Clinically intractable infertility and recurrent miscarriage due to irreversible endometrial
damage need to be treated with biomaterial- and cell-based therapies. Some previous
studies have reported on the efficacy of a collagen scaffold and/or bone marrow-derived
mesenchymal stem cells. However, the functional differentiation of grafted cells was
uncertain, and the time required for regeneration was long in these studies. Here,
we show the synergistic regenerative effects of hyaluronic acid (HA) hydrogel with
in vitro decidualized endometrial stromal cells (EMSCs) in a murine uterine infertility
(synechiae) model. Decidualized EMSCs (dEMSCs) were encapsulated with HA hydrogel,
combined with three different doses of fibrinogen/thrombin (5, 50, and 500 mIU/mL).
The HA/fibrin gel showed biocompatibility when mixed with dEMSCs. The addition of
thrombin enhanced gel formation (5 and 50 mIU/mL) and engraftment and enabled the
effective release of adhesion molecules. Within two weeks, which is a short duration,
treatment with hydrogel decreased the fibrous tissue and increased the thickness of
the endometrium. The regenerated endometrium demonstrated functional recovery, as
evidenced by the expression and secretion of molecules essential for embryonic implantation,
such as Desmin, CD44, PECAM, and IGF-1. Transferred embryos successfully implanted
and the normal development of implanted embryos (n = 37) were evaluated by co-localization
of distinct markers of the three germ layers (Sox2, Nestin, Brachyury, AFP, and HNF4α).
Live birth of offspring was achieved in the regenerated endometrium by HA hydrogel.
Therefore, HA hydrogel-mixed dEMSCs can be an innovative treatment strategy with rapid
recovery of endometrial damage and may also have therapeutic potential in intractable
infertility or recurrent miscarriage. STATEMENT OF SIGNIFICANCE: Decidualized EMSCs
(dEMSCs) encapsulated with HA hydrogel combined with fibrinogen/thrombin (50 mIU/mL)
showed injectability and biocompatibility when mixed with dEMSCs. Hydrogel-encapsulated
dEMSCs can be a useful treatment for damaged endometrium in short duration, with successful
implantation and normal development in a murine model.