The biology of CD44 and HCELL in hematopoiesis: the 'step 2-bypass pathway' and other emerging perspectives

Abstract

Purpose of review: The homing and egress of hematopoietic stem and progenitor cells (HSPCs) to and from marrow, respectively, and the proliferation and differentiation of HSPCs within marrow are complex processes critically regulated by the ordered expression and function of adhesion molecules that direct key cell-cell and cell-matrix interactions. The integral membrane molecule CD44, known primarily for its role in binding hyaluronic acid, is characteristically expressed on HSPCs. Conspicuously, human HSPCs uniquely display a specialized glycoform of CD44 known as hematopoietic cell E-/L-selectin ligand (HCELL), which is the most potent ligand for both E-selectin and L-selectin expressed on human cells. This review focuses on recent advances in our understanding of the biology of CD44 and HCELL in hematopoiesis.

Recent findings: New data indicate that CD44-mediated events in hematopoiesis are more complex than previously imagined. Ex-vivo glycan engineering has established that HCELL serves as a 'bone marrow homing receptor'. Moreover, biochemical studies now show that CD44 forms bimolecular complexes with a variety of membrane proteins, one of which is VLA-4. Engagement of CD44 or of HCELL directly induces VLA-4 activation via G-protein-dependent signaling, triggering a 'step 2-bypass pathway' of cell migration, and extravascular lodgment, in absence of chemokine receptor engagement.

Summary: Recent studies have further clarified the roles of CD44 and its glycoform HCELL in hematopoietic processes, providing key insights on how targeting these molecules may be beneficial in promoting hematopoiesis and in treating hematologic malignancies.

FIGURE 1. Schematic representation of CD44 gene structure in mouse and man

The CD44 gene is located on chromosome 2 in humans and 11 in mice. The red X shown in variant exon 1 (V1) designates the absence of a functional V1 product in humans due to the presence of an in-frame stop codon. Parentheses below blocks show usual numbering of CD44 exons; for clarity, exons here are depicted as members of two groups: Standard (S) and Variant (V). See text for details.

FIGURE 2. The Canonical Multistep Paradigm of Cell Migration

Schematic representation of the multiple steps in cell migration from vascular to extravascular compartments. Step 2 integrin activation via chemokine receptor/ligand interactions confers selectivity in cell recruitment, depending on the relevant chemokine(s) present in the target endothelial bed and the chemokine receptor(s) expressed by circulating cell(s). Depicted here is the conventional view of cellular homing to marrow: Following initial tethering/rolling contact of blood-borne cell on the endothelium (Step 1), chemokine receptor CXCR4 binds to its cognate ligand CXCL1 (SDF-1), thereby triggering G-protein-coupled VLA-4 activation (Step 2), with subsequent firm adhesion (Step 3) and transmigration (Step 4).

FIGURE 3. The Step 2-bypass Pathway of Cell Migration

Schematic representation of steps in cell migration for blood-borne cells expressing HCELL together with VLA-4, encountering endothelial beds expressing E-selectin and VCAM-1. Note that compared to canonical pathway (see Figure 2), VLA-4 activation (Step 2) occurs via G-protein-mediated mechanosignalling primed by HCELL binding to E-selectin (and/or activated CD44 binding to endothelial HA), bypassing the need for chemokine input.