CXCL12 Promotes Stem Cell Recruitment and Uterine Repair after Injury in Asherman’s Syndrome

Abstract

Asherman’s syndrome is an acquired condition of uterine fibrosis and adhesions in response to injury that adversely affects fertility and pregnancy. We have previously demonstrated that bone marrow-derived mesenchymal stem cells (BMDSCs) contribute to uterine repair after injury and that stem cells supplementation improves fertility. Here, we demonstrate that CXCL12 is the chemokine that mediates stem cell engraftment and functional improvement using a murine model of Asherman’s syndrome. After uterine injury, we demonstrate that CXCL12 augmentation increased BMDSC engraftment and that the CXCL12 receptor (CXCR4) antagonist, ADM3100, blocked stem cell recruitment. CXCL12 reduced, whereas ADM3100 increased fibrosis. CXCL12 treatment led to improved fertility and litter size, whereas ADM3100 treatment reduced fertility and litter size. ADM3100 prevented optimal spontaneous uterine repair mediated by endogenous CXCL12 production, reducing pregnancies after injury in the absence of supplemental CXCL12 administration; however, ADM3100 treatment could be partially rescued by CXCL12 augmentation. CXCL12 or other CXCR4 receptor agonists may be useful in the treatment of infertility or adverse pregnancy outcomes in Asherman’s syndrome and other related uterine disorders.

PGS Scaffolds Promote the In Vivo Survival and Directional Differentiation of Bone Marrow Mesenchymal Stem Cells Restoring the Morphology and Function of Wounded Rat Uterus

“…The disappearance of normal endometrium structure changes the functionality of this organ . Loss of native stem cells or injury of stem cells niche caused by iatrogenic curettage often leads to failed regeneration of the functional layer of endometrium and results in amenorrhea, infertility, or pregnancy complications …”

The CXL12/CXCR4/CXCR7 axis in female reproductive tract disease: Review

“…Asherman's syndrome is an acquired condition of uterine fibrosis and adhesions in response to injury. 54 Specifically, following uterine injury to create a model of AS, it was demonstrated that CXCL12 augmentation increased BMDSC engraftment and that the CXCL12 receptor (CXCR4) antagonist, ADM3100 (Plerixafor which is FDA approved), blocked stem cell recruitment. 41,49-51 While the generation and growth of the uterine endometrium are important physiologically for reproduction, it is defective in AS.…”

“…49,53 Aside from surgery, which is not fully effective, no therapies are currently available to treat this disease. 54 Unlike the case for endometriosis in which the CXCL12/ CXCR4/CXCR7 axis plays a key role in promoting disease, the interaction of CXCL12 with CXCR4 on murine models of AS has shown a decrease in fibrosis and improved fertility. Sites of injury are known to increase expression of CXCL12; however, CXCL12 is rapidly proteolyzed and does not mobilize cells for a prolonged duration.…”

“…A recent study utilizing murine models of AS demonstrated partial repair of the endometrium using bone marrow-derived stem cell treatment plus CXCL12 to enhance homing of stem cells to sites of injury. 54…”

Decreased CXCL5 expression associated with intrauterine adhesions in a rat model and human endometrial tissues

“…The most common early symptoms of IUA patients are menstrual abnormalities, recurrent abdominal pain, and amenorrhea [4]. IUA often leads to infertility, recurrent miscarriage, and various complications of pregnancy, such as placenta implantation, placental abruption, preterm premature rupture of membranes, and developmental abnormalities in the fetus as a result of the loss of normal endometrium and insu cient the blood supply to the uterus [5][6][7]. In recent years, IUA has become one of the common causes of female infertility in China, and its incidence has been on the rise with uterine cavity surgery increasing [4,8].…”