How does hyaluronan promote implantation?

The mechanism involved in the embryo implantation promotion effect of hyaluronan has yet to be clarified. However, there are several possible means by which hyaluronan could facilitate embryo implantation.

Benefits of HA in embryo implantation

Improve cell-cell and cell-matrix adhesion
Degradation products of hyaluronan improve implantation
Rapid physical diffusion with uterine secretion
Receptor mediated biological function

Improve cell-cell and cell-matrix adhesion

Hyaluronan has been shown to increase cell-cell adhesion and cell-matrix adhesion (Turley and Moore 1984) thereby functioning during the initial stages of apposition and attachment of the blastocyst and endometrium.

Degradation products of hyaluronan improve implantation

Hyaluronan can promote angiogenesis by both its degradation products (West et al, 1985) and by interaction with epidermal growth factor EGF (Sato et al, 1991). The latter point is of particular interest in relation to the stimulatory effect of EGF on implantation in the mouse (Paria et al, 1991).

Rapid physical diffusion with uterine secretion

Hyaluronan may facilitate rapid diffusion of the contents of the transfer medium into the viscous secretion of the uterus. An aqueous medium containing an appropriate concentration of hyaluronan represents far higher viscosity in comparison to a solution only containing proteins (Stojkovic et al, 2002).

However, it is noteworthy that the preimplantation embryos do not float in a bath of maternal secretion, but are tightly surrounded by the maternal endometrium according to the ultrasound investigation (Herrler et al, 2003). Even so, the similarity in the physical properties of the transfer medium and the thin uterine secretion on the surface of epithelium could effectively facilitate the dispersal of embryo into the luminal environment.

Not all high viscosity solutions can improve the implantation

Not all high viscosity solutions can improve the implantation. It was demonstrated by Menezo at al (1989) that human placental collagen added to increase the viscosity of the transfer medium does not improve pregnancy rates after human embryo replacement. Considering the implantation promoting effect of hyaluronan in both human and mouse and the increased hyaluronan synthesis but not the synthesis of other types of glucosaminoglycans in the uterus, it is concluded that hyaluronan plays a specific role in embryo implantation.

Water binding capacity of hyaluronan and implantation

It has been reported that hyaluronan functions to retain water in other tissues and enhances tissue invasion processes (Toole et al, 1979). Consistent with this notion is the classical observation that increased fluid uptake is characteristic of early stages of implantation (Psychoyos, 1973). These observations indicate that the water binding capacity of hyaluronan is probably also closely associated with the embryo implantation process.

Receptor mediated biological function

The cell-surface adhesion glycoprotein CD44 molecule, the hyaluronan receptor, is present both in human (Campbell et al, 1995) and bovine models (Valcarcel et al, 1999). The CD 44 is also expressed in human endometrium and decidua (Bhzad et al, 1994), and the expression is exclusively at the mid to late secretary phase, indicating the involvement of this molecule in implantation process (Yaegashi et al, 1995). The RHAMM/IHABP, another type of receptor for hyaluronan is also expressed on the embryo at the preimplantation stage with the highest level at the expanded blastocyst stage (Stojkovic et al 2003). These data indicate that the various functions of hyaluronan including the implantation promoting effect can be receptor mediated.

It is concluded that the implantation promoting effect of hyaluronan is possibly associated with several, if not all, mechanisms as described.