NDLI: Prolonged self-renewal activity unmasks telomerase control of telomere homeostasis and function of mouse hematopoietic stem cells

Content Provider	PubMed Central
Author	Sekulovic, Sanja Vala, Gylfadottir Irma, Vulto Gasparetto, Maura Even, Yasmine Brookes, Christy Smith, Clayton Eaves, Connie J. Lansdorp, Peter M. Rossi, Fabio M. Humphries, R. Keith
Copyright Year	2011
Abstract	Strategies for expanding hematopoietic stem cells (HSCs) could have significant utility for transplantation-based therapies. However, deleterious consequences of such manipulations remain unknown. Here we examined the impact of HSC self-renewal divisions in vitro and in vivo on their subsequent regenerative and continuing ability to sustain blood cell production in the absence of telomerase. HSC expansion in vitro was obtained using a NUP98-HOXA10hd transduction strategy and, in vivo, using a serial transplant protocol. We observed ∼ 10kb telomere loss in leukocytes produced in secondary mice transplanted with HSCs regenerated in primary recipients of NUP98-HOXA10hd-transduced and in vitro-expanded Tert −/− HSCs 6 months before. The second generation leukocytes also showed elevated expression of γH2AX (relative to control) indicative of greater accumulating DNA damage. In contrast, significant telomere shortening was not detected in leukocytes produced from freshly isolated, serially transplanted wild-type (WT) or Tert −/− HSCs, suggesting that HSC replication posttransplant is not limited by telomere shortening in the mouse. These findings document a role of telomerase in telomere homeostasis, and in preserving HSC functional integrity on prolonged self-renewal stimulation.
Related Links	http://dx.doi.org/10.1182/blood-2010-11-319632
Ending Page	1773
Page Count	8
Starting Page	1766
File Format	PDF
ISSN	00064971
e-ISSN	15280020
Journal	Blood
Issue Number	7
Volume Number	118
Language	English
Publisher	American Society of Hematology
Publisher Date	2011-08-18
Access Restriction	Open
Rights Holder	American Society of Hematology
Subject Keyword	Immunology Cell Biology Biochemistry Hematology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Hematology Biochemistry Immunology

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