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Blood, 15 April 2002, Vol. 99, No. 8, pp. 2767-2775
HEMATOPOIESIS
Long-term repopulating ability of telomerase-deficient murine
hematopoietic stem cells
Enrique Samper,
Piedad Fernández,
Raúl Eguía,
Luis Martín-Rivera,
Antonio Bernad,
María A. Blasco, and
Miguel Aracil
From the Department of Immunology and Oncology, Centro
Nacional de Biotecnología-CSIC, Campus Cantoblanco, Madrid,
Spain.
Telomere length must be tightly regulated in highly proliferative
tissues, such as the lymphohematopoietic system. Under steady-state conditions, the levels and functionality of hematopoietic-committed or
multipotent progenitors were not affected in late-generation telomerase-deficient mice (mTerc /) with critically
short telomeres. Evaluation of self-renewal potential of
mTerc/ day-12 spleen colony-forming units
demonstrated no alteration as compared with wildtype progenitors.
However, the replating ability of
mTerc/ granulocyte-macrophage CFUs
(CFU-GMs) was greatly reduced as compared with wildtype
CFU-GMs, indicating a diminished capacity of late-generation
mTerc/ committed progenitors when forced to
proliferate. Long-term bone marrow cultures of mTerc/
bone marrow (BM) cells show a reduction in proliferative capacity; this
defect can be mainly attributed to the hematopoietic, not to the
stromal, mTerc/ cells. In serial and competitive
transplantations, mTerc/ BM stem cells show reduced
long-term repopulating capacity, concomitant with an increase in
genetic instability compared with wildtype cells. Nevertheless, in
competitive transplantations late-generation mTerc/ precursors can occasionally overcome this
proliferative impairment and reconstitute irradiated recipients. In
summary, our results demonstrate that late-generation
mTerc/ BM cells with short telomeres, although
exhibiting reduced proliferation ability and reduced long-term
repopulating capacity, can still reconstitute myeloablated animals
maintaining stem cell function.
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