Hyaluronan in the healthy and malignant hematopoietic microenvironment

The fate of both endogenous and transplanted stem cells is dependent on the functional status of the regulatory local microenvironment, which is compromised by disease and therapeutic intervention. The glycosaminoglycan hyaluronan (HA) is a critical component of the hematopoietic microenvironment. We summarize recent advances in our understanding of the role of HA in regulating mesenchymal stem cells, osteoblasts, fibroblasts, macrophages, and endothelium in bone marrow (BM) and their crosstalk within the hematopoietic microenvironment. HA not only determines the volume, hydration, and microfluidics of the BM interstitial space, but also, via interactions with specific receptors, regulates multiple cell functions including differentiation, migration, and production of regulatory factors. The effects of HA are dependent on the polymer size and are influenced by the formation of complexes with other molecules. In healthy BM, HA synthases and hyaluronidases form a molecular network that maintains extracellular HA levels within a discrete physiological window, but HA homeostasis is often perturbed in pathological conditions, including hematological malignancies. Recent studies have suggested that HA synthases may have functions beyond HA production and contribute to the intracellular regulatory machinery. We discuss a possible role for HA synthases, intracellular and extracellular HA in the malignant BM microenvironment, and resistance to therapy.