Studies from five independent laboratories conclude that bone marrow stem cells transdifferentiate into endometrial stroma, epithelium, and endothelium. We investigated the nature of bone marrow-derived cells in the mouse endometrium by reconstituting irradiated wild type recipients with bone marrow containing transgenic mTert-green fluorescent protein (GFP) or chicken b-actin (Ch b-actin)-GFP reporters. mTert-GFP is a telomerase marker identifying hematopoietic stem cells and subpopulations of epithelial, endothelial, and immune cells in the endometrium. Ch b-actin-GFP is a ubiquitous reporter previously used to identify bone marrowderived cells in the endometrium. Confocal fluorescence microscopy for GFP and markers of endometrial and immune cells were used to characterize bone marrow-derived cells in the endometrium of transplant recipients. No evidence of GFP 1 bone marrow-derived stroma, epithelium, or endothelium was observed in the endometrium of mTert-GFP or Ch b-actin-GFP recipients. All GFP 1 cells detected in the endometrium were immune cells expressing the pan leukocyte marker CD45, including CD3 1 T cells and F4/80 1 macrophages. Further examination of the Ch b-actin-GFP transplant model revealed that bone marrow-derived F4/80 1 macrophages immunostained weakly for CD45. These macrophages were abundant in the stroma, infiltrated the epithelial and vascular compartments, and could easily be mistaken for bone marrow-derived endometrial cells. We conclude that it is unlikely that bone marrow cells are able to transdifferentiate into endometrial stroma, epithelium, and endothelium. This result has important therapeutic implications, as the expectation that bone marrow stem cells contribute directly to endometrial regeneration is shaping strategies designed to regenerate endometrium in Asherman's syndrome and to control aberrant endometrial growth in endometriosis. STEM CELLS 2018;36:91-102
SIGNIFICANCE STATEMENTThe endometrium (the lining of the uterus) is one of the most regenerative tissues in the body, is central to fertility, and is prone to disease. Bone marrow stem cells have been widely reported to transdifferentiate into endometrial cells. This phenomenon was investigated in mouse models, and no evidence of bone marrow cell transdifferentiation into endometrialspecific cell types was found. It was concluded that bone marrow cells are unlikely to transdifferentiate into endometrial cells and that previous reports of this occurring involve the misidentification of immune cells. This result has important implications for the development of therapies to treat diseases of the endometrium.