Stem cells


Nature’s most recent “Insight” supplement is devoted to a topic near and dear to our hearts, even when spelled with that superfluous UK “e”: Ageing. From the introductory editorial:

Ageing, the accumulation of damage to molecules, cells and tissues over a lifetime, often leads to frailty and malfunction. Old age is the biggest risk factor for many diseases, including cancer and cardiovascular and neurodegenerative diseases. … Ageing research is clearly gaining momentum, as the reviews in this Insight testify, bringing hope that at some time in the future we will be able to keep age-related diseases at bay by suppressing ageing itself.

The five reviews are all by prominent scholars — many of whose work we’ve discussed here — and cover a wide range of subjects within gerontology and biogerontology:

As always, Nature Insight supplements are free-access, so even if you don’t have access to a university subscription, you can still read these articles.

(For a previous aging-related Nature Insight on DNA repair, see here.)

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Here are the biogerontological reviews from the last month or so that I’ve found interesting and noteworthy. The field as a whole continues to massively overproduce review papers; by my totally unscientific estimate, these represent less than ten percent of the review abstracts that crossed my desk since Thanksgiving.

The last installment of review roundup can be found here. As always, each Review Roundup is guaranteed to contain at least one link to a review you will find highly educational, or your money back.

Comparative biogerontology:

A while back I attended a NAKFI meeting about aging. Along with a few others, I applied for (and got) a seed grant to use comparative zoology to study aging — in a nutshell, to study the various ways that nature has solved various problems that arise during aging, and see whether we might learn something that could be applied to enhancing human healthspan or lifespan.

The initial small grant funded a series of meetings, culminating in a large-scale gathering of scientist with wide expertise not only in biogerontology but also zoology, evolutionary biology, metabolomics, and other disparate fields. While this conference didn’t end up leading to the creation a single comprehensive Comparative Biogerontology Initiative, as some of my fellow applicants had hoped, it did provoke a great deal of excellent discussion. There are a few smaller-scale efforts currently underway, initiated by people who came together to talk about the original idea.

Two of the attendees of the big meeting have published reviews recently. I haven’t asked them personally but I am assuming that they’re discussing ideas that germinated at the CBI conferences.

Gene regulation:

Inflammation:

Mitochondria:

One of the authors of the first paper is Thomas Nyström, whose lab recently described the role of cell polarity in sorting protein aggregates preferentially into the mother cell during cell division. That story lacked a significant mitochondrial component, so this review is a nice complement to the primary study published earlier this year.

Nuclear organization:

Stem cells:

Leanne Jones, the senior author on this review, is one of the folks writing the proverbial book on the critical interactions between stem cells and the tissue microenvironment. Her lab uses the Drosophila gonad as a model system.

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The hottest thing in stem cells right now is induced pluripotency, i.e., converting somatic cells back into pluripotent cells by introducing a few stem cell-specific genes (or even the encoded proteins). Induced pluripotent stem cells (iPS) harvested from a donor’s skin would be automatically immunologically matched; furthermore, they completely circumvent some of the “ethical” and supply issues raised when using embryonic stem cells.

The process is slow and inefficient — but happily, an inexpensive and ubiquitous compound you might be familiar with can help boost both speed and efficiency:

Vitamin C Enhances the Generation of Mouse and Human Induced Pluripotent Stem Cells

Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) by defined factors. However, the low efficiency and slow kinetics of the reprogramming process have hampered progress with this technology. Here we report that a natural compound, vitamin C (Vc), enhances iPSC generation from both mouse and human somatic cells. Vc acts at least in part by alleviating cell senescence, a recently identified roadblock for reprogramming. In addition, Vc accelerates gene expression changes and promotes the transition of pre-iPSC colonies to a fully reprogrammed state. Our results therefore highlight a straightforward method for improving the speed and efficiency of iPSC generation and provide additional insights into the mechanistic basis of the reprogramming process.

If it really is true that vitamin C (ascorbate) is acting by blocking senescence, then there will be other paths to improving the efficiency of iPS generation, including rapamycin, which also blocks senescence. Compounds other than ascorbate will almost certainly be more expensive, but on the other hand, ascorbate probably won’t prevent all types of senescence. Vitamin C is an anti-oxidant, and it’s a good bet that it prevents induction of senescence by oxidative damage — but that’s not the only way senescence is induced. Combining a number of methods to block senescence will likely have a synergistic effect, helping us get closer to 100% efficiency.

Beyond that, all I have to say is that this is a damn handy result. Nice that it’s something so cheap and readily available.

