Sachin Malhotra1, Paul W Kincade. 1. Immunobiology and Cancer Program, Oklahoma Medical Research Foundation and the Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Abstract
OBJECTIVE: The Wnt family may contribute to hematopoietic stem cell (HSC) maintenance in bone marrow, but many questions remain concerning mechanisms. Vascular cell adhesion molecule-1 (VCAM-1) is expressed in cellular compartments of the bone marrow and might contribute to the HSC niche, but mechanisms concerning its constitutive expression are largely unknown. We now explore the influence of Wnt signaling on cellular adhesion molecule expression by bone marrow stromal and hematopoietic cells. MATERIALS AND METHODS: Recombinant Wnt ligands, retroviral Wnt transductions and cocultures with Wnt-secreting cells were used to analyze the effect of Wnt on adhesion molecule expression by stromal and hematopoietic cells. In vivo experiments were also done to assess the ability of Wnt3a-induced, VCAM-1 deficient hematopoietic cells to engraft bone marrow. RESULTS: We now report that the beta-catenin-dependent canonical Wnt signaling pathway negatively regulates VCAM-1 expression on two types of bone marrow cells. Wnt pathway inhibitors, Axin (intracellular) or Dickkopf-1 (extracellular) blocked the regulation of VCAM-1 by diffusible Wnt3a. Interestingly, lipopolysaccharide restored a substantial degree of VCAM-1 expression, suggesting functional cross-talk between Wnt and TLR4 signaling pathways. Decreasing VCAM-1 on HSC-enriched Lin(-) Sca-1(+) c-Kit(Hi) Thy1.1(Lo) cells by exposure to Wnt3a did not prevent their successful transplantation. CONCLUSIONS: Our results suggest that cells comprising and residing in the HSC niche can respond to Wnt ligands and extinguish VCAM-1. This response may be important for export of hematopoietic cells. Given the known contribution of VCAM-1 to inflammation, this may represent a new avenue for therapeutic intervention.
OBJECTIVE: The Wnt family may contribute to hematopoietic stem cell (HSC) maintenance in bone marrow, but many questions remain concerning mechanisms. Vascular cell adhesion molecule-1 (VCAM-1) is expressed in cellular compartments of the bone marrow and might contribute to the HSC niche, but mechanisms concerning its constitutive expression are largely unknown. We now explore the influence of Wnt signaling on cellular adhesion molecule expression by bone marrow stromal and hematopoietic cells. MATERIALS AND METHODS: Recombinant Wnt ligands, retroviral Wnt transductions and cocultures with Wnt-secreting cells were used to analyze the effect of Wnt on adhesion molecule expression by stromal and hematopoietic cells. In vivo experiments were also done to assess the ability of Wnt3a-induced, VCAM-1 deficient hematopoietic cells to engraft bone marrow. RESULTS: We now report that the beta-catenin-dependent canonical Wnt signaling pathway negatively regulates VCAM-1 expression on two types of bone marrow cells. Wnt pathway inhibitors, Axin (intracellular) or Dickkopf-1 (extracellular) blocked the regulation of VCAM-1 by diffusible Wnt3a. Interestingly, lipopolysaccharide restored a substantial degree of VCAM-1 expression, suggesting functional cross-talk between Wnt and TLR4 signaling pathways. Decreasing VCAM-1 on HSC-enriched Lin(-) Sca-1(+) c-Kit(Hi) Thy1.1(Lo) cells by exposure to Wnt3a did not prevent their successful transplantation. CONCLUSIONS: Our results suggest that cells comprising and residing in the HSC niche can respond to Wnt ligands and extinguish VCAM-1. This response may be important for export of hematopoietic cells. Given the known contribution of VCAM-1 to inflammation, this may represent a new avenue for therapeutic intervention.
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