Keratinocyte Migration, Proliferation, and Differentiation in Chronic Ulcers From Patients With Diabetes and Normal Wounds

Abstract

Epithelialization of normal acute wounds occurs by an orderly series of events whereby keratinocytes migrate, proliferate, and differentiate to restore barrier function. The keratinocytes in the epidermis of chronic ulcers fail to execute this series of events. To better understand the epithelial dynamics of chronic ulcers, we used immunohistochemistry to evaluate proliferation, differentiation, adhesion, and migration in keratinocytes along the margin of chronic ulcers from patients with diabetes mellitus. We compared these features with keratinocytes from the migrating epithelial tongues of acute incisional and excisional wounds from normal volunteers. Keratinocytes at the chronic ulcer edge are highly proliferative (Ki67 proliferation marker), have an activated phenotype (K16), do not stain for keratins involved in epidermal differentiation (K10 and K2), and show a reduced expression of LM-3A32 (uncleaved, precursor of the alpha3 chain of laminin 5), a key molecule present on migrating epithelium. In contrast, keratinocytes in normal acute wound migrating epithelium do not express the proliferation marker Ki67 but do express K10, K2, and LM-3A32. A better understanding of molecular mechanisms involved in keratinocyte migration may lead to molecular targets for therapies for impaired wound healing.

FGF receptors 1 and 2 are key regulators of keratinocyte migration in vitro and in wounded skin

“…This phenotype is characterized by severely impaired reepithelialization combined with reduced wound contraction (Usui et al, 2008). The latter effect is obviously indirect in the K5-R1/R2 mice, because the loss of FGFR1 and FGFR2 occurred specifically in keratinocytes and not in cells of the dermis/ granulation tissue.…”

Alternative method of treating prolonged wound defects of trunk and extremities

“…In most cases, they were characterized by the formation of a thick, hyperproliferative epidermis containing mitotic active cells not only in the basal but also in the supra-basal layers, which according to some literature data is the result of activation and excessive expression of c-myc [9]. Furthermore, the other differences were found -the presence of hyperkeratosis (thick corneal layer) and parakeratosis (the presence of nuclei in the corneal layer), which can give evidence of the incomplete differentiation of keratinocytes and often characterizes the epidermis of chronic ulcers [7]. It is known that induction of c-myc and suppression of K6/K16 can lead to inhibition of keratinocytes migration in human skin, which contributes to the incomplete activation of keratinocytes and possibly the development of chronic wounds [8,9].…”

FOXO1 differentially regulates both normal and diabetic wound healing

“…Reduced keratinocyte migration is an important factor in impaired reepithelialization of chronic and diabetic healing (Stojadinovic et al, 2005;Lan et al, 2008;Usui et al, 2008;Jacobsen et al, 2010). We identified two distinct mechanisms through which FOXO1 affects keratinocyte migration, both of which are affected by diabetes in vivo and by high levels of glucose, an AGE, or TNF in vitro.…”