Densification: Hyaluronan Aggregation in Different Human Organs

Abstract

Hyaluronan (HA) has complex biological roles that have catalyzed clinical interest in several fields of medicine. In this narrative review, we provide an overview of HA aggregation, also called densification, in human organs. The literature suggests that HA aggregation can occur in the liver, eye, lung, kidney, blood vessel, muscle, fascia, skin, pancreatic cancer and malignant melanoma. In all these organs, aggregation of HA leads to an increase in extracellular matrix viscosity, causing stiffness and organ dysfunction. Fibrosis, in some of these organs, may also occur as a direct consequence of densification in the long term. Specific imaging evaluation, such dynamic ultrasonography, elasto-sonography, elasto-MRI and T1ρ MRI can permit early diagnosis to enable the clinician to organize the treatment plan and avoid further progression of the pathology and dysfunction.

Evidence of Renin–Angiotensin System Receptors in Deep Fascia: A Role in Extracellular Matrix Remodeling and Fibrogenesis?

“…Ang II through AT1R could promote the fascial remodeling of these elements and fibrinogenesis up to fibrosis. Indeed, the latter, as reported by Stecco et al, in some organs and tissues as fasciae, may occur as a direct consequence of HA densification in the long term [ 15 ]. Moreover, Schleip et al [ 1 ] observed that the density of fascial myofibroblasts (MFBs) in human lumbar fascia could be associated with an augmented occurrence of (micro)injuries and related repair processes in the TLF.…”

“…Although recent studies showed that fascial fibroblasts are sensitive to different stimuli, from biochemical [ 12 , 13 ] to biophysical [ 14 ], promoting ECM remodeling, as well as synthetic activity (collagen fibers of type I and III, and hyaluronan). Stecco et al [ 15 ] suggested that fibrosis may occur in different organs as a long-term consequence of hyaluronan densification due to excessive collagen fiber deposition and consequent ECM remodeling, and this mechanism was also found in the deep fascia [ 15 ].…”

Pathophysiological and Therapeutic Roles of Fascial Hyaluronan in Obesity-Related Myofascial Disease

“…RHAMM is a centrosome- and microtubule-associated protein that is highly expressed before and during mitosis and hence prominent in neoplastic and other hyperproliferative tissues [ 24 ]. Besides the widely distributed CD44, hyaluronan fragments may also activate RHAMM, LYVE-1 (lymphatic vessel endothelial hyaluronan receptor), HARE (hyaluronan-receptor for endocytosis), ICAM-1 (intercellular adhesion molecule 1), layilin, Toll-like receptor 4, and other cell surface receptors which modulate gene expression via signaling pathways [ 23 , 25 ]. Accordingly, hyaluronan binding is critical for morphogenesis, matrix organization, wound repair/regeneration, inflammation, and metastasis [ 23 ].…”

“…It was shown that hyaluronan degradation occurs at pH < 4 and pH > 11 [ 111 ]. Alterations in hyaluronan function may result from the effects of van der Waals and hydrophobic forces on its concentration, polyelectrolyte properties, and aggregation characteristics [ 25 , 108 ]. Hyaluronan takes on non-Newtonian characteristics and becomes more viscous at higher concentrations [ 112 ].…”

“…While fascial densification and fibrosis describe alterations in the fascia resulting in myofascial pain syndromes, it is important to differentiate both processes as they have distinct pathological and therapeutic implications. Densification indicates a potentially easily reversible modification in the loose connective tissue due to hyaluronan super-aggregation with a decreased water-binding capacity resulting in altered mechanical characteristics of the fascia but not its overall structure, whereas fibrosis refers to a difficult-to-reverse modification of the general tissue structure and mechanical properties from the excessive deposition of fibrous connective tissue as part of a reparative or reactive response [ 25 , 116 ]. The loose connective tissue found within the deep fascia can be altered by diet, exercise, and overuse syndromes, resulting in fascial densification, whereas trauma, surgery, and diabetes can modify the fibrous layers of the deep fasciae, resulting in fibrosis of the fascia [ 116 ].…”