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"CELLULAR ORIGINS OF ENDOMETRIAL CELLS"

by
Sara Sinha Morelli
Interdisciplinary Biomedical Sciences Program
M.D. 2003, Mount Sinai School of Medicine, New York, NY
B.S. 1999, Cornell University, Ithaca, NY


Thesis Advisor: Laura T. Goldsmith, Ph.D.
Professor
Department of Obstetrics, Gynecology, and Women’s Health

Tuesday, November 8, 2016
11:00 A.M., MSB E609b


Abstract

Successful reproduction in mammalian species requires normal function of the uterine endometrium. The endometrium is a dynamic tissue required for implantation and maintenance of pregnancy. In women, shedding/loss of the functional layer of the endometrium occurs on a monthly basis via menstruation, and regeneration of the tissue occurs with each menstrual cycle. Despite the critical nature of the cyclic renewal of all endometrial cell types, the source of these cell types is unknown. In various mammalian tissues, bone marrow (BM) cells are a source of nonhematopoietic, parenchymal cell types. However, it is not known whether BM cells are a source of any parenchymal cell type in the endometrium. The studies reported herein tested the hypothesis that the BM is a source of multiple endometrial cell types.
A well-characterized murine BM transplant model was established to test this hypothesis. Whole BM cells were harvested from transgenic donor mice which ubiquitously express green fluorescent protein (GFP), and transplanted into lethally irradiated, syngeneic female recipient mice. GFP-positive cells in the endometrium were detected using confocal laser microscopy, and cell numbers were quantitated in various endometrial cellular compartments at multiple time points after transplant. BM-derived hematopoietic cells (GFP-positive/CD45-positive) were distinguished from BM-derived nonhematopoietic cells (GFP-positive/CD45-negative). In the endometrial stromal compartment, BM-derived cells (BMDCs) were detectable as early as 3 months post transplant. BM remained a persistent, long-term source of nonhematopoietic stromal compartment cells for at least 12 months. BM-derived, nonhematopoietic endometrial cells comprised 47.3%-72.2% of total BMDCs in the stromal compartment at 12 months. BMDCs were not detected in the epithelial compartments until 12 months post transplant, at which time 0-2.3% of epithelial cells expressed GFP.
Normal endometrial function requires the actions of the ovarian steroid hormones estradiol and progesterone. To determine whether GFP-positive BMDCs detected in the endometrium are potentially steroid-responsive endometrial cells, expression of the receptor proteins for these steroid hormones was assessed. At 12 months post transplant, 42.8±8.5% (mean±SD) of BMDCs in the endometrial stromal compartment expressed estrogen receptor (ER) alpha, 94.6±2.4% expressed ER beta, and 98.1±1.5% expressed progesterone receptor (PR). Of the very few BMDCs detected in the endometrial epithelial compartments, 50.0% expressed ER alpha and 100% of BMDCs detected in the endometrial epithelial compartments expressed both ER beta and PR.
These results demonstrate that the bone marrow is a source of multiple parenchymal endometrial cell types, nearly all of which express ovarian steroid hormone receptors. These novel data suggest an important role for bone marrow cells in the cyclic regeneration of the multiple endometrial cell types required for successful reproduction, an important advance in our understanding of normal endometrial function. These data also open a new avenue for the potential use of BM cells in the treatment of endometrial dysfunction, currently the rate-limiting problem in infertility therapy.


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