CD82/KAI1 Maintains the Dormancy of Long-Term Hematopoietic Stem Cells through Interaction with DARC-Expressing Macrophages

Cell Stem Cell. 2016 Apr 7;18(4):508-21. doi: 10.1016/j.stem.2016.01.013. Epub 2016 Mar 17.

Abstract

Hematopoiesis is regulated by crosstalk between long-term repopulating hematopoietic stem cells (LT-HSCs) and supporting niche cells in the bone marrow (BM). Here, we examine the role of CD82/KAI1 in niche-mediated LT-HSC maintenance. We found that CD82/KAI1 is expressed predominantly on LT-HSCs and rarely on other hematopoietic stem-progenitor cells (HSPCs). In Cd82(-/-) mice, LT-HSCs were selectively lost as they exited from quiescence and differentiated. Mechanistically, CD82-based TGF-β1/Smad3 signaling leads to induction of CDK inhibitors and cell-cycle inhibition. The CD82 binding partner DARC/CD234 is expressed on macrophages and stabilizes CD82 on LT-HSCs, promoting their quiescence. When DARC(+) BM macrophages were ablated, the level of surface CD82 on LT-HSCs decreased, leading to cell-cycle entry, proliferation, and differentiation. A similar interaction appears to be relevant for human HSPCs. Thus, CD82 is a functional surface marker of LT-HSCs that maintains quiescence through interaction with DARC-expressing macrophages in the BM stem cell niche.

Keywords: CD82/KAI1; DARC/CD234; LT-HSCs; bone marrow; macrophage; quiescence; stem cell niche; tetraspanin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Duffy Blood-Group System / metabolism*
  • Female
  • Hematopoietic Stem Cells / metabolism*
  • Humans
  • Kangai-1 Protein / biosynthesis
  • Kangai-1 Protein / deficiency
  • Kangai-1 Protein / metabolism*
  • Macrophages / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Receptors, Cell Surface / metabolism*

Substances

  • Cd82 antigen, mouse
  • Dfy protein, mouse
  • Duffy Blood-Group System
  • Kangai-1 Protein
  • Receptors, Cell Surface