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Death-Defying Stem Cells


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#1 manofsan

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Posted 05 July 2004 - 02:45 AM


Here's an interesting article:

http://www.newscient...p?id=ns99996096

Anybody have any explanations as to why the stem cells are more resilient to apoptosis?

#2 Cyto

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Posted 05 July 2004 - 09:45 AM

Well man, I find that quite odd. The news bit is vauge on which caspases are active, and I assume that they were detecting the active autocleaving caspases and not inactive via XIAPs and 14-3-3 proteins. And since even the most latent of apoptic pathways such as the caspase-3 effecting a ~20 hour activation period for caspase-7 don't seem to be causing DNA fragmentation (etc) I really think this sounds like a all pervading inhibition. Assuming that there are apoptosomes being formed for the activation of caspase-3... something could be stoping endonuclease G from being activated. But if the Bcl-2 and Bcl-XL have already been surpassed then cyt. c is abound and whatever it is, its no whimp.

But anyways if ya want a huge reviews on apoptosis stuff, Biochimica Et Biophysica Acta published (2004) a lot of reviews on the different aspects of what goes into the cell death process. Give me a shout and I send in a jet. [lol]

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#3

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Posted 05 July 2004 - 05:16 PM

Lets look at this. This is what was reported as being found unexpectedly in vigorously proliferating embryonic stem cells (ESCs):

a) high levels of caspase activity (caspase species not mentioned but we know that caspases activate other caspaces downstream in signals that lead to cell death )
b) "chewed-up protein called PARP-1 (PARP-1 is a DNA repair enzyme that is activated in response to single strand breaks. It is cleaved by caspace-3)
c) depolarization of their membranes (mitochondria) (enables cytochrome c to seep out of mitochondria and into cytosol activating downstream caspases)

Anyone familiar with apoptotic signaling (such as Bates) would see why this is so unexpected: all 3 of the above observations are indicative of imminent cell death via apoptosis. Therefore this is a truly paradigm shifting discovery if it's true.

We know from trophic factors such as NGF that apoptosis is a default pathway that is always on and must be suppressed by the presence of trophic or survival factors to enable the cell to continue living. Thus one question is: does the trophic/survival factor model apply to ESCs in the same way or does it to differentiated cells? Does the apoptotic signal in ECSs actually signal proliferation instead instead of apoptosis?

According to the article: "Zwaka speculates that the process of self-renewal may have evolved alongside cell death, and some of the processes may be the same". This is a sensible conclusion based on the above observations. Alternatively, these events may not be as unexpected as initially expected. We should look at the three observations more carefully:

(a) Caspase activity: We know that caspase activity is also associated with other cell functions aside from apoptosis including cytoskeletal mediated migration (1, 2) and T-cell activation (3). And of course we are also aware of caspase independent apoptosis. Thus caspase activity does not always equal cell death, so it is not inconceivable that a novel function of proliferation could be associated with caspases.

(b) "chewed" PARP-1: Whilst PARP-1 participates in the the first events of DNA repair, overactivity of PARP-1 can lead to initiation of a nuclear signal that propagates to mitochondria and triggers the release of apoptosis inducing factor which then shuttles from mitochondria to the nucleus and induces peripheral chromatin condensation, large-scale fragmentation of DNA and apoptosis (4). Thus PARP-1 cleavage by caspase may not be such a bad thing after all as it may provide a protective effect.

© mitochondrial membrane depolarization (MMD): MMD results in the release of cytochrome c with subsequent caspase-9 activation followed by caspase-3 (5). However, we also know that as per (a) caspases do not always signal cell death.

Therefore it is not that stem cells are more resilient to apoptosis per se, rather they are using elements of traditionally apoptotic signaling for other purposes.


(1) Y. Watanabe and T. Akaike. Possible involvement of caspase-like family in maintenance of cytoskeleton integrity. J Cell Physiol 1999. 179: 45-51.
(2) C. Antonopoulos, M. Cumberbatch, and R.J. Dearman. Functional caspase-1 is required for Langerhans cell migration and optimal contact sensitization in mice. J Immunol 2001. 166: 3672-3677.
(3) A. Alam, L.Y. Cohen, and S. Aouad. Early activation of caspases during T lymphocyte stimulation results in selective substrate cleavage in nonapoptotic cells. J Exp Med 1999. 190: 1879-90.
(4) Hong SJ, Dawson TM, Dawson VL. Nuclear and mitochondrial conversations in cell death: PARP-1 and AIF signaling. Trends Pharmacol Sci. 2004 May;25(5):259-64.
(5) Eldering E, Mackus WJ, Derks IA, Evers LM, Beuling E, Teeling P, Lens SM, Van Oers MH, Van Lier RA. Apoptosis via the B cell antigen receptor requires Bax translocation and involves mitochondrial depolarization, cytochrome C release, and caspase-9 activation. Eur J Immunol. 2004 Jul;34(7):1950-60.

