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Prepublished online as a Blood First Edition Paper on March 27, 2003; DOI 10.1182/blood-2002-07-2334.
Submitted August 5, 2002
Accepted March 11, 2003
Telomerase is required to slow telomere shortening and extend replicative lifespan of HSC during serial transplantation
Richard C Allsopp*, Gregg B Morin, Ronald DePinho, Calvin B Harley, and Irving L Weissman
Pathology Department, Stanford University, Stanford, CA, USA
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
Dana Farber Cancer Institute, Harvard University, Boston, MA, USA
Geron Corporation, Menlo Park, CA, USA
* Corresponding author; email: rallsopp{at}cmgm.stanford.edu.
Telomeres shortening ultimately limits the replicative lifespan of cultured human somatic cells. Telomeres also shorten during replicative aging in vivo in hematopoietic cells, including early hematopoietic progenitors and hematopoietic stem cells (HSC), from humans and mice, despite readily detectable levels of telomerase in these cells. To assess the relevance of telomerase to the long term replicative capacity of HSC in vivo, we serially transplanted HSC from wild-type and telomerase deficient mice until exhaustion and monitored telomere length in HSC during this process. Telomerase deficient HSC could only be serially transplanted for 2 rounds, whereas wild-type HSC could be serially transplanted for at least 4 rounds. Furthermore, the rate of telomere shortening was increased ~2 fold during serial transplantation of telomerase deficient HSC. These findings suggest that, one role for telomerase in the HSC is to partially counter the rate of telomere shortening during division of HSC, thereby preventing pre-mature loss of telomere function and providing added replicative capacity.
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