The Niche

Aging stem cells: trade-offs between vigor and cancer

Two papers from the University of Michigan show how tissue-specific stem cells trade regenerative potential to control unwanted proliferation. One, in fly testes from Yukiko Yamasita, shows that cells halt their division if the daughter cells would be misoriented. The other, in mice brains, shows how gene expression changes with age to favor decreased regeneration with decreased risk for tumorigenesis.

I’ll put those research highlights below. If you’re interested in how stem-cell rigor declines with age, you’ll also be interested in A metasignalling network makes muscles age , which shows that muscle tissue doesn’t so much lose its regenerative potential as actively inhibit it.

Both these highlights will show up as formal article in Nature Reports Stem Cells next week. Already going live this week are two highlights that show just how many ways there are to be pluripotent. One features separate work by Azim Surani and Myriam Hemberger on how pluripotency is governed within the embryo. (See Plasticity of the pluripotent). The other highlight also combines coverage of two separate papers. Shinya Yamanaka and Konrad Hochedlinger show that reprogramming cultured mouse skin cells to pluripotency need not require genetic modification.

Neural stem cells, young and old: How aging stem cells trade regeneration for tumour suppression

When saving for retirement, people are advised to adjust investments as they age, sacrificing the potential for robust growth for protection against loss of assets. New work shows how neural stem cells adopt a similar strategy, trading regenerative capacity for protection against cancer.

In newborn mice, blood-forming cells (haematopoeitic stem cells, HSCs) rely on a transcription factor known as Sox17 for self-renewal, but adult HSCs rely on a different transcription factor, Bmi-1. Sean Morrison and his colleagues at the University of Michigan wanted to know if similar shifts occurred with age in neural stem cells. They and others had already shown that one reason blood and other stem cells decline with age is because of increased expression of a tumour repressor gene called p16Ink4a.

A full-genome screen in blood cells showed that Hmga2, a small chromatin-associated protein, was the only protein that was both highly expressed in HSCs compared to other blood cells and whose expression was lower in old adult mice than in young adult mice. Further investigation found a similar phenomenon in neural stem cells.

Next, the researchers began a series of in vitro and in vivo experiments using mice that could not make Hmga2. (These mice have stunted growth and small brains but do not die early.) Compared with wild-type mice, young Hmga2-deficient mice had fewer stem cells and less self-renewal within the central and peripheral nervous systems; however, this difference disappeared when old mice were compared. Indeed, Hmga2 expression could not be detected in older wild-type mice. Experiments in neurospheres showed that as Hmga2 expression rose, expression of p16Ink4a and a related gene, p19Arf, fell.

But what causes Hmga2 expression to decline with age? The researchers suggest this is mediated by another gene, let-7b, a microRNA, whose expression increases with age and which binds to Hmga2. Stem-cell self-renewal was greater in neurospheres expressing a version of Hmga2 that could not bind let-7b.

“As Hmga2 is turned off in aging stem cells by increasing let-7b expression, this allows Ink4a and Arf to be expressed,” explains Morrison. “The take home message of the paper is that we have identified an entire pathway of genes that change in expression with age in stem cells.” This, in turn, reveals a complex mechanism of how stem cells trade the tendency to age as a way to ward of cancer.

Morrison’s team is now investigating exactly how HmgA regulates the tumour suppressors p16Ink4a and p19Arf, but Jan van Deursen, who is also investigating p16Ink4a in senescence at the Mayo Clinic in Rochester, Minnesota, says the mechanism is likely to grow even more complex. Because HmgA alters chromatin, one would expect its effects to be more global than a handful of genes, he says. Furthermore, the genomic screen that identified HmgA was based on HSCs, he notes, “so additional mechanisms employed by other stem cells are entirely possible.”

Nishino, J., Kim, I. Chada, K. and Morrison, S. Hmga2 promotes neural stem cell self-renewal in young but not old mice by reducing p16Ink4a and p19Arf expression. Cell 135, 227–239 (2008)

Mis-oriented stem cells don’t divide: An apparent checkpoint against unwanted proliferation lowers sperm production in aging flies

By definition, stem cells can self renew indefinitely. But they definitely age, and an active area of research is figuring out how. Working in fruit flies, a team of researchers led by Yukiko Yamashita at the University of Michigan reports a way that organisms balance the risk of tissue degeneration with that of tissue proliferation. Germline stem cells (GSCs) do not divide unless they are set up to do so in the proper orientation.

Long-lived stem cells are able to produce many copies of short-lived specialized cells because of asymmetric divisions. These produce one cell that remains a stem cell and another that commits to many more divisions and further specialization, Within the Drosophila testes, GSCs cluster around a structure called the hub. Physical location determines which cell is which: the inner cell closer to the hub stays a stem cell and the outer differentiates. This balance is maintained by a precise orientation of centrosomes, structures within cells that help duplicated chromosomes segregate evenly during cell division. By examining Drosophila testes from flies of different ages, the researchers found that GSCs with misoriented centrosomes accumulate with age and that these cells would not divide until these centrosomes became properly aligned. Thus, the more misoriented GSCs, the fewer cell divisions over a period of time, and a decrease in the number of sperm produced. Were such a checkpoint not in place, Yamashita says, the cells could proliferate uncontrollably, a trait characteristic of cancers.

To some extent GSCs with the misoriented centrosomes might be as much a symptom as cause of misorientation. Yamashita and colleagues found that some of these GSCs come from a surprising source: spermatagonia that dedifferentiate back into stem cells rather than going forward to produce sperm. In fact, she believes that this is the major mechanism of replacing GSCs in aging flies.

Leanne Jones of the Salk Institute who also studies spermatogenesis in Drosophila, says that the paper is important for helping explain why GSCs in aging males either stop dividing or progress through the cell cycle slowly. “Yukiko’s paper provides a clear mechanism for that,” she says. “What will be interesting is to see if other stem cells that divide with a specific orientation, like epithelial progenitor cells, also arrest when the centrosomes are mis-positioned.” If so, the next questions would be whether mis-positioning increases with age, and whether the same checkpoint mechanism is used for different sorts of stem cells.

How stem cell function declines with age is a growing area of research, with hints that cell-signaling, epigenetic regulation, and other factors all play a part. This checkpoint that prevents cell division unless the daughter cells will be properly oriented within the niche, thus, cell orientation could provide another balance, between degeneration and cancer.

Cheng, J. et al. Centrosome misorientation reduces stem cell division during ageing. Nature Published online, 10.1038/nature07386 (15 October 2008)


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