 

*conjecture-> challenge welcomed*

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#4 Cyto

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Posted 10 July 2004 - 06:46 PM

Found more on this from Trends in Cell Biology:

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Despite the stereotyped view that caspases are chief executioners of cell death, there are several instances where caspase activation fails to trigger cell death. Somewhat paradoxically, deadly caspases play an important role at the beginning of life itself, during sperm formation in Drosophila. Caspases aid the process of sperm individualization, through which spermatids become separated from syncytia and lose the bulk of their cytoplasm [53]. During individualization, a cytoskeletal membrane complex, known as the individualization complex, translocates along spermatids, disconnecting cytoplasmic ‘bridges’ between them and expelling spermatid cytoplasm and unnecessary organelles into a membrane bag called the cystic bulge. Immunostaining for activated drice marked the pre-individualized part of the spermatid and the cystic bulge [53]. Indeed, the cystic bulge also stained with the apoptosis-associated marker acridine orange [53]. Synthetic and viral pan-caspase inhibitors severely impaired movement of the individualization complex and prevented removal of bulk cytoplasm from the spermatids [53]. It is not known how the activated caspase facilitates the movement of the individualization complex. It is also unclear whether caspases have a direct role in exclusion of cytoplasm from the spermatid, although it is reasonable to hypothesize that caspase activity might aid the degradation of expelled cytoplasm in the cystic bulge. The morphological defects and sterility of Drosophila sperm treated with caspase inhibitors strikingly resemble a common abnormality in human sperm; mouse knockouts of some apoptotic genes also cause male sterility [53]. Thus, although these mammalian defects are largely uncharacterized, they might also point to a non-lethal role of caspases.

In red blood cells and lens fiber cells, caspase activation leads to a subset of apoptotic morphological changes without causing cell death. As embryonic erythroid cells differentiate into adult red blood cells, they show signs of apoptosis, including chromatin compaction, nuclear destruction and caspase activation [54]. Yet, although the cytoplasm of an apoptotic cell contracts, that of a differentiating red blood cell expands [55]. Lens fiber cells develop from epithelial cells that degrade their organelles and nuclei during differentiation, presumably to allow cellular transparency. Caspases are expressed in developing lens fiber cells [56], and zVAD.fmk can reduce nuclear destruction in an in vitro model of rat lens-fiber differentiation [56]. In transgenic mice that overexpressed Bcl-xL, the lens fibers did not lose their nuclei [57]. In both of these cell examples, it is unclear how caspase activity is controlled to trigger only non-lethal aspects of the apoptotic program.

There are also examples of caspase activation promoting differentiation in the absence of any morphological signs of apoptosis. For example, during infection, human monocytes differentiate to form macrophages. The differentiation process does not show morphological features of apoptosis [58]; however, antibody staining showed caspase activation at the time of the switch; and the monocyte–macrophage switch was blocked by caspase inhibitors [58]. Caspase-8 might also play a role in differentiation because caspase-8 knockout mice exhibit defects in the development of heart muscle and also have a dramatically decreased pool of hematopoietic precursors [59]. These defects are not apparently related to abnormal cell death. The activity of human Caspase-14 was associated with the terminal differentiation of keratinocytes [60 and 61].

Immune functions are probably the best-characterized examples of non-lethal roles for caspases that do not involve apoptotic changes. Murine knockouts of caspase-1 [62 and 63] and caspase-11 [64] develop normally, apart from defects in the production of IL-1 and IL-1 in response to the bacterial compound lipopolysaccharide (LPS). A human family pedigree showed that caspase-8 mutations are linked to defects in the activation of T, B and NK cells [65]. Mice studies corroborated a role for caspase-8 in T-cell function, because a targeted caspase-8 deletion in T cells caused defects in activation-induced expansion of peripheral T cells, T-cell activation and the ability of T cells to clear lymphocyte choriomeningitis virus [66]. Interestingly, in addition to their immune functions, caspase-1, -8 and -11 can also promote apoptosis, because cells from mice harboring knockout alleles of these caspases have impaired death-receptor-mediated PCD [59, 63 and 67]. The link between caspases and the immune system also extends to Drosophila. A fly screen to identify mutants defective in innate immunity revealed that a mutant of the caspase Dredd mounted a defective immune response when challenged with Gram-negative
bacteria [17].
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Trends in Cell Biology
Volume 14, Issue 4 , 1 April 2004, Pages 184-193
doi:10.1016/j.tcb.2004.03.002



So, it does seem that this should be not too alarming for it to be present within ESCs.




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