Hyaluronic acid production and CD44 expression in cultured dermal fibroblasts of patients with non-insulin-dependent diabetes mellitus with and without chronic ulcers on the lower extremity

Abstract

It is well known that hyaluronic acid and its principal receptor, CD44, are implicated in the regulation of the tissue repair process, but their role in the formation of chronic diabetic ulcers has not been studied. Hyaluronic acid metabolism and CD44 expression are regulated by lactate, where their increased production is considered to affect the properties of fibroblasts in non-insulin-dependent diabetes mellitus. The aim of our work was to investigate the possible role of hyaluronic acid and CD44, and their regulation by lactate, in the abnormal wound healing of diabetes. Fibroblasts were derived from uninjured skin from four non-insulin-dependent diabetic patients with ulcers and four without ulcers; and from four healthy age-matched volunteers. We observed that diabetic fibroblasts of both groups produced more L-lactate ( approximately 30%) and incorporated more (3)H-glucosamine into the medium hyaluronic acid ( approximately 28%) than controls. Fibroblasts of the diabetic group with ulcers, unlike those of the group without ulcers, showed significant increases in the high molecular weight hyaluronic acid accumulation in the pericellular matrix (30.5%, p < 0.01) and CD44 expression (27.0%, p < 0.05). Exogenous L-lactate dose-dependently, and equally for all fibroblasts lines, stimulated the accumulation of medium hyaluronic acid (3.7-fold) and CD44 expression (1.5-fold). However, fibroblasts from diabetic patients with ulcers were more (1.4-fold) sensitive to L-lactate in terms of CD44 expression, and responded to L-lactate by the increased accumulation of high molecular weight hyaluronic acid in the pericellular matrix (32.1%, p < 0.01). We propose that specific properties of fibroblasts from diabetic patients with ulcers may be involved in the increased susceptibility of these patients to chronic ulceration.

Identification of marker genes in diabetic wounds by DNA microarray study

“…In particular, CD44 expression is upregulated in non-insulin-de- pendent diabetes mellitus, and the increased expression is considered to affect the properties of fibroblasts. Specific properties of fibroblasts may be involved in the increased susceptibility of patients with diabetes to chronic ulceration (Yevdokimova and Podpryatov, 2005). When considered with other research (Cha and Falanga, 2007;Schwarz et al, 2013), our study indicates that fibroblasts could potentially become a therapeutic cell population in diabetic wounds.…”

Rosiglitazone increases matrix production and quenches inflammation: studies in human cells

“…An obvious candidate is a 'glucose memory' effect, by which cells exposed to chronic hyperglycaemia in vivo carry over to the in vitro conditions upregulated pathways installed in the matrix via only partially known mechanisms [28]. An alternative, more specific possibility is that the increased accumulation of hyaluronic acid and the synergistic CD44 overexpression, described in human fibroblasts of T2D patients [29], could lead to enhanced fibronectin transcripts [30].…”

Hyaluronan in wound healing: Rediscovering a major player

“…A curious compensatory effect occurs in diabetes. Fibroblasts from wounds of diabetic patients produce 30% more lactate, and thus more HA, than wounds from age‐matched controls . Even fibroblasts from uninjured sites produce more lactate than controls.…”

“…Fibroblasts from wounds of diabetic patients produce 30% more lactate, and thus more HA, than wounds from age-matched controls. 103,104 Even fibroblasts from uninjured sites produce more lactate than controls. Fibroblasts from diabetic patients show higher levels of CD44 expression, greater sensitivity to lactate, and significant increases in HMW-HA.…”