Adult bone marrow progenitors become decidual cells and contribute to embryo implantation and pregnancy

by Reshef Tal, Shafiq Shaikh, Pallavi Pallavi, Aya Tal, Francesc López-Giráldez, Fang Lyu, Yuan-Yuan Fang, Shruti Chinchanikar, Ying Liu, Harvey J. Kliman, Myles Alderman III, Nicola Pluchino, Jehanzeb Kayani, Ramanaiah Mamillapalli, Diane S. Krause, Hugh S. Taylor

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. Adult bone marrow (BM)-derived cells (BMDCs) differentiate into rare populations of nonhematopoietic endometrial cells in the uterus. However, whether adult BMDCs become nonhematopoietic decidual cells and contribute functionally to pregnancy is unknown. Here, we show that pregnancy mobilizes mesenchymal stem cells (MSCs) to the circulation and that pregnancy induces considerable adult BMDCs recruitment to decidua, where some differentiate into nonhematopoietic prolactin-expressing decidual cells. To explore the functional importance of nonhematopoietic BMDCs to pregnancy, we used Homeobox a11 (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. 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.