Hyaluronan and cardiac regeneration

Abstract

Hyaluronan (HA) is abundantly expressed in several human tissues and a variety of roles for HA has been highlighted. Particularly relevant for tissue repair, HA is actively produced during tissue injury, as widely evidenced in wound healing investigations. In the heart HA is involved in physiological functions, such as cardiac development during embryogenesis, and in pathological conditions including atherosclerosis and myocardial infarction. Moreover, owing to its relevant biological properties, HA has been widely used as a biomaterial for heart regeneration after a myocardial infarction. Indeed, HA and its derivatives are biodegradable and biocompatible, promote faster healing of injured tissues, and support cells in relevant processes including survival, proliferation, and differentiation. Injectable HA-based therapies for cardiovascular disease are gaining growing attention because of the benefits obtained in preclinical models of myocardial infarction. HA-based hydrogels, especially as a vehicle for stem cells, have been demonstrated to improve the process of cardiac repair by stimulating angiogenesis, reducing inflammation, and supporting local and grafted cells in their reparative functions. Solid-state HA-based scaffolds have been also investigated to produce constructs hosting mesenchymal stem cells or endothelial progenitor cells to be transplanted onto the infarcted surface of the heart. Finally, applying an ex-vivo mechanical stretching, stem cells grown in HA-based 3D scaffolds can further increase extracellular matrix production and proneness to differentiate into muscle phenotypes, thus suggesting a potential strategy to create a suitable engineered myocardial tissue for cardiac regeneration.

Figure 1

Schematic model showing the possible receptor-mediated signal transduction pathways through which HA of different molecular weights can modulate cell functions. High molecular weight-HA (HMW) and low molecular weight-HA (LMW) differently modulate receptor-mediated cell functions. Endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) interacting with LMW can promote angiogenesis via CD44 and RHAMM transduction signaling leading to increased cell migration, cell proliferation, and tube formation. Inflammatory cells (ICs), such as monocytes/macrophages and dendritic cells, are stimulated by LMW through Toll-like receptor-2 and Toll-like receptor-4 (TLR-2, TLR-4) that promote cell migration, recruitment, and homing in damaged tissues. LMW, through CD44 and growth factors receptors (GFsR), can also induce fibroblasts and myofibroblasts (MFs) to proliferate and generate a fibrotic scar. ERM (ezrin, radixin, and moesin) protein family/merlin system seems to be largely involved in the interplay between LMW and GFs. Specifically, a non-yet identified GF-stimulated protein kinase (PK) phosphorylates ERM and promotes its migration from the cytoplasm to CD44 with consequent re-arrangement of cytoskeletal proteins that leads to cyclin D1 overexpression and increased cell proliferation. HMW exerts opposite effects, due to its antiangiogenic and antifibrotic action, at least through the activation of a CD44-dependent protein phosphatase (PP). It has been hypothesized that HMW can induce the formation of HA-receptor clusters whose signal transduction pathways are different from those stimulated by single and separated HA-receptors interacting with LMW. HMW is also involved in cell survival through the stimulation of PI3K/Akt downstream of CD44.

Figure 2

HA structure and sites of modification. The disaccharide repeat units of HA are shown with the primary sites for chemical modifications generally used for tissue engineering applications. The hydroxyl groups of HA form covalent linkages such as ether, esters, and hemiacetal bonds. The carboxyl groups can form ether, anhydride, and carbamide bonds, while Schiff bases can originate from HA dialdehyde reacting with amino groups. Some HA adducts commonly employed in regenerative medicine are also shown.

Figure 3

Potential effects of HA-based scaffolds and conveyed stem/progenitor cells on cardiac regeneration after MI. HA-based biomaterial can be injected as a hydrogel or grafted as a solid mesh providing improvements in left ventricular (LV) structure and functions. Delivered stem/progenitor cells and/or released growth factors can further increase regeneration efficacy by promoting cell survival, reducing inflammatory reaction, increasing neoangiogenesis, and favoring resident or transplanted cell differentiation.