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Blood, 15 June 2004, Vol. 103, No. 12, pp. 4440-4448.
Prepublished online as a Blood First Edition Paper on January 15, 2004; DOI 10.1182/blood-2003-09-3079.
Submitted September 8, 2003
Accepted January 6, 2004
Elevated telomerase activity, minimal telomere loss in cord blood long-term cultures with extensive stem cell replication
Loretta Gammaitoni, Katja C Weisel, Monica Gunetti, Kai-Da Wu, Stefania Bruno, Silvana Pinelli, Antonio Bonati, Massimo Aglietta, Malcolm A Moore, and Wanda Piacibello*
Division of Clinical Oncology, IRCC Istitute for Cancer Research and Treatment, Candiolo, Torino, Italy
James Ewing Laboratory of Developmental Hematopoiesis, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
Department of Clinical Sciences, Section of Hematology/Oncology, University of Parma Medical School, Parma, Italy
* Corresponding author; email: wanda.piacibello{at}ircc.it.
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 Tpo, or stimulated by a cytokine cocktail in the absence of stroma, with, in one method, CD34+ cells re-isolated 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 18-20 weeks and by SCID Repopulating Cells (SRC), capable of repopulating and serially passage in NOD/SCID mice, for 16 weeks. Despite this extensive proliferation, telomere length initially increased and only at late stages of culture was there evidence of telomere shortening. 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 3-4 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.
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