Selective matrix (hyaluronan) interaction with CD44 and RhoGTPase signaling promotes keratinocyte functions and overcomes age-related epidermal dysfunction

Abstract

Background Mouse epidermal chronologic aging is closely associated with aberrant matrix (hyaluronan, HA) -size distribution/production and impaired keratinocyte proliferation/differentiation, leading to a marked thinning of the epidermis with functional consequence that causes a slower recovery of permeability barrier function. Objective The goal of this study is to demonstrate mechanism-based, corrective therapeutic strategies using topical applications of small HA (HAS) and/or large HA (HAL) [or a sequential small HA (HAS) and large HA(HAL) (HAs-»HAL) treatment] as well as RhoGTPase signaling perturbation agents to regulate HA/CD44-mediated signaling, thereby restoring normal epidermal function, and permeability barrier homeostasis in aged mouse skin. Methods A number of biochemical, cell biological/molecular, pharmacological and physiological approaches were used to investigate matrix HA-CD44-mediated RhoGTPase signaling in regulating epidermal functions and skin aging. Results In this study we demonstrated that topical application of small HA (HAS) promotes keratinocyte proliferation and increases skin thickness, while it fails to upregulate keratinocyte differentiation or permeability barrier repair in aged mouse skin. In contrast, large HA (HAL) induces only minimal changes in keratinocyte proliferation and skin thickness, but restores keratinocyte differentiation and improves permeability barrier function in aged epidermis. Since neither HAS nor HAL corrects these epidermal defects in aged CD44 knock-out mice, CD44 likely mediates HA-associated epidermal functions in aged mouse skin. Finally, blockade of Rho-kinase activity with Y27632 or protein kinase-Nγ activity with Ro31-8220 significantly decreased the HA (HAS or HAL)-mediated changes in epidermal function in aged mouse skin. Conclusion The results of our study show first that HA application of different sizes regulates epidermal proliferation, differentiation and barrier function in aged mouse skin. Second, manipulation of matrix (HA) interaction with CD44 and RhoGTPase signaling could provide further novel therapeutic approaches that could be targeted for the treatment of various aging-related skin disorders.

Glycosaminoglycan and proteoglycan in skin aging

“…Therefore, HA is recently used as a major component of skin fillers [24]. HA also reacts with cell membrane-associated HA receptors such as CD44, a receptor for hyaluronan-mediated motility (RHAMM), or lymphatic vessel endothelial receptor 1 (LYVE-1), to regulate cell proliferation, differentiation, and migration [14,25].…”

“…CS attachment occurs on constant exon 5, while HS attachment occurs on variant exon v3 [9]. Epidermal knockout of CD44 in mice or downregulation of CD44 in epidermal keratinocytes results in impaired cell growth, survival, migration, lipid synthesis, differentiation, and epidermal barrier function [25,27].…”

Specific Sizes of Hyaluronan Oligosaccharides Stimulate Fibroblast Migration and Excisional Wound Repair

“…For example, several reports in this understudied field identify ranges of polymer sizes that exhibit differential effects on wound repair. Intermediate sized HA fragments (100–300 kDa) promoted scratch wound closure by human keratinocytes while smaller fragments (5–20 kDa) did not [16], and 50–400 kDa but not <50 kDa HA fragments promoted keratinocyte proliferation and epidermal hyperplasia [17]. Moreover, a heterogeneous mixture of small HA oligosaccharides (4–20mers, 0.8–4 kDa) increased angiogenesis and repair of excisional wounds [18].…”

Intense Pulsed Light Increases Hyaluronan and CD44 in Epidermal Keratinocytes and Improves Age-Related Epidermal Structure Defects in Mice

“…Recently, age-dependent change in the metabolism of epidermal hyaluronan (HA) is suggested to be responsible for these epidermal dysfunctions by activating CD44 signaling. A decrease in epidermal HA has been found in aged human and murine skin23, and the application of HA restored permeability barrier structure and function in aged murine skin, suggesting a role in cutaneous aging2. Expression of CD44 and hyaluronan synthases (HAS) was also shown to be reduced in aged skin24.…”

“…A recent study demonstrated that large HA induces keratinocyte differentiation via Rac-PKNγ signaling, while small HA promotes keratinocyte proliferation via RhoA-ROK activation2. Further studies evaluating HA size distribution following IPL treatment and the biomolecular mechanism of IPL treatment on epidermal HA metabolism are needed.…”