CD44-mediated hyaluronan binding marks proliferating hematopoietic progenitor cells and promotes bone marrow engraftment

PLoS One. 2018 Apr 23;13(4):e0196011. doi: 10.1371/journal.pone.0196011. eCollection 2018.


CD44 is a widely expressed cell adhesion molecule that binds to the extracellular matrix component, hyaluronan. However, this interaction is not constitutive in most immune cells at steady state, as the ability of CD44 to engage hyaluronan is highly regulated. While activated T cells and macrophages gain the ability to bind hyaluronan by CD44, the status in other immune cells is less studied. Here we found a percentage of murine eosinophils, natural killer and natural killer T cells were capable of interacting with hyaluronan at steady state. To further investigate the consequences of hyaluronan binding by CD44 in the hematopoietic system, point mutations of CD44 that either cannot bind hyaluronan (LOF-CD44) or have an increased affinity for hyaluronan (GOF-CD44) were expressed in CD44-deficient bone marrow. Competitive bone marrow reconstitution of irradiated mice revealed an early preference for GOF-CD44 over WT-CD44 expressing cells, and for WT-CD44 over LOF-CD44 expressing cells, in the hematopoietic progenitor cell compartment. The advantage of the hyaluronan-binding cells was observed in the hematopoietic stem and progenitor populations, and was maintained throughout the immune system. Hematopoietic stem cells bound minimal hyaluronan at steady state, and this was increased when the cells were induced to proliferate whereas multipotent progenitors had an increased ability to bind hyaluronan at steady state. In vitro, the addition of hyaluronan promoted their proliferation. Thus, proliferating hematopoietic progenitors bind hyaluronan, and hyaluronan binding cells have a striking competitive advantage in bone marrow engraftment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Transplantation
  • Cell Proliferation
  • Eosinophils / metabolism
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / metabolism
  • Hematopoietic Stem Cells / radiation effects
  • Hyaluronan Receptors / genetics*
  • Hyaluronan Receptors / metabolism*
  • Hyaluronic Acid / metabolism*
  • Killer Cells, Natural / metabolism
  • Mice
  • Mutation
  • Protein Binding


  • Cd44 protein, mouse
  • Hyaluronan Receptors
  • Hyaluronic Acid

Grant support

This work was supported by the Canadian Institute of Health Research (MOP 119503) to P.J., the Natural Sciences and Engineering Research Council of Canada (NSERC) to P.J., and the Galloway Leukemia Research Seed Funding to C.A.M. S.S.M.L. was supported by scholarships from NSERC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.