CD44, Hyaluronan, the Hematopoietic Stem Cell, and Leukemia-Initiating Cells

Abstract

CD44 is an adhesion molecule that varies in size due to glycosylation and insertion of so-called variant exon products. The CD44 standard isoform (CD44s) is highly expressed in many cells and most abundantly in cells of the hematopoietic system, whereas expression of CD44 variant isoforms (CD44v) is more restricted. CD44s and CD44v are known as stem cell markers, first described for hematopoietic stem cells and later on confirmed for cancer- and leukemia-initiating cells. Importantly, both abundantly expressed CD44s as well as CD44v actively contribute to the maintenance of stem cell features, like generating and embedding in a niche, homing into the niche, maintenance of quiescence, and relative apoptosis resistance. This is surprising, as CD44 is not a master stem cell gene. I here will discuss that the functional contribution of CD44 relies on its particular communication skills with neighboring molecules, adjacent cells and, last not least, the surrounding matrix. In fact, it is the interaction of the hyaluronan receptor CD44 with its prime ligand, which strongly assists stem cells to fulfill their special and demanding tasks. Recent fundamental progress in support of this “old” hypothesis, which may soon pave the way for most promising new therapeutics, is presented for both hematopoietic stem cell and leukemia-initiating cell. The contribution of CD44 to the generation of a stem cell niche, to homing of stem cells in their niche, to stem cell quiescence and apoptosis resistance will be in focus.

Loss of CD44dim Expression from Early Progenitor Cells Marks T-Cell Lineage Commitment in the Human Thymus

“…This suggests conservation of a functional role for CD44 in uncommitted thymocytes. CD44 is an glycosylated adhesion and migration molecule with several isoforms due to alternatively spliced exons in the extracellular domain (33). The standard CD44 isoform (CD44s) is expressed on hematopoietic (stem) cells (as well as many other cell types) and is required for HSC niche formation and quiescence during early hematopoietic development.…”

“…In many other cancer types and leukemias, CD44 has gained clinical interest because CD44s and variant isoforms (CD44v) feature “stemness” potential. Currently, multiple anti-CD44-based therapeutic approaches are investigated for their ability to target leukemia- or cancer-initiating cells (LIC/CIC) with this “stemness” potential (33). …”

The role of CD44 in fetal and adult hematopoietic stem cell regulation

“…24 In addition, adult BM cells with colony-forming-unit granulocytes-macrophage and burst-forming unit-erythroid are H. Cao et al 32 haematologica | 2016; 101(1) Figure 6. CD44 on adult BM LSK cells has a functional role in supporting stem and progenitor engraftment.…”

Hyaluronan as a therapeutic target in human diseases

“…In addition, CD44 may have a role in regulating stem cell functions. A recent review suggests that although CD44 is not a master stem cell gene, CD44 contributes to the generation of a stem cell niche and homing of stem cells in their niche [166]. HA is required for the regulation of the hematopoiesis-supportive function of bone marrow accessory cells and participates in hematopoietic niche assembly [167].…”