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Blood, 15 May 2001, Vol. 97, No. 10, pp. 3075-3085
HEMATOPOIESIS
Numerous growth factors, cytokines, and chemokines are secreted
by human CD34+ cells, myeloblasts, erythroblasts, and
megakaryoblasts and regulate normal hematopoiesis in an
autocrine/paracrine manner
Marcin Majka,
Anna Janowska-Wieczorek,
Janina Ratajczak,
Karen Ehrenman,
Zbigniew Pietrzkowski,
M. Anna Kowalska,
Alan M. Gewirtz,
Stephen G. Emerson, and
Mariusz Z. Ratajczak
From the Department of Pathology and Laboratory
Medicine and the Department of Medicine, University of Pennsylvania
School of Medicine, Philadelphia, PA; and the Department of Medicine,
University of Alberta, and the Canadian Blood Services, Edmonton,
Alberta, Canada.
The aim of this study was to explore further the hypothesis
that early stages of normal human hematopoiesis might be coregulated by
autocrine/paracrine regulatory loops and by cross-talk among early
hematopoietic cells. Highly purified normal human CD34+
cells and ex vivo expanded early colony-forming
unit-granulocyte-macrophage (CFU-GM)-derived, burst forming
unit-erythroid (BFU-E)-derived, and CFU-megakaryocyte
(CFU-Meg)-derived cells were phenotyped for messenger RNA
expression and protein secretion of various growth factors, cytokines,
and chemokines to determine the biological significance of this
secretion. Transcripts were found for numerous growth factors
(kit ligand [KL], FLT3 ligand, fibroblast growth factor-2 [FGF-2],
vascular endothelial growth factor [VEGF], hepatocyte growth factor
[HGF], insulinlike growth factor-1 [IGF-1], and thrombopoietin
[TPO]); cytokines (tumor necrosis factor- , Fas ligand, interferon
, interleukin 1 [IL-1], and IL-16); and chemokines (macrophage
inflammatory protein-1 [MIP-1], MIP-1 , regulated upon
activation, normal T cell expressed and secreted [RANTES], monocyte chemotactic protein-3 [MCP-3], MCP-4, IL-8,
interferon-inducible protein-10, macrophage-derived chemokine
[MDC], and platelet factor-4 [PF-4]) to
be expressed by CD34+ cells. More importantly, the
regulatory proteins VEGF, HGF, FGF-2, KL, FLT3 ligand, TPO, IL-16,
IGF-1, transforming growth factor-1 (TGF-1), TGF-2, RANTES,
MIP-1, MIP-1, IL-8, and PF-4 were identified in media conditioned
by these cells. Moreover, media conditioned by CD34+ cells
were found to inhibit apoptosis and slightly stimulate the
proliferation of other freshly isolated CD34+ cells;
chemo-attract CFU-GM- and CFU-Meg-derived cells as well as other
CD34+ cells; and, finally, stimulate the
proliferation of human endothelial cells. It was also demonstrated that
these various hematopoietic growth factors, cytokines, and chemokines
are expressed and secreted by CFU-GM-, CFU-Meg-, and BFU-E-derived
cells. It is concluded that normal human CD34+ cells and
hematopoietic precursors secrete numerous regulatory molecules that
form the basis of intercellular cross-talk networks and regulate in an
autocrine and/or a paracrine manner the various stages of normal human hematopoiesis.
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