Think of stem cells as self-correcting master copies, with two key traits:
- they defy replicative senescence by activating telomerase, and
- when a stem cell divides, it exactly reproduces itself with one daughter and makes a more differentiated cell with the other daughter (asymmetric cell division)
A zygote (fertilized egg made from sperm+egg) has the potential to become all cells (totipotentiality.) This chart shows that with each phase of differentiation, subsequent stem cells lose potentiality while retaining the two key traits of “stemness.” The last stem is the terminally-differentiated (or nullipotent cell, whose descendants will succumb to the Hayflick Limit because of the loss of a functional copy of telomerase.
The Shortest Telomeres are the Weakest Links
The next two figures are the most important of the entire site because they experimentally verify the principle of TA with regard to our Theory of Aging. They come from Blasco et al’s article:
“Telomerase reverses epidermal hair follicle stem cell defects and loss of long-term survival associated with critically short telomeres”. The Journal of Cell Biology, Vol. 179, No. 2, October 22, 2007 277–290, http://www.jcb.org/cgi/doi/10.1083/jcb.200704141
Figure 2. Rescue of mean telomere length and percentage of short telomeres in late generation telomerase-reconstituted G3 Terc+/−* keratinocytes. (A) Telomere length histogram obtained by Q-FISH in primary murine skin keratinocytes. The histogram shown is representative of three independent pairs of G3 Terc−/− and G3 Terc+/−* littermates (see B). Note a greater abundance of short telomeres in the G3 Terc−/− mouse compared with the G3 Terc+/−* littermate.
Red lines facilitate visualization of short (<100 a.u.f.) and long (>1,000 a.u.f.) telomeres. The total number of telomere dots used for the quantifi cation and the percentage of short and long telomeres are indicated. (B) Mean telomere length is signifi cantly increased (P < 0.001) in G3 Terc+/−* compared with G3 Terc−/− mice. Concomitantly, these mice show a signifi cant (P < 0.001) decrease in the percentage of short telomeres and a signifi cant (P = 0.015) increase in the percentage of long telomeres. Data are mean values ± SEM for three independent pairs of G3 Terc−/− and G3 Terc+/−* littermates.
In plain English: G3 mice are unable to make telomerase and their descendants live shorter and shorter because of this. They themselves age prematurely. If you splice in one copy of the telomerase gene (G3 Terc +/-,) the numbers of telomeres drop from 3936 to 2049 but the critically short percentage drops from 12.5% to 1.7%.
A reasonable conclusion might be that when telomerase is reintroduced into the progeric mice, p53 and other mechanisms are at work to force bad cells into suicide.
Telomerase Activation Prevents Chromosomes from Forming Non-viable Fragments
Figure 3. Signifi cant rescue of signal-free ends and end-to-end chromosomal fusions in G3 Terc+/−* keratinocytes. (A) Quantifi cation of the frequency of the indicated chromosomal aberrations in primary keratinocytes from G3 Terc−/− and G3 Terc+/−* mice. The total number of chromosomes scored for the analysis is indicated on top of each bar. Statistical comparisons using the χ2 test are shown. (B) Representative examples of the indicated chromosomal aberrations are shown below the graph. Note that signal-free ends and end-to-end fusions are signifi cantly rescued in Terc-reconstituted G3 mice compared with the G3 Terc-defi cient littermates, which is in agreement with the fact that telomerase elongates short telomeres, thus preventing telomere dysfunction. Bar, 0.4 µM
In plain English, giving G3 mice active telomerase prevents their tips from sticking to where they don’t belong, If the 46 chromosomes start recombining in our stem cells, the best we can hope for is death of it’s descendants. More likely, apoptosis, dysfunction, or even cancer could results (see the Philadelphia Chromosome.)
Addendum: a Primer of your Aging Stem Cells
|Cell Type||Lineage||Growth||Telomerase Activation (TA)||Telomere lengths||Reference|
|Hematopoietic||Blood/immune||Limited||Absent/low||Shortened/(maintained)||Brummendor et al (2006)|
|Mesenchymal||Various (bone, muscle, fat)||Limited||Absent/low (inducible)||Shortened/(maintained)||Izadpanah et al (2006)|
|Skin||Epidermis||Limited||Low||Shortened||Sarin et al (2005)|
|Intestinal Crypt||Intestinal Mucosa||Limited||Low||Shortened|
|Neuronal||Neurons (and supporting glial cells)||Limited||Low/absent||Shortened||Wright et al (2006)|
|Pancreatic||Ductal Epithelium||Limited||Absent||Shortened||Moriscot et al (2005)|
|Liver epithelial||Bi-Potential (liver and bile ducts)||Limited(durable)||Low||Maintainedor shortened||Dan et al (2006)|
|Cancer Stem Cells||Multipotent||Unlimited||High||Maintained||Ju et al (2006)|
IN THE FUTURE?