humans is often associated with decline and a loss of powers, an analogous state in sure cells -- called ageing -- is proving to be one of ironic potency. Scientists at Cold Spring Harbor Laboratory (CSHL) reported that a particular class of senescent liver cells orchestrates a succession of events in living mice that can limit fibrosis, a natural response of the liver to acute damage.
The surprising finding follows on the heels of experiments conducted by the same CSHL squad last year linking agedness in liver cells with the organ's ability to fight sour liver genus Cancer, also called hepatocellular carcinoma, or HCC.
The new findings are the first to establish a specific part for cellular senescence in a non-cancer pathology, and, the CSHL team notes, suggests a new remedial approach that could serve human patients with precursors of serious liver diseases such as cirrhosis, which is the 12th to the highest degree common causal agent of death in the United States.
Anti-cancer role of senescence provides an example
In technical footing, cellular ageing is described by team leader Scott W. Lowe, Ph.D. as "a stable form of cell-cycle stop." By this he substance senescent cells are typically ones that no yearner actively divide. Senescence is therefore a highly stable state, as exemplified by benign moles in which senescent cells can persist without dividing over the course of an entire human lifetime.
Dr. Lowe, a CSHL Professor and Howard Hughes Medical Institute Investigator, was drawn almost inexorably to this curiously quiet cellular state for its potential implications in cancer research, the prime nidus of his work. Lowe's team last year demonstrated that activeness of p53, a powerful gene that suppresses tumor formation, likewise promotes senescence.
While it seemed to produce sense that a identical stable province in which cells don't divide could work against processes that cause cells to separate uncontrollably -- the stylemark of malignant neoplastic disease -- it was the mechanics of the linkage that surprised Lowe's team. When they activated p53 in mice with HCC, tumors receded -- and this regression was associated directly with activation of the immune system, whose killer cells were drawn to tumors to "exculpate" the ageing cells.
Lowe's young work, to be reported August 22 in the journal Cell, reveals something analogous that is no less surprising: senescent cells located in areas of damaged liver tissue called fibroses similarly provoke a beneficial resistant reaction. This reaction, involving NK, or natural killer cells, and other components of the innate resistant system, serve to limit fibrotic lesions and curb episodes of induced piercing liver equipment casualty in mice.
The role of senescence in liver fibrosis
Lowe's team studied the copulation of aging to liver disease in two very different contexts: one in which damage to liver tissue was acute and another in which the damage was chronic. These contrasting experiments served to define how senescence could help terminus ad quem damage, and how, when the senescence process was overwhelmed by chronic price to the liver, tissue paper damage could accelerate out of control.
In experiments designed to mimicker damage caused by needlelike insults, the CSHL scientists administered a toxin to the murine liver and observed a consistent traffic pattern: the death of liver cells, or hepatocytes, followed by the rise of fibrotic lesions -- portion of the body's natural reaction, in mice as in humanity, to tissue paper damage. These fibroses were specifically generated by activated stellate cells, or HSCs, that proliferated in direct response to liver cell death.
Subsequent steps were of greatest interestingness: "After we observed the HSC cells to proliferate intensely," Dr. Lowe aforementioned, "we found that finally they senesced and were cleared from the liver, to protect it from an overweening fibrogenic response to penetrating injury."
Several curative mechanisms at the same time engaged
Just as in liver cancer, the role of senescence in limiting fibrosis was two-pronged. "Cell-cycle collar in the cells that generate the fibrosis places a kind of brake on the process, constraining how far it rump go," Lowe explained. "We hypothesize that HSCs, when they mature, secret less fibrogenic protein and as well stimulate a process that tends to degrade proteins that are still present in a lesion." Lowe's team proposes that senescent cells reach this in part by increasing the activity of genes that stimulate the immune system.
Thus, just as senescent liver cells can play a role in tumor fixation by stimulant an immune reaction, so can senescent HSCs in damaged liver tissue help clear the fibrosis by calling immune system slayer cells to the shot of the damage. In such a scenario, "senescence is a kind of homeostatic mechanism that enables the tissue to return to its pre-damaged state," Lowe notable. "This english hawthorn prove to be broadly relevant to other wound-healing processes."
Senescence overwhelmed: the moral of chronic tissue damage
In marked contrast, separate experiments in mice that sculpturesque chronic liver damage, such as that caused by alcoholism, chronic hepatitis, or fatty liver disease, showed that the mice produced senescent cells more speedily than they could be "cleared." According to Lowe, this resulted in "persistent inflammation and advancing fibrosis" -- a state that can track to cancer in some instances.
Considered together, the results of the experiments in chronic vs. acute fibrosis suggest, in the chronic instance, how fibrosis can lead to cirrhosis, a predisposing condition for the genetic mutations and early cellular transformations that cause liver genus Cancer. But in the acute instance, the experiments hint that future therapy designed to excite the resistant cells that target aging cells in fibrotic lesions may provide effective treatment for patients with intense liver harm, particularly in its early stages undermentioned short-term vulnerability to toxic agents.
"Senescence of activated stellate cells limits liver fibrosis" appears in Cell on August 22, 2008. The complete cite is: Valery Krizhanovsky, Monica Yon, Ross A. Dickins, Stephen Hearn, Janelle Simon, Cornelius Miething, Herman Yee, Lars Zender, and Scott W. Lowe.
CSHL is a private, nonprofit research and education establishment dedicated to exploring molecular biology and genetics in order to advance the understanding and ability to diagnose and treat cancers, neurological diseases, and other causes of human suffering.
Source: Peter Tarr
Cold Spring Harbor Laboratory
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