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Blood, Vol. 94 No. 5 (September 1), 1999:
pp. 1623-1636
Long-Term Ex Vivo Maintenance and Expansion of Transplantable Human
Hematopoietic Stem Cells
Chu-Chih Shih,
Mickey C.-T. Hu,
Jun Hu,
Jeffrey Medeiros, and
Stephen J. Forman
From the Department of Hematology/Bone Marrow Transplantation and the
Department of Anatomic Pathology, City of Hope National Medical Center,
Duarte, CA; the Department of Cell Biology, Amgen Inc, Thousand Oaks,
CA; and the Department of Molecular Biology, Beckman Research Institute
at City of Hope, Duarte, CA.
We have developed a stromal-based in vitro culture system that
facilitates ex vivo expansion of transplantable CD34+
thy-1+ cells using long-term hematopoietic reconstitution
in severe combined immunodeficient-human (SCID-hu) mice as
an in vivo assay for transplantable human hematopoietic stem cells
(HSCs). The addition of leukemia inhibitory factor (LIF) to purified
CD34+ thy-1+ cells on AC6.21 stroma, a
murine bone marrow-derived stromal cell line, caused expansion of
cells with CD34+ thy-1+ phenotype. Addition
of other cytokines, including interleukin-3 (IL-3), IL-6,
granulocyte-macrophage colony-stimulating factor, and stem cell factor,
to LIF in the cultures caused a 150-fold expansion of cells retaining
the CD34+ thy-1+ phenotype. The ex
vivo-expanded CD34+ thy-1+ cells gave rise
to multilineage differentiation, including myeloid, T, and B cells,
when transplanted into SCID-hu mice. Both murine LIF (cannot bind to
human LIF receptor) and human LIF caused expansion of human
CD34+ thy-1+ cells in vitro, suggesting
action through the murine stroma. Furthermore, another human HSC
candidate, CD34+ CD38 cells, shows a
similar pattern of proliferative response. This suggests that
ex vivo expansion of transplantable human stem cells under this
in vitro culture system is a general phenomenon and not just specific
for CD34+ thy-1+ cells.
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