Elevated telomerase activity and minimal telomere loss in cord blood long-term cultures with extensive stem cell replication

Telomerase activity, telomere length, stem/progenitor cell production, and function of CD34+ cells from cord blood (CB), bone marrow, and mobilized peripheral blood were evaluated in long-term cultures. CB cells were cultured either on OP-9 stromal cells transduced with an adenovector expressing thr...

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Bibliographic Details
Published in:Blood 2004-06, Vol.103 (12), p.4440-4448
Main Authors: Gammaitoni, Loretta, Weisel, Katja C., Gunetti, Monica, Wu, Kai-Da, Bruno, Stefania, Pinelli, Silvana, Bonati, Antonio, Aglietta, Massimo, Moore, MalcolmA.S., Piacibello, Wanda
Format: Article
Language:English
Subjects:
Adenoviridae - genetics
Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy
Animals
Antigens, CD - blood
Antigens, CD34 - blood
Biological and medical sciences
Bone marrow, stem cells transplantation. Graft versus host reaction
Cell differentiation, maturation, development, hematopoiesis
Cell Division
Cell physiology
Fetal Blood - cytology
Fundamental and applied biological sciences. Psychology
Genetic Vectors
Hematopoietic Stem Cells - cytology
Hematopoietic Stem Cells - enzymology
Humans
Infant, Newborn
Medical sciences
Mice
Mice, Inbred NOD
Mice, SCID
Molecular and cellular biology
Telomerase - blood
Telomerase - deficiency
Telomerase - metabolism
Thrombopoietin - genetics
Transfection
Transfusions. Complications. Transfusion reactions. Cell and gene therapy
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Summary:Telomerase activity, telomere length, stem/progenitor cell production, and function of CD34+ cells from cord blood (CB), bone marrow, and mobilized peripheral blood were evaluated in long-term cultures. CB cells were cultured either on OP-9 stromal cells transduced with an adenovector expressing thrombopoietin (TPO) or stimulated by a cytokine cocktail in the absence of stroma, with, in one method, CD34+ cells reisolated at monthly intervals for passage. Continuous expansion of stem cells as measured by in vitro cobblestone area and secondary colony-forming assays was noted for 18 to 20 weeks and by severe combined immunodeficiency (SCID)-repopulating cells (SRCs), capable of repopulating and serially passage in nonobese diabetic/SCID mice, for 16 weeks. Despite this extensive proliferation, telomere length initially increased and only at late stages of culture was evidence of telomere shortening noted. This telomere stabilization correlated with maintenance of high levels of telomerase activity in the CD34+ cell population for prolonged periods of culture. Cytokine-stimulated cultures of adult CD34+ cells showed CD34+ and SRC expansion (6-fold) for only 3 to 4 weeks with telomere shortening and low levels of telomerase. There is clearly a clinical value for a system that provides extensive stem cell expansion without concomitant telomere erosion. (Blood. 2004;103:4440-4448)
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2003-09-3079