Clearance of Senescent Liver Cells Following Cell Transplant

Cellular senescence is an important topic in aging: the number of senescent cells increases with age, and they cause harm to surrounding tissues. The research community is on the verge of being able to effectively remove these cells, however, using the tools under development by the cancer research community to target and destroy cancer cells with minimal side effects.

There may also be other ways to deal with senescent cells. The research result below was published earlier this year and makes for an interesting companion piece to a more recently published paper in which researchers showed that a method of growing large numbers of liver cells called hepatocytes via serial transplantation in mice was reversing cellular senescence along the way. Here cancer researchers find that cell transplants into rats have a similar effect, at least for cellular senescence that is artificially induced via introduction of a mild toxin that causes DNA damage and other cellular dysfunction leading to cancer. I would have to see a similar result in old animals with natural levels of cellular senescence before becoming too enthusiastic about this:

Increasing evidence indicates that carcinogenesis is dependent on the tissue context in which it occurs, implying that the latter can be a target for preventive or therapeutic strategies. We tested the possibility that re-normalizing a senescent, neoplastic-prone tissue microenvironment would exert a modulatory effect on the emergence of neoplastic disease.

Rats were exposed to a protocol for the induction of hepatocellular carcinoma (HCC). Using an orthotopic and syngeneic system for cell transplantation, one group of animals was then delivered 8 million normal hepatocytes, via the portal circulation. Hepatocytes transplantation resulted in a prominent decrease in the incidence of both pre-neoplastic and neoplastic lesions.

At the end of 1 year 50% of control animals presented with HCC, while no HCC were observed in the transplanted group. Extensive hepatocyte senescence was induced by the carcinogenic protocol in the host liver; however, senescent cells were largely cleared following infusion of normal hepatocytes. Furthermore, levels of Il-6 increased in rats exposed to the carcinogenic protocol, while they returned to near control values in the group receiving hepatocyte transplantation. These results support the concept that strategies aimed at normalizing a neoplastic-prone tissue landscape can modulate progression of neoplastic disease.



Interesting that reversing senescence reduced the risk of cancer rather than raising it.

However, as you point out, this was in a model of aging and not the liver of actual aged mice.

This raises a number of interesting questions. There has been speculation as to whether adult liver stem cells exist, or if adult liver cells retain some adult stem cell like properties. Some claim that 'oval' cells are the progenerator cells in the adult liver. But if all liver cells are also liver stem cells, repopulating the liver with hepatocytes could be the same thing as treating it with adult liver stem cells.

Also, perhaps this is a further hint that cellular senescence is just borrowing from the future to spend today. Cells becoming senescent in rsponse to damage or damage signals perhaps means there is an immediate decreased risk of cancer, but an increased risk in the not too distant future.

Posted by: Jim at April 29th, 2014 6:01 PM
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