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

Abstract

We report that the bone marrow stroma-released LL-37, a member of the cathelicidin family of antimicrobial peptides, primes/increases 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 increases their i) adhesiveness, ii) SDF-1-mediated actin polymerization, and iii) MAPKp42/44 phosphorylation. Mice transplanted with bone marrow (BM) cells ex vivo primed by LL-37 showed accelerated recovery of platelet and neutrophil counts by ~3–5 days compared to mice transplanted with unprimed control cells. These priming effects were not mediated by LL-37 binding to its receptor and depended instead on 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 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.

Bioactive Lipids and Cationic Antimicrobial Peptides as New Potential Regulators for Trafficking of Bone Marrow-Derived Stem Cells in Patients with Acute Myocardial Infarction

“…The limited contribution of SDF-1 to myocardial regeneration may be explained by its active degradation at the sites of inflammation and myocardial infarction by metalloproteinases [33,35,36]. However, as recently demonstrated, despite SDF-1 degradation by proteases, the chemotactic responsiveness of HSCs to even low SDF-1 gradient could be significantly enhanced by members of the family of cationic antimicrobial peptides (CAMPs), including products of complement cascade (CC) activationanaphylatoxin C3a [37][38][39][40] and fibroblast-and leukocytederived-cathelicidin and b-2 defensin [41]. Thus, an increase in the level of CAMPs at sites of injury enhances the responsiveness of stem cells to even very low levels of SDF-1.…”

“…However, since infracted myocardium is enriched in proteolytic enzymes [eg, metalloproteinases-matrix metalloproteinases (MMPs)] [56] that degrade SDF-1 [35,36], its actual chemotactic gradient is usually low. As we have recently demonstrated, despite SDF-1 degradation by MMPs, the chemotactic responsiveness of stem cells to even low SDF-1 gradient could be significantly enhanced by members of the family of CAMPs, including products of CC activationanaphylatoxin C3a [57] and fibroblast-and leukocyte-derived cathelicidin and b-2 defensin [41]. Given the above data, we investigated the expression and potential role of CAMPs in homing of non-HSCs into infracted myocardium.…”

A novel view of paroxysmal nocturnal hemoglobinuria pathogenesis: more motile PNH hematopoietic stem/progenitor cells displace normal HSPCs from their niches in bone marrow due to defective adhesion, enhanced migration and mobilization in response to erythrocyte-released sphingosine-1 phosphate gradient

“…Next, because adhesion to fibronectin and SDF-1 is mediated by integrin and CXCR4 receptors, respectively, which are known as MLR-associated receptors, 3 we evaluated MLR formation on FLAER þ CD34 þ and FLAER À CD34 þ cells sorted from the PB of a PNH patient. In this assay, based on the fact that the antimicrobial cationic peptide cathelicidin (LL-37), which is secreted by BM stromal cells and granulocytes, enhances incorporation of CXCR4 into MLRs, 14 we exposed these cells to a low dose of SDF-1 þ LL-37 and performed confocal analysis of MLR formation. As demonstrated in Figure 1b, PNH-affected FLAER…”

Mouse Bone Marrow Sca-1 + CD44 + Mesenchymal Stem Cells Kill Avirulent Mycobacteria but Not Mycobacterium tuberculosis through Modulation of Cathelicidin Expression via the p38 Mitogen-Activated Protein Kinase-Dependent Pathway

“…In humans, cathelicidin, encoded by CAMP, is synthesized as a propeptide known as human cationic antimicrobial peptide 18 (hCAP-18), which is then cleaved extracellularly into cathelin and C-terminal LL-37, with the latter exhibiting broad antimicrobial activity (16). hCAP-18/LL-37 is produced mainly by phagocytic leukocytes and epithelial cells, but it is also expressed in bone marrow (17,18). Likewise, there is only one mouse gene encoding cathelicidin, Camp, which is highly homologous to the human gene.…”