Long-term repopulating ability of telomerase-deficient murine hematopoietic stem cells.
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.
Samper
Enrique
E
Department of Immunology and Oncology, Centro Nacional de Biotecnología-CSIC, Campus Cantoblanco, Madrid, Spain.
Fernández
Piedad
P
Eguía
Raúl
R
Martín-Rivera
Luis
L
Bernad
Antonio
A
Blasco
María A
MA
Aracil
Miguel
M
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000201:enzymology; D016026:Bone Marrow Transplantation; D018929:Cell Culture Techniques / Q000379:methods; D002454:Cell Differentiation; D002455:Cell Division; D020732:Cytogenetic Analysis; D005260:Female; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000145:classification / Q000166:cytology / Q000201:enzymology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012313:RNA / Q000235:genetics; D019098:Telomerase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014178:Translocation, Genetic
C422952:telomerase RNA; D012313:RNA; D019098:Telomerase