Platelet senescence is regulated by an internal timer, not damage inflicted by hits.
The mechanisms responsible for the brief life span of blood platelets have been a subject of speculation since the 1950s. The most popular hypothesis to date has been the "multiple-hit" model, whereby damage inflicted by external "hits" triggers recognition and clearance by the reticuloendothelial system. Recently, it was demonstrated that platelets contain an apoptotic pathway that mediates their survival in vivo. Using a novel labeling technique to measure population and cohort survival in mice carrying mutations in this pathway, combined with mathematical modeling, we have studied the internal and external control of platelet fate. Our results cast doubt on the veracity of the multiple-hit model. An alternative model, under which platelets are born with an internal "timer," provides a more parsimonious interpretation of the data. Thus, at steady state, platelet senescence is probably the product of internal processes rather than external hits.
Dowling
Mark R
MR
Immunology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
Josefsson
Emma C
EC
Henley
Katya J
KJ
Hodgkin
Philip D
PD
Kile
Benjamin T
BT
D000465:Algorithms; D000818:Animals; D017209:Apoptosis; D001710:Biotin / Q000031:analogs & derivatives / Q000737:chemistry; D001792:Blood Platelets / Q000737:chemistry / Q000166:cytology* / Q000378:metabolism; D016922:Cellular Senescence; D005260:Female; D005434:Flow Cytometry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D010976:Platelet Count; D013388:Succinimides / Q000737:chemistry; D013997:Time Factors; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
C494773:Bak1 protein, mouse; C494812:Bcl2l1 protein, mouse; D013388:Succinimides; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein; C033788:biotinyl N-hydroxysuccinimide ester; D001710:Biotin