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Clinical evidence suggests that the prevalence of cardiac disease is lower in premenopausal women compared to postmenopausal women and men. Although multiple factors contribute to this difference, uterine stem cells may be a major factor, as a high abundance of these cells are present in the uterus. Uterine-derived stem cells have been reported in several studies as being able to contribute to cardiac neovascularization after injury. However, our studies uniquely show the presence of an "utero-cardiac axis", in which uterine stem cells are able to home to cardiac tissue to promote tissue repair. Additionally, we raise the possibility of a triangular relationship among the bone marrow, uterus, and heart. In this review, we discuss the exchange of stem cells across different organs, focusing on the relationship that exists between the heart, uterus, and bone marrow. We present increasing evidence for the existence of an utero-cardiac axis, in which the uterus serves as a reservoir for cardiac reparative stem cells, similar to the bone marrow. These cells, in turn, are able to migrate to the heart in response to injury to promote healing. [ABSTRACT FROM AUTHOR]

Canopy FGF signaling regulator 2 (CNPY2) is a FGF21-modulated protein containing a saposin B-type domain. In vitro studies have shown CNPY2 is able to enhance neurite outgrowth in neurons and stabilize the expression of low density lipoprotein receptor in macrophages and hepatocytes. However, no in vivo data are available on the normal expression of CNPY2 and information is lacking on which cell types express this protein in tissues. To address this, the present study examined CNPY2 expression at the mRNA and protein levels. Quantitative PCR and ELISA examination of mouse tissues showed that CNPY2 varies between organs, with the highest expression in the heart, lung and liver. Immunohistochemistry detected CNPY2 in a variety of cell types including skeletal, cardiac and smooth muscle myocytes, endothelial cells and epithelial cells. CNPY2 was also detectable in mouse blood and human and mouse uteri. These data demonstrate CNPY2 is widely distributed in tissues and suggest the protein has biological functions that have yet to be identified. Using these new observations we discuss possible functions of the protein. [ABSTRACT FROM AUTHOR]

Problem Understanding of uterine natural killer (u NK) cell functions during normal pregnancy remains incomplete. Method of study Cloud tag analysis of literature was used to document themes addressed experimentally for u NK cells. Immunohistochemistry, including whole-mount staining of early implantation sites, separation of u NK cells into molecularly distinct subsets, and physiologic measurements in normal and mutant mice, are further advancing understanding of u NK cell biology. Results Literature analyses revealed three key, current u NK cell research themes: angiogenesis, spiral arterial remodeling/pre-eclampsia/hypertension and infertility. UNK cells are being defined as cells potentially regulated by Wnt signaling that are heterogeneous in progenitor source and function and make unique contributions to implantation site development prior to spiral arterial remodeling. Conclusion Future studies are poised to define uNK cell progenitor cells, identify the signaling pathways supporting established u NK cell functions and move current understanding of mouse u NK cells to clinical research questions. [ABSTRACT FROM AUTHOR]

Angiotensin II receptor type 1 (AT1) activation leads to vasoconstriction and type 2 receptor (AT2) leads to vasodilation. Atrial natriuretic peptide (ANP) antagonizes the effects of AT1. In human and murine pregnancies, uterine natural killer (uNK) cells closely associate with decidual blood vessels. Protein localization of AT1, AT2, and ANP to mouse uNK cells was examined between gestation days (gds) 6 and 12, the interval of uNK cell expansion. Percentages of uNK cells expressing AT1 or AT2 changed between gd6 and gd10. Atrial natriuretic peptide did not localize to uNK cells at gd6 or 8, but did colocalize to uNK cells at gd10 and 12, times immediately after spiral arterial modification. This is the first report of AT1, AT2, and ANP expression in uterine immune cells. Expression of these molecules suggests that uNK cells have the potential to contribute to the changes in blood pressure that occur between days 5 and 12 of pregnancy in mice. [ABSTRACT FROM PUBLISHER]

Problem To identify plasma immuno-regulatory molecules up or down regulated between the follicular phase and ovulation of the human menstrual cycle. Method of study RayBio® cytokine arrays were used to screen 174 immuno-regulatory molecules in plasma collected during the follicular phase at menstrual cycle day 5 and at ovulation from five healthy, non-smoking, fertile women of reproductive age not using hormonal contraception. Results A total of 23 differentially expressed molecules were found: 10 molecules were differentially up-regulated and 13 down-regulated at ovulation compared with that at the follicular phase (α = 0.05, false discovery rate of 0.45). Conclusion Circulating immuno-regulatory molecules fluctuate over the menstrual cycle in healthy women. The combination of differentially expressed molecules suggests roles in cyclical regulation of angiogenesis and immune cell trafficking. [ABSTRACT FROM AUTHOR]

Problem Uterine natural killer (uNK) cells are enriched in the post-ovulatory uterus and during pregnancy. Whether these cells arise from blood pre-cursors or from stem cells in the uterus is undefined. To support a hypothesis that precursors of uNK cells are recruited from blood, adhesive function of blood CD56+ subsets were assessed during one cycle and during pregnancy. Method of study Fifteen women of proven fertility provided serial blood samples during one menstrual cycle and thirty women with a history of implantation failure or recurrent spontaneous abortion provided serial samples during infertility treatment. Results CD56bright cells, but not CD56dim cells or NKT cells, increased in ligand-binding capacity during ovulation in fertile cycles only and during the first 2 weeks from date of missed menses. Conclusion Enhanced adhesive function at ovulation in CD56bright cells in fertile cycles and during early gestation supports a hypothesis of recruitment of pre-uNK cells from the blood CD56bright subset. [ABSTRACT FROM AUTHOR]

Abstract: We evaluated the hypothesis that uterine cells home to the heart after injury and improve cardiac outcomes. Premenopausal women have fewer cardiovascular complications than age-matched men, but the mechanisms responsible for this protection have not been conclusively identified. Hysterectomy was performed in young female rats (leaving the ovaries intact), and 7days later the left coronary artery was ligated to produce a myocardial infarction (MI). Cardiac function at 28days post-MI was measured using echocardiography. Fractional shortening was best in non-hysterectomized (non-Hx) females and lower in both Hx females and males. Uteri were then removed from GFP rats and heterotopically transplanted into non-GFP recipients to investigate homing of uterine cells to the infarcted myocardium. Seven days later, the uterine transplant recipients underwent coronary ligation. GFP+ cells were found in the recipient hearts 7days after MI and persisted for 6months. Confocal analysis showed that homed uterine cells were located around blood vessels, suggesting their involvement in neovascularization. We then evaluated uterine cell transplantation by intravenously injecting GFP+ uterine cells into Hx females immediately after MI. These GFP+ cells were found to home to the injured myocardium, stimulate angiogenesis, improve cardiac function, and increase survival. This study demonstrates that uterine cells can home to the injured myocardium, enhance tissue repair, and prevent cardiac dysfunction. Uterine cells may play a role in the prevention of cardiovascular complications in females. [Copyright &y& Elsevier]

Problem Patients with elevated blood natural killer (NK) cells may be offered intravenous immunoglobulin (IVIG) treatment, but there is controversy about the utility of blood NK cell testing. Human CD56+ NK cells include several subpopulations that include the putatively cytotoxic CD56+ CD16+ subset. In mouse models of pregnant failure, NKT cells appear to be important. However, a mouse model may only be pertinent to a subset of patients, as recurrent pregnancy failure