Stromal cell-derived factor-1/CXCL12 selectively counteracts inhibitory effects of myelosuppressive chemokines on hematopoietic progenitor cell proliferation in vitro

Hal Broxmeyer, Scott Cooper, Giao Hangoc, Chang H. Kim

Research output: Contribution to journalArticle

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Abstract

A variety of cytokines and chemokines exert potent myelosuppressive effects that play a role in the maintenance of hematopoiesis, which, if unchecked, may result in pathological impairment of blood cell production. Processes that modulate these myelosuppressive effects are not well defined. Here we demonstrate that stromal cell-derived factor-1 (SDF-1/CXCL12), known for its ability to attract and to promote survival of hematopoietic progenitor cells (HPCs) and stem cells, blocks the effects of a broad range of myelosuppressive chemokines on proliferation of HPCs in vitro. The regulatory effects of SDF/CXCL12 on colony formation by mouse bone marrow granulocyte-macrophage (CFU-GM), erythroid (BFU-E), and multipotential (CFU-GEMM) progenitor cells were assessed. These cells were stimulated to proliferate by combinations of growth factors, such that responses of immature HPCs could be assessed. SDF-1/CXCL12 potently blocked myelosuppressive responses induced by CCL2/MCP-1, CCL3/MIP-1α, CCL19/CKβ-11, CCL25/TECK, CXCL4/PF4, CXCL8/IL-8, CXCL10/IP-10, and XCL1/Lymphotactin. However, SDF/CDL12 did not influence myelosuppression induced by tumor necrosis factor (TNF)-α, Interferon (IFN)-γ, transforming growth factor (TGF)-β or the iron-binding proteins H-ferritin or lactoferrin (LF). LF, previously shown to suppress release of growth factors, is shown here to also suppress proliferation of immature subsets of HPCs. HPCs from marrows of mice expressing an SDF-1/CXCL12 transgene were insensitive to inhibition by SDF/CXCL12-sensitive myelosuppressive chemokines, but not to SDF/CCL12-insensitive cytokines (TNF-α, IFN-γ, TGF-β, H-Ferritin, or LF). Thus, SDF-1/CXCL12 differentially and selectively regulates suppression of HPC proliferation by chemokines. These effects may counter myelosuppressive effects of certain chemokines in vivo, where proliferation of HPCs must be sustained.

Original languageEnglish
Pages (from-to)199-203
Number of pages5
JournalStem Cells and Development
Volume14
Issue number2
DOIs
StatePublished - Apr 2005

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Chemokine CXCL12
Hematopoietic Stem Cells
Chemokines
Cell Proliferation
Lactoferrin
Apoferritins
Transforming Growth Factors
Interferons
Intercellular Signaling Peptides and Proteins
Stem Cells
Tumor Necrosis Factor-alpha
Bone Marrow
Iron-Binding Proteins
Cytokines
Myeloid Progenitor Cells
Complement Factor H
Granulocyte-Macrophage Progenitor Cells
Erythroid Precursor Cells
Hematopoiesis
In Vitro Techniques

ASJC Scopus subject areas

  • Hematology

Cite this

Stromal cell-derived factor-1/CXCL12 selectively counteracts inhibitory effects of myelosuppressive chemokines on hematopoietic progenitor cell proliferation in vitro. / Broxmeyer, Hal; Cooper, Scott; Hangoc, Giao; Kim, Chang H.

In: Stem Cells and Development, Vol. 14, No. 2, 04.2005, p. 199-203.

Research output: Contribution to journalArticle

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AB - A variety of cytokines and chemokines exert potent myelosuppressive effects that play a role in the maintenance of hematopoiesis, which, if unchecked, may result in pathological impairment of blood cell production. Processes that modulate these myelosuppressive effects are not well defined. Here we demonstrate that stromal cell-derived factor-1 (SDF-1/CXCL12), known for its ability to attract and to promote survival of hematopoietic progenitor cells (HPCs) and stem cells, blocks the effects of a broad range of myelosuppressive chemokines on proliferation of HPCs in vitro. The regulatory effects of SDF/CXCL12 on colony formation by mouse bone marrow granulocyte-macrophage (CFU-GM), erythroid (BFU-E), and multipotential (CFU-GEMM) progenitor cells were assessed. These cells were stimulated to proliferate by combinations of growth factors, such that responses of immature HPCs could be assessed. SDF-1/CXCL12 potently blocked myelosuppressive responses induced by CCL2/MCP-1, CCL3/MIP-1α, CCL19/CKβ-11, CCL25/TECK, CXCL4/PF4, CXCL8/IL-8, CXCL10/IP-10, and XCL1/Lymphotactin. However, SDF/CDL12 did not influence myelosuppression induced by tumor necrosis factor (TNF)-α, Interferon (IFN)-γ, transforming growth factor (TGF)-β or the iron-binding proteins H-ferritin or lactoferrin (LF). LF, previously shown to suppress release of growth factors, is shown here to also suppress proliferation of immature subsets of HPCs. HPCs from marrows of mice expressing an SDF-1/CXCL12 transgene were insensitive to inhibition by SDF/CXCL12-sensitive myelosuppressive chemokines, but not to SDF/CCL12-insensitive cytokines (TNF-α, IFN-γ, TGF-β, H-Ferritin, or LF). Thus, SDF-1/CXCL12 differentially and selectively regulates suppression of HPC proliferation by chemokines. These effects may counter myelosuppressive effects of certain chemokines in vivo, where proliferation of HPCs must be sustained.

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