Systemic administration of bone marrow-derived cells leads to better uterine engraftment than use of uterine-derived cells or local injection

Abstract

Stem cells are recruited to the uterus where they differentiate into endometrial cells and have been suggested as potential therapy for uterine injury such as Asherman's syndrome. However, it is unknown whether local intrauterine injection may result in better stem cell engraftment of the uterus compared with systemic administration, and whether uterine-derived cells (UDCs) may confer an advantage over BM-derived cells (BMDCs). Mice underwent local injury to a single uterine horn. Green fluorescent protein (GFP)-expressing BMDCs, UDCs or saline (control) were injected either intravenously or locally (uterine lumen) into wild-type recipients. Two or 3 weeks post-transplant, uterine tissues were collected for fluorescence-activated cell sorting (FACS) and immunohistochemistry/immunofluorescence studies. Mice injected intravenously with BMDCs or UDCs had increased GFP+ cells recruitment to the non-injured or injured uterus compared to those injected locally. No significant differences were noted in GFP+ cell recruitment to the injured versus non-injured horn. In addition, systemic injection of BMDCs led to greater recruitment of GFP+ cells at 2 weeks and 3 weeks compared with UDCs. Immunohistochemical staining demonstrated that GFP+ cells were found in stroma but not in epithelium or blood vessels. Immunofluorescence analysis revealed that GFP+ cells were mostly CD45-negative, and negative for CD31 and cytokeratin, confirming their stromal identity. In conclusion, the systemic route of administration results in better recruitment of BMDCs or UDCs to the injured uterus than local injection. In addition, BMDCs recruitment to the uterus is greater than UDCs. These findings inform the development of stem cell-based therapies targeting the uterus.