title: Specific sizes of hyaluronan oligosaccharides stimulate fibroblast migration and excisional wound repair.
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 (4-10 mer 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 4-10 mer mixtures significantly stimulated scratch wound repair and further report that only the 6 and 8 mer oligosaccharides in this mixture are responsible for this effect. The HA 6 mer promoted wound closure, accumulation of wound M1 and M2 macrophages and the M2 cytokine TGFβ1, but did not increase myofibroblast differentiation. The effect of 6 mer 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 6 mer 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.
authors.affiliation: London Regional Cancer Program, London Health Sciences Center, Victoria Hospital, London, Ontario, Canada.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Tolg
authors.affiliation: London Regional Cancer Program, London Health Sciences Center, Victoria Hospital, London, Ontario, Canada.
authors.forename: Patrick
authors.initials: P
authors.lastname: Telmer
authors.affiliation: London Regional Cancer Program, London Health Sciences Center, Victoria Hospital, London, Ontario, Canada ; Departments of Oncology, Biochemistry and Surgery, Schulich School of Medicine and Dentistry, Western University London, London, Ontario, Canada.
authors.forename: Eva
authors.initials: E
authors.lastname: Turley
mesh_terms: D000818:Animals; D002465:Cell Movement; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D006820:Hyaluronic Acid / Q000494:pharmacology*; D007249:Inflammation / Q000517:prevention & control; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008970:Molecular Weight; D009844:Oligosaccharides / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000187:drug effects* / Q000293:injuries; D013329:Structure-Activity Relationship; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects* / Q000502:physiology
chemical_list: D016326:Extracellular Matrix Proteins; D018960:Hyaluronan Receptors; D009844:Oligosaccharides; D053773:Transforming Growth Factor beta1; C098946:hyaluronan-mediated motility receptor; D006820:Hyaluronic Acid