The bone marrow-expressed antimicrobial cationic peptide LL-37 enhances the responsiveness of hematopoietic stem progenitor cells to an SDF-1 gradient and accelerates their engraftment after transplantation

Leukemia. 2012 Apr;26(4):736-45. doi: 10.1038/leu.2011.252. Epub 2011 Sep 20.

Abstract

We report that the bone marrow (BM) stroma-released LL-37, a member of the cathelicidin family of antimicrobial peptides, primes/increases the responsiveness of murine and human hematopoietic stem/progenitor cells (HSPCs) to an α-chemokine stromal-derived factor-1 (SDF-1) gradient. Accordingly, LL-37 is upregulated in irradiated BM cells and enhances the chemotactic responsiveness of hematopoietic progenitors from all lineages to a low physiological SDF-1 gradient as well as increasing their (i) adhesiveness, (ii) SDF-1-mediated actin polymerization and (iii) MAPK(p42/44) phosphorylation. Mice transplanted with BM cells ex vivo primed by LL-37 showed accelerated recovery of platelet and neutrophil counts by ∼3-5 days compared with mice transplanted with unprimed control cells. These priming effects were not mediated by LL-37 binding to its receptor and depended instead on the incorporation of the CXCR4 receptor into membrane lipid rafts. We propose that LL-37, which has primarily antimicrobial functions and is harmless to mammalian cells, could be clinically applied to accelerate engraftment as an ex vivo priming agent for transplanted human HSPCs. This novel approach would be particularly important in cord blood transplantations, where the number of HSCs available is usually limited.

Publication types

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

MeSH terms

  • Animals
  • Antimicrobial Cationic Peptides / pharmacology*
  • Chemokine CXCL12 / physiology*
  • Chemotaxis
  • Complement C5a / physiology
  • Female
  • Hematopoietic Stem Cell Transplantation*
  • Hematopoietic Stem Cells / drug effects*
  • Membrane Microdomains / physiology
  • Mice
  • Mice, Inbred C57BL
  • Receptors, CXCR4 / physiology
  • Receptors, Cell Surface / physiology
  • Receptors, Formyl Peptide / physiology

Substances

  • Antimicrobial Cationic Peptides
  • CXCR4 protein, mouse
  • Chemokine CXCL12
  • Cxcl12 protein, mouse
  • Receptors, CXCR4
  • Receptors, Cell Surface
  • Receptors, Formyl Peptide
  • formyl peptide receptor 2, mouse
  • ropocamptide
  • Complement C5a