Annexin-2 Is a Regulator of Stromal Cell-Derived factor-1/CXCL12 Function in the Hematopoietic Stem Cell Endosteal Niche

Exp Hematol. 2011 Feb;39(2):151-166.e1. doi: 10.1016/j.exphem.2010.11.007. Epub 2010 Nov 22.

Abstract

Objective: Previously, we reported that annexin-2 (anxa2) plays an important role in hematopoietic stem cell (HSC) localization to the endosteal/osteoblastic marrow niche. This study explored the role that annexin-2 plays in presenting stromal cell-derived factor-1 (or CXCL12) to HSCs.

Materials and methods: Competitive long-term bone marrow transplant assays were used to determine if HSC engraftment is altered in annexin-2-deficient animals. Colony-forming cell assays, CXCL12 enzyme-linked immunosorbent assay, and real-time reverse transcription polymerase chain reaction analyses were used to determine stem or progenitor cell mobilization by granulocyte colony-stimulating factor. Immunohistochemistry, immunoprecipitation, binding assays, and chemotactic assays were employed to determine if annexin-2 is associated with CXCL12. Degradation assays were also used to determine if annexin-2 and CXCL12 protect each other from proteolytic degradation.

Results: Anxa2(-/-) animals had fewer HSCs in their marrow, and the HSCs in anxa2(-/-) animals express less CXCR4 and CXCR7, suggesting a cell intrinsic defect. Transplantation studies of wild-type marrow into anxa2(-/-) animals demonstrated a cell-extrinsic defect in the anxa2(-/-) animals. CXCL12 binds directly to annexin-2, and this interaction facilitates presentation of CXCL12 to HSCs. Yet the binding of CXCL12 to annexin-2 did not protect CXCL12 from proteolytic cleavage after stem or progenitor cell mobilization by granulocyte colony-stimulating factor.

Conclusions: These results suggest that annexin-2 serves as an anchor for CXCL12 to help in the localization of HSCs to the niche.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Annexin A2 / deficiency
  • Annexin A2 / genetics
  • Annexin A2 / metabolism*
  • Chemokine CXCL12 / metabolism*
  • Gene Expression Regulation
  • Hematopoietic Stem Cells / metabolism*
  • Immunohistochemistry
  • Mice
  • Mice, Knockout
  • Protein Binding
  • Stem Cell Niche / metabolism*

Substances

  • Annexin A2
  • Chemokine CXCL12