ResearchBlogging.orgEsteban, M., Wang, T., Qin, B., Yang, J., Qin, D., Cai, J., Li, W., Weng, Z., Chen, J., & Ni, S. (2010). Vitamin C Enhances the Generation of Mouse and Human Induced Pluripotent Stem Cells Cell Stem Cell, 6 (1), 71-79 DOI: 10.1016/j.stem.2009.12.001

Cells tend to produce unwanted protein aggregates and other molecular refuse slightly faster than they can get rid of it, resulting in a time-dependent accumulation of potentially toxic cellular garbage. This, in turn, can cause an age-dependent loss of cellular viability, which is (in certain contexts) a fair operational definition of aging.

How can cells deal with their garbage? Protein aggregates are both sticky and insoluble, making it hard for cellular machinery to deal with them at an enzymatic level. If the gunk can’t be eliminated, however, it might still be possible to move it around in a useful way. Specifically, at mitosis, the cell could make sure that all the potentially toxic aggregates stay in one of the progeny. To illustrate the argument I’ll turn to the words of the estimable Alex Palazzo:

One approach is to distribute everything equally amongst your two offspring. …

A second approach is to give all the crap to one of the two new cells and keep the other one pristine. Lets call these two cells the crap cell and the pristine cell. What’s the result of this second strategy? Using our crap metric from above, the first cell accumulates 10 units of garbage over its lifetime and then gives it all to one offspring, the crap cell, and none to the other offspring, the pristine cell. Those cells then grow and by the time they divide each second generation cells have made 10 units of additional crap each. The crap cell has 20 units the pristine cell 10. The two cells divide and dump all their garbage on one of their offsprings. One cell starts with 20 units of crap, one cell with 10 units and two cells are again crap free. The end result of this strategy? Part of your descendents will become more and more decrepit as they fill up with crap, while others remain pristine.

The crap cell (I love this nomenclature) will become inviable sooner under this strategy, but the alternative would be a symmetric division strategy in which all descendants accumulate garbage, ultimately causing the extinction of the entire lineage. The idea here is that assuming certain values for adjustable parameters re: the rate of garbage accumulation and the effect of garbage level on reproductive fitness, this can be an advantageous strategy to ensure reproductive success. Both single-celled yeast and mammalian stem cells employ this asymmetric strategy in order to preserve the viability of an indefinitely dividing lineage.

In yeast, the crap cell is called the “mother”; the pristine cell is called the “daughter” — mom accumulates garbage of various kinds, both protein aggregates and rDNA circles. When the mother is ready to divide, a bud forms at a specific site on her cell wall, defined by a set of macromolecular complexes that determine cellular polarity. Liu et al. have demonstrated that the daughter cell is using some of the same polarity-determining machinery (the “polarisome”) to actively transport protein aggregates back into the mother:

The Polarisome Is Required for Segregation and Retrograde Transport of Protein Aggregates

The paradigm sirtuin, Sir2p, of budding yeast is required for establishing cellular age asymmetry, which includes the retention of damaged and aggregated proteins in mother cells. By establishing the global genetic interaction network of SIR2 we identified the polarisome, the formin Bni1p, and myosin motor protein Myo2p as essential components of the machinery segregating protein aggregates during mitotic cytokinesis. Moreover, we found that daughter cells can clear themselves of damage by a polarisome- and tropomyosin-dependent polarized flow of aggregates into the mother cell compartment. The role of Sir2p in cytoskeletal functions and polarity is linked to the CCT chaperonin in sir2Δ cells being compromised in folding actin. We discuss the findings in view of recent models hypothesizing that polarity may have evolved to avoid clonal senescence by establishing an aging (soma-like) and rejuvenated (germ-like) lineage.

Note the role for Sir2p, the founding member of the sirtuin family of longevity assurance genes: Sir2p is required, via another protein’s activity, for the normal folding of actin, the cytoskeletal protein from which the daughter-mother transport cable is built. It’s an indirect interaction, and more complex than I’m making it out to be here. Nonetheless, it is satisfying for those of us looking for unifying theories in aging that one of the most widely studied proteins in lifespan regulation is involved in the deep connection between polarity and aging.

I’ll close with a few questions:

  • Why can’t the mother cell export the aggregates? One of our initial premises was that aggregates are biochemically hard to handle, which is why they accumulate rather than being degraded. But now we know that cells can bundle aggregates onto actin cables and move them around — why not sort the aggregates into vesicles or membrane blebs and dispose of them? Granted, in order to export an aggregate out of the cell, it would have to cross a membrane, but this would be no more difficult topologically than mitophagy. The obvious (and trivial) answer to this question is “because it didn’t evolve that way,” but I’m curious to know whether there’s some compelling reason why it couldn’t have evolved that way.
  • How do symmetrically dividing cells overcome this problem? In order to exploit asymmetric division, one must first establish polarity. The argument above about the rate of garbage accumulation would seem to apply equally well to non-polarized cells like bacteria – why, then, do clonal lineages of symmetrically dividing cells not invariably go extinct? Maybe the cells that we think are symmetric are secretly asymmetric, with a crap/pristine segregation that has yet to be uncovered. Or maybe the symmetric cells know something about garbage disposal that we don’t. In either case, there’s something important to learn that might help us keep mammalian cells youthful.

ResearchBlogging.orgLiu, B., Larsson, L., Caballero, A., Hao, X., Öling, D., Grantham, J., & Nyström, T. (2010). The Polarisome Is Required for Segregation and Retrograde Transport of Protein Aggregates Cell, 140 (2), 257-267 DOI: 10.1016/j.cell.2009.12.031

Arguing in support of President Obama’s stem cell research policy, genomics guru (and Open Access maven) Michael Eisen points out that researchers are moral entities, not appliances:

Hey Mr. Bioethicist, Scientists are Not Amoral

Yuval Levin, former Executive Director of the President’s Council on Bioethics, has an op-ed in Tuesday’s Washington Post arguing that Obama’s new stem cell policy is dangerous. Levin does not argue that stem cell research is bad. Rather he is upset that Obama did not dictate which uses of stem cells are appropriate, but rather asked the National Institutes of Health to draft a policy on which uses of stem cells are appropriate:

It [Obama’s policy] argues not for an ethical judgment regarding the moral worth of human embryos but, rather, that no ethical judgment is called for: that it is all a matter of science. This is a dangerous misunderstanding. Science policy questions do often require a grasp of complex details, which scientists can help to clarify. But at their core they are questions of priorities and worldviews, just like other difficult policy judgments.

Lost in this superficially unobjectionable – if banal – assertion of the complexity of ethical issues involving science is Levin’s (and many other bioethicists) credo: that the moral complexity of scientific issues means that scientists should not make decisions about them.

Well said: Scientists are capable of evaluating the morally complex landscape in which we work, and we have our own capacity for moral judgment. We don’t need graduate-school dropouts bioethicists to provide us with a surrogate conscience. Speaking more broadly: morality in science can and should be “bottom-up” — driven by the values of those individuals doing the work, and in conversation with other stakeholders — rather than “top-down”. Look where “top-down” morality got us during the Bush years.

The flip side? We’re morally on the hook for the consequences of our actions. I hope that the biologists of the 21st century are more willing to accept than than the nuclear scientists of the 20th century were.

Here’s the latest in our series of review roundups — links, without extensive further comment, to the reviews I found most intriguing over the past few weeks. For the previous foray into the secondary literature, see here.

Cancer:

Endocrinology:

IGF-1:

Inflammation:

Mitochondria:

Sarcopenia:

Stem cells:

Telomeres:

Continuing with the theme of unifying theories in aging: Over at The Daily Transcript, Alex Palazzo has written up a thoughtful and detailed analysis of a recent review (the original paper is entitled Polarity and Differential Inheritance: Universal Attributes of Life?). In his post, he also introduces some fantastic new nomenclature (emphasis in the original).

Let’s pretend you are a unicellular organism – what would be the best strategy to ensure the long-term multi-generational survival of your lineage?

One approach is to distribute everything equally amongst your two offspring. …

A second approach is to give all the crap to one of the two new cells and keep the other one pristine. Lets call these two cells the crap cell and the pristine cell. What’s the result of this second strategy? Using our crap metric from above, the first cell accumulates 10 units of garbage over its lifetime and then gives it all to one offspring, the crap cell, and none to the other offspring, the pristine cell. Those cells then grow and by the time they divide each second generation cells have made 10 units of additional crap each. The crap cell has 20 units the pristine cell 10. The two cells divide and dump all their garbage on one of their offsprings. One cell starts with 20 units of crap, one cell with 10 units and two cells are again crap free. The end result of this strategy? Part of your descendents will become more and more decrepit as they fill up with crap, while others remain pristine.

Somewhat reminiscent of the garbage catastrophe, but with important differences — and this time with evolutionary legs.

Alex has teased us with the suggestion that this will be the first of multiple parts to his coverage of this issue. If so, that’s exciting news; he has done some excellent multi-part stories in the past (e.g. these posts on cancer and metabolism). I’m looking forward to the next chapter.

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