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Blood, 15 September 2000, Vol. 96, No. 6, pp. 2074-2080
HEMATOPOIESIS
Impairment of lymphopoiesis and myelopoiesis in mice
reconstituted with bone marrow-hematopoietic progenitor cells
expressing SDF-1-intrakine
Nobuyuki Onai,
Yan-yun Zhang,
Hiroyuki Yoneyama,
Toshio Kitamura,
Sho Ishikawa, and
Kouji Matsushima
From the Department of Molecular Preventive Medicine
and CREST, School of Medicine, and the Department of Hematopoietic
Factor, Institute of Medical Science, University of Tokyo,
Japan.
Both SDF-1 and CXCR4 disruption are lethal to mice at the
embryonic stage and cause abnormalities in B lymphopoiesis,
myelopoiesis, cardiogenesis, vasculogenesis, and cerebellar
development. To investigate the role of SDF-1 and CXCR4 in
hematopoiesis during the adult stage, mice reconstituted with bone
marrow-derived hematopoietic progenitor cells transduced with either
the SDF-1 or a genetically modified SDF-1-intrakine gene using a
retroviral expression vector were analyzed. Flow cytometric (FCM)
analysis showed a dramatic reduction of CXCR4 expression on the cells
of intrakine-transduced mice, whereas CCR7 and CCR1 expression was
unchanged or marginally decreased on splenocytes. Migration of
splenocytes and bone marrow cells to SDF-1 was markedly suppressed in
intrakine-transduced mice. FCM analysis of bone marrow cells of
intrakine-transduced mice exhibited decreased numbers of pro-B
(B220+ CD43+), pre-B (B220+
CD43 ), and immature B (B220+
IgM+) cells and a decreased number of granulocytes/myeloid
(Gr1+ CD11b+) cells. Impaired B lymphopoiesis
and myelopoiesis in intrakine-transduced mice were confirmed by an in
vitro colony-forming assay of bone marrow cells. In contrast, B
lymphopoiesis and myelopoiesis were enhanced in SDF-1-transduced mice.
Interestingly, T-cell maturation in the thymus was impaired both in
intrakine- and SDF-1-transduced mice, suggesting that SDF-1 and CXCR4
play an important role in T lymphopoiesis as well as in B lymphopoiesis
and myelopoiesis in adults. These results demonstrate an essential role
of CXCR4 and its ligand SDF-1 in adult hematopoiesis, and they indicate the intrakine method as a powerful tool for functional analysis of
chemokines/chemokine receptors in vivo and as a potential therapeutic approach for acquired immunodeficiency syndrome.
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