title: Prolonged self-renewal activity unmasks telomerase control of telomere homeostasis and function of mouse hematopoietic stem cells.
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.
authors: Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, Canada.
authors: Sanja
authors: S
authors: Sekulovic
authors: Vala
authors: V
authors: Gylfadottir
authors: Irma
authors: I
authors: Vulto
authors: Maura
authors: M
authors: Gasparetto
authors: Yasmine
authors: Y
authors: Even
authors: Christy
authors: C
authors: Brookes
authors: Clayton
authors: C
authors: Smith
authors: Connie J
authors: CJ
authors: Eaves
authors: Peter M
authors: PM
authors: Lansdorp
authors: Fabio M
authors: FM
authors: Rossi
authors: R Keith
authors: RK
authors: Humphries
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D004249:DNA Damage; D017353:Gene Deletion; D005786:Gene Expression Regulation; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D006657:Histones / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D016615:Telomere
chemical_list: D006657:Histones; C475961:gamma-H2AX protein, mouse; D019098:Telomerase