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Blood, Vol. 95 No. 6 (March 15), 2000:
pp. 1957-1966
A secreted and LIF-mediated stromal cell-derived activity that
promotes ex vivo expansion of human hematopoietic stem cells
Chu-Chih Shih,
Mickey C.-T. Hu,
Jun Hu,
Yehua Weng,
Paul J. Yazaki,
Jeffrey Medeiros, and
Stephen J. Forman
From the Department of Hematology/Bone Marrow Transplantation, City
of Hope National Medical Center, Duarte, CA; Department of Molecular
Biology, Beckman Research Institute at City of Hope, Duarte, CA;
Department of Cell Biology, Amgen Inc, Thousand Oaks, CA; and
Department of Pathology, University of Texas M. D. Anderson Cancer
Center, Houston, TX.
The development of culture systems that facilitate ex vivo
maintenance and expansion of transplantable hematopoietic stem cells
(HSCs) is vital to stem cell research. Establishment of such culture
systems will have significant impact on ex vivo manipulation and
expansion of transplantable stem cells in clinical applications such as
gene therapy, tumor cell purging, and stem cell transplantation. We
have recently developed a stromal-based culture system that facilitates
ex vivo expansion of transplantable human HSCs. In this stromal-based
culture system, 2 major contributors to the ex vivo stem cell expansion
are the addition of leukemia inhibitory factor (LIF) and the AC6.21
stromal cells. Because the action of LIF is indirect and mediated by
stromal cells, we hypothesized that LIF binds to the LIF receptor on
AC6.21 stromal cells, leading to up-regulated production of stem cell
expansion promoting factor (SCEPF) and/or down-regulated production of
stem cell expansion inhibitory factor (SCEIF). Here we demonstrate a
secreted SCEPF activity in the conditioned media of LIF-treated AC6.21
stromal cell cultures (SCM-LIF). The magnitude of ex vivo stem cell
expansion depends on the concentration of the secreted SCEPF activity
in the SCM-LIF. Furthermore, we have ruled out the contribution of 6 known early-acting cytokines, including interleukin-3, interleukin-6, granulocyte macrophage colony-stimulating factor, stem cell factor, flt3 ligand, and thrombopoietin, to this SCEPF activity. Although further studies are required to characterize this secreted SCEPF activity and to determine whether this secreted SCEPF activity is
mediated by a single factor or by multiple growth factors, our results
demonstrate that stromal cells are not required for this secreted
SCEPF activity to facilitate ex vivo stem cell expansion.
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