Abstract: The decidua is a transient uterine tissue shared by mammals with hemochorial placenta and is essential for pregnancy. The decidua is infiltrated by many immune cells promoting pregnancy. Bone marrow-derived progenitor cells (BMDPC) contribute to various nonhematopoietic cell populations in the endometrium but their role in reproduction has been unknown. We developed a non-gonadotoxic bone marrow transplantation mouse model for studying BM-derived cell (BMDC) trafficking in reproduction. Our objectives were to characterize the spatiotemporal contribution of BMDPCs to the decidua, explore their functional importance to implantation and pregnancy, and study the role of CXCR4-CXCL12 axis in mediating their recruitment to the pregnant uterus. To investigate the nonhematopoietic physiologic contribution of BMDC to decidua, we utilized our reported 5-fluorouracil-based non-gonadotoxic bone marrow transplant (BMT) regimen to transplant BM from GFP donors into wild-type (WT) C57BL6/J female mice (~45% donor chimerism). Detailed characterization of GFP-labeled BMDC in the uterus throughout gestation was performed. To explore the functional importance of BMDPC to implantation and pregnancy, we performed BMT experiments in Homeobox A11 (Hoxa11) genetic knockout (KO) mice models which are associated with endometrial stromal defects leading to decidualization failure in homozygous (KO), and pregnancy loss in heterozygous (+/-) mice. In addition, to investigate the role of CXCL12-CXCR4 axis in mediating recruitment of BMDCs to the pregnant uterus, we developed BM-specific CXCR4 KO (tamoxifen-inducible Cre) mice. We show that pregnancy mobilizes mesenchymal BMDCs to the circulation and induces considerable adult BMDCs recruitment to decidua, where some differentiate into nonhematopoietic prolactin-expressing decidual cells. To explore the functional importance of nonhematopoietic BMDPCs to pregnancy, we used Hoxa11-deficient mice, having endometrial stromal-specific defects precluding decidualization and successful pregnancy. Hoxa11 expression in BM is restricted to nonhematopoietic cells. BM transplant (BMT) from wild-type (WT) to Hoxa11-/- mice results in stromal expansion, gland formation, and marked decidualization otherwise absent in Hoxa11-/- mice. Moreover, in Hoxa11+/- mice, which have increased pregnancy losses, BMT from WT donors leads to normalized uterine expression of numerous decidualization-related genes and rescue of pregnancy loss. Single cell RNAseq analysis of E9.5 implantation site identified GFP+ BM-derived cells in decidual stromal cell (DSC) clusters expressing multiple mesenchymal/stromal markers similar to resident DSCs and without expression of hematopoietic markers, confirming their mesenchymal lineage. Knockout of CXCR4 in BM cells led to inhibition of recruitment of nonhematopietic BMDCs to the pregnant uterus. Collectively, these findings reveal that adult BMDCs have a previously unrecognized nonhematopoietic physiologic contribution to decidual stroma, thereby playing important roles in decidualization and pregnancy. The receptor CXCR4 plays an important role in mediating recruitment of nonhematopoietic BMDCs to the pregnant decidua.

Biography: Dr. Reshef Tal is Assistant Professor of Obstetrics and Gynecology and Reproductive Sciences at the Yale School of Medicine and a Women’s Reproductive Health Research (WRHR) Scholar. He obtained his M.D. and Ph.D. in Molecular Biology at Sackler School of Medicine in Tel-Aviv University, Israel. Following a postdoctoral research fellowship at the Lunenfeld Research Institute at the University of Toronto, he completed his residency in Obstetrics and Gynecology at Maimonides Medical Center, NY, followed by a fellowship in Reproductive Endocrinology and Infertility at Yale University. His laboratory is focused on investigating the role of bone marrow-derived progenitor cells and immune cells in embryo implantation and pregnancy maintenance with the ultimate goal of developing new therapies for patients with infertility. His clinical interests include infertility, IVF, polycystic ovarian syndrome (PCOS), recurrent pregnancy loss (RPL) and endometrial pathologies including Asherman’s syndrome, thin endometrium and implantation failure. Dr. Tal is the recipient of many research awards including the New England Fertility Society/Ferring Fellow Research Award, the Society of Reproductive Endocrinology & Infertility (SREI)/American Society for Reproductive Medicine (ASRM) Fellow Research Award, Patterson Trust Fellow Award, Society for Reproductive Investigation (SRI) President's Plenary Award and the Albert S. McKern Award. Dr. Tal has published over 60 peer-reviewed scientific articles, authored five book chapters and also edited a book (Antimullerian Hormone: Biology, Role in Ovarian Function and Clinical Significance). In addition, he serves as an Associate Editor for the journal Reproductive Biology and Endocrinology.