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Blood, Vol. 94 No. 12 (December 15), 1999:
pp. 4093-4102
Distinct Requirements for Optimal Growth and In Vitro Expansion of
Human CD34+CD38 Bone Marrow Long-Term
Culture-Initiating Cells (LTC-IC), Extended LTC-IC, and Murine In Vivo
Long-Term Reconstituting Stem Cells
Veslemøy Ramsfjell,
David Bryder,
Helga Björgvinsdóttir,
Sten Kornfält,
Lars Nilsson,
Ole J. Borge, and
Sten E.W. Jacobsen
From the Stem Cell Laboratory, Department of Molecular Medicine and
Gene Therapy, Department of Internal Medicine, Institute for Laboratory
Medicine, University Hospital of Lund, Lund, Sweden.
Recently, primitive human bone marrow (BM) progenitors supporting
hematopoiesis in extended (>60 days) long-term BM cultures were
identified. Such extended long-term culture-initiating cells (ELTC-IC)
are of the CD34+CD38 phenotype, are
quiescent, and are difficult to recruit into proliferation, implicating
ELTC-IC as the most primitive human progenitor cells detectable in
vitro. However, it remains to be established whether ELTC-IC can
proliferate and potentially expand in response to early acting
cytokines. Here, CD34+CD38 BM ELTC-IC
(12-week) were efficiently recruited into proliferation and expanded in
vitro in response to early acting cytokines, but conditions for
expansion of ELTC-IC activity were distinct from those of traditional
(5-week) LTC-IC and murine long-term repopulating cells. Whereas c-kit
ligand (KL), interleukin-3 (IL-3), and IL-6 promoted proliferation and
maintenance or expansion of murine long-term reconstituting activity
and human LTC-IC, they dramatically depleted ELTC-IC activity. In
contrast, KL, flt3 ligand (FL), and megakaryocyte growth and
development factor (MGDF) (and KL + FL + IL-3) expanded murine
long-term reconstituting activity as well as human LTC-IC and ELTC-IC.
Expansion of LTC-IC was most optimal after 7 days of culture, whereas
optimal expansion of ELTC-IC activity required 12 days, most likely
reflecting the delayed recruitment of quiescent
CD34+CD38 progenitors. The need for high
concentrations of KL, FL, and MGDF (250 ng/mL each) and serum-free
conditions was more critical for expansion of ELTC-IC than of LTC-IC.
The distinct requirements for expansion of ELTC-IC activity when
compared with traditional LTC-IC suggest that the ELTC-IC could prove
more reliable as a predictor for true human stem cell activity after in
vitro stem cell manipulation.
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