Stem cells of bone marrow origin have a remarkable ability to transdifferentiate into multiple nonhematopoietic cell types;these including hepatocytes, endothelial cells, cardiomyocytes, skin and gastrointestinal epithelium in humans. We have recently demonstrated the engraftment of endometrial stroma and epithelium with bone marrow-derived mesenchymal stem cells in women who had undergone bone marrow transplantation. The ability of bone marrow-derived stem cells to generate endometrium may contribute to the regenerative capacity of the uterus, and may also have clinical implications in the establishment of pregnancy, the failure of uterine ablative procedures or therapeutic augmentation of stem cell transdifferentiation to endometrium. The ability of bone marrow-derived stem cells to become uterine cells suggests an alternative hypothesis for the origin of endometriosis. We present preliminary data that bone marrow-derived stem cells can engraft the human uterus, that nonuterine stem cells engraft the mouse uterus. These cells are indistinguishable from endometrial stromal or glandular epithelial cells and express appropriate markers of endometrial differentiation. We hypothesize that bone marrow-derived stem cells engraft the uterus and can alter uterine function including the ability to conceive. We will test this hypothesis and characterize this process in three specific aims.
Specific Aim one will fully characterize the ability of bone marrow cells to engraft the uterus though the use of male to female GFP+ bone marrow transplantation.
Specific Aim two will determine the mechanisms that recruit bone marrow-derived stem cells to the endometrium.
Specific Aim three will characterize the functional significance of bone marrow engraftment through rescue of mice with targeted disruption of genes required for implantation;in this aim we will also test the ability of bone marrow-derived stem cells to contribute to the pathophysiology of endometriosis. Stem cells of bone marrow origin have a remarkable ability to transdifferentiate. We will determine the extent to which this process occurs in the uterus, the mechanisms that drive stem cell recruitment, and the significance of this engraftment in the function of this tissue in pregnancy and disease. These findings are expected to produce novel paradigms of endometrial regeneration with clinically important ramifications.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZHD1)
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Yale University
New Haven
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Liu, Ying; Tal, Reshef; Pluchino, Nicola et al. (2018) Systemic administration of bone marrow-derived cells leads to better uterine engraftment than use of uterine-derived cells or local injection. J Cell Mol Med 22:67-76
Flannery, Clare A; Choe, Gina H; Cooke, Katherine M et al. (2018) Insulin Regulates Glycogen Synthesis in Human Endometrial Glands Through Increased GYS2. J Clin Endocrinol Metab 103:2843-2850
Sahin, Cagdas; Mamillapalli, Ramanaiah; Yi, Kyong W et al. (2018) microRNA Let-7b: A Novel treatment for endometriosis. J Cell Mol Med 22:5346-5353
Pluchino, Nicola; Mamillapalli, Ramanaiah; Moridi, Irene et al. (2018) G-Protein-Coupled Receptor CXCR7 Is Overexpressed in Human and Murine Endometriosis. Reprod Sci 25:1168-1174
Sahin, Cagdas; Mamillapalli, Ramanaiah; Taylor, Hugh S (2018) Bone Marrow-Derived Cells Trafficking to the Oviduct: Effect of Ischemia-Reperfusion Injury. Reprod Sci 25:1037-1044
Moridi, Irene; Mamillapalli, Ramanaiah; Cosar, Emine et al. (2017) Bone Marrow Stem Cell Chemotactic Activity Is Induced by Elevated CXCl12 in Endometriosis. Reprod Sci 24:526-533
Naqvi, Hanyia; Mamillapalli, Ramanaiah; Krikun, Graciela et al. (2016) Endometriosis Located Proximal to or Remote From the Uterus Differentially Affects Uterine Gene Expression. Reprod Sci 23:186-91
Flannery, Clare A; Saleh, Farrah L; Choe, Gina H et al. (2016) Differential Expression of IR-A, IR-B and IGF-1R in Endometrial Physiology and Distinct Signature in Adenocarcinoma. J Clin Endocrinol Metab 101:2883-91
Flannery, Clare A; Fleming, Andrew G; Choe, Gina H et al. (2016) Endometrial Cancer-Associated FGF18 Expression Is Reduced by Bazedoxifene in Human Endometrial Stromal Cells In Vitro and in Murine Endometrium. Endocrinology 157:3699-3708
Kulp, Jennifer L; Mamillapalli, Ramanaiah; Taylor, Hugh S (2016) Aberrant HOXA10 Methylation in Patients With Common Gynecologic Disorders: Implications for Reproductive Outcomes. Reprod Sci 23:455-63

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