Abstract
The extracellular matrix polysaccharide hyaluronan (HA) plays a key role in both fibrotic and regenerative tissue repair. Accumulation of high molecular weight HA is typical of regenerative repair, which is associated with minimal inflammation and fibrosis, while fragmentation of HA is typical of postnatal wounds, which heal in the presence of inflammation and transient fibrosis. It is generally considered that HA oligosaccharides and fragments of a wide size range support these processes of adult, fibrotic wound repair yet the consequences of sized HA fragments/oligosaccharides to each repair stage is not well characterized. Here, we compared the effects of native HA, HA oligosaccharide mixtures and individual sizes (4–10mer oligosaccharides, 5 and, 40 kDa) of HA oligosaccharides and fragments, on fibroblast migration in scratch wound assays and on excisional skin wound repair in vivo. We confirm that 4–10mer mixtures significantly stimulated scratch wound repair and further report that only the 6 and 8mer oligosaccharides in this mixture are responsible for this effect. The HA 6mer promoted wound closure, accumulation of wound M1 and M2 macrophages and the M2 cytokine TGFβ1, but did not increase myofibroblast differentiation. The effect of 6mer HA on wound closure required both RHAMM and CD44 expression. In contrast, The 40 kDa HA fragment inhibited wound closure, increased the number of wound macrophages but had no effect on TGFβ1 accumulation or subsequent fibrosis. These results show that specific sizes of HA polymer have unique effects on postnatal wound repair. The ability of 6mer HA to promote wound closure and inflammation resolution without increased myofibroblast differentiation suggests that this HA oligosaccharide could be useful for treatment of delayed or inefficient wound repair where minimal fibrosis is advantageous.
Highlights
Rapid and efficient wound repair is crucial for infection prevention but can come at the expense of scar formation due to tissue fibrosis
Topical application of mixtures of 6–20mer HA fragments have been reported to augment the repair of full thickness excisional wounds by stimulating angiogenesis, lymph-angiogenesis and fibroplasia [19] [18]
This same mixture of HA fragments stimulate scratch wound induced migration of endothelial cells in culture suggesting that increased cell migration is at least partly responsible for the augmented angiogenesis observed in vivo [19]
Summary
Rapid and efficient wound repair is crucial for infection prevention but can come at the expense of scar formation due to tissue fibrosis. Fibrotic repair is a process characterized by inflammation, wound contraction, excessive accumulation and cross-linking of collagen and neo-angiogenesis. Mid-gestation fetal wounds heal by a ‘‘scarless’’ or regenerative type of repair in the absence of fibrosis [1,4], and this is characterized by an attenuated inflammatory response, increased Collagen III to Collagen I ratios, reduced TGFb 1 but increased TGFb 3 levels and, of relevance to the present study, increased and prolonged accumulation of high molecular weight (MWavg. million Da) hyaluronan (HA) but reduced HA fragmentation. HA fragmentation has been shown to stimulate key aspects of fibrotic wound repair including wound contraction, inflammation, neoangiogenesis, fibroplasia, myofibroblast differentiation and increased collagen production/crosslinking. High molecular weight native HA dampens the fibrotic process by attenuating inflammation and fibroplasia [1,10,11,12]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
