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Blood, Vol. 93 No. 2 (January 15), 1999:
pp. 481-487
Human Growth Factor-Enhanced Regeneration of Transplantable Human
Hematopoietic Stem Cells in Nonobese Diabetic/Severe
Combined Immunodeficient Mice
Johanne D. Cashman and
Connie J. Eaves
From the Terry Fox Laboratory, British Columbia Cancer Agency and
Department of Medical Genetics, University of British Columbia,
Vancouver, BC, Canada.
Self-renewal is considered to be the essential defining property of
a stem cell. Retroviral marking, in vitro amplification, and serial
transplantation of human cells that can sustain long-term lymphomyelopoiesis in vivo have provided evidence that human
hematopoietic stem cell self-renewal occurs both in vitro and in vivo.
To investigate whether this process can be manipulated by cytokines, we
administered two different combinations of human growth factors to
sublethally irradiated nonobese diabetic/severe combined
immunodeficient (SCID) mice transplanted with
107 light-density human cord blood cells and then performed
secondary transplants to compare the number of transplantable human
lymphomyeloid reconstituting cells present 4 to 6 weeks
post-transplant. A 2-week course of Steel factor + interleukin (IL)-3 + granulocyte-macrophage colony-stimulating factor + erythropoietin
(3 times per week just before sacrifice) specifically and significantly
enhanced the numbers of transplantable human lymphomyeloid stem cells
detectable in the primary mice (by a factor of 10). Steel factor + Flt3-ligand + IL-6 (using either the same schedule or
administered daily until sacrifice 4 weeks post-transplant) gave a
threefold enhancement of this population. These effects were obtained
at a time when the regenerating human progenitor populations in such
primary mice are known to be maximally cycling even in the absence of growth factor administration suggesting that the underlying mechanism may reflect an ability of these growth factors to alter the probability of differentiation of stem cells stimulated to proliferate in vivo.

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