Chemokine C-X-C receptor 4 mediates recruitment of bone marrow-derived nonhematopoietic and immune cells to the pregnant uterus

Abstract

Bone marrow-derived progenitor cells (BMDPCs) are mobilized to the circulation in pregnancy and get recruited to the pregnant decidua where they contribute functionally to decidualization and successful implantation. However, the molecular mechanisms underlying BMDPCs recruitment to the decidua are unknown. CXCL12 ligand and its CXCR4 receptor play crucial roles in mobilization and homing of stem/progenitor cells to various tissues. To investigate the role of CXCL12-CXCR4 axis in BMDPCs recruitment to decidua, we created transgenic GFP mice harboring CXCR4 gene susceptible to tamoxifen-inducible Cre-mediated ablation. These mice served as BM donors into wild-type C57BL/6 J female recipients using a 5-fluorouracil-based non-gonadotoxic submyeloablation to achieve BM-specific CXCR4 knockout (CXCR4KO). Successful CXCR4 ablation was confirmed by RT-PCR and in-vitro cell migration assays. Flow cytometry and immunohistochemistry showed a significant increase in GFP+ BM-derived cells (BMDCs) in the implantation site as compared to the nonpregnant uterus of control (2.7-fold) and CXCR4KO (1.8-fold) mice. This increase was uterus-specific and was not observed in other organs. This pregnancy-induced increase occurred in both hematopoietic (CD45+) and nonhematopoietic (CD45-) uterine BMDCs in control mice. In contrast, in CXCR4KO mice there was no increase in nonhematopoietic BMDCs in the pregnant uterus. Moreover, decidual recruitment of myeloid cells but not NK cells was diminished by BM CXCR4 deletion. Immunofluorescence showed the presence of nonhematopoietic GFP+ cells that were negative for CD45 (panleukocyte) and DBA (NK) markers in control but not CXCR4KO decidua. In conclusion, we report that CXCR4 expression in nonhematopoietic BMDPCs is essential for their recruitment to the pregnant decidua.

Maternal CXCR4 deletion results in placental defects and pregnancy loss mediated by immune dysregulation

“…Specifically, the proportions of NK cells, macrophages, and monocytes were significantly decreased, while granulocytes were significantly increased in decidua of CXCR4-KO mice. In agreement, we have previously shown that genetic ablation of CXCR4 in adult BM cells — including NK cells, monocytes, macrophages and granulocytes — affects their recruitment to the mouse implantation site ( 27 ). Moreover, the CXCL12/CXCR4 axis has been reported to be important for recruitment of NK cells ( 50 ) and DCs ( 51 ) to decidua.…”

“…Mice were maintained in a controlled environment at the Animal Facility of Yale School of Medicine with a 12-hour light, 12-hour dark cycle with ad libitum access to food and water. To generate TM-inducible CXCR4-KO mice, we used the Cre/LoxP TM-inducible system, as we described before ( 27 ). All mice were purchased from The Jackson Laboratory.…”

Miscarriage syndrome: Linking early pregnancy loss to obstetric and age-related disorders

“…Thus, transformation of the cycling endometrium into the decidua of pregnancy depends critically on uterine chemokine signals, transvascular migration of circulating NK cells and BM-MSC, and their proliferative expansion and phenotypic differentiation into effective homeostatic regulators of the maternal-fetal interface. 16 , 17 , 18 , 22 , 23 , 24 Interference at any stage of this pathway can potentially compromise placenta formation and cause miscarriage. For example, recurrent miscarriage is associated with loss of BM-MSC during the implantation window with the level of depletion correlating to the number of previous losses.…”

“…Notably, other immune cells also play important roles in maintaining the integrity of the maternal-fetal interface in early gestation, including dentritic cells, activated regulatory T cells, and anti-inflammatory (M2) macrophages. 16 , 17 , 18 , 22 , 23 , 24 , 28 , 29 , 30 …”

Uterus: A Unique Stem Cell Reservoir Able to Support Cardiac Repair via Crosstalk among Uterus, Heart, and Bone Marrow

“…For instance, the chemokine C-X-C motif chemokine ligand 12 (CXCL12) has been found to play a major role in recruiting BM-derived progenitor cells into the uterus during pregnancy in mice, via its interaction with the C-X-C chemokine receptor type 4 (CXCR4) receptor on these cells. This recruitment, in turn, facilitates the formation of the characteristic decidual structures of the pregnant endometrium, which is essential for ensuring successful implantation of the fetus in the uterus [ 100 ]. Even under non-pregnant conditions, these BM-derived progenitor cells are still able to traffic into the uterus and differentiate into cells similar to that of endogenous uterine cells, such as the endometrium, in a BM replacement study [ 101 ].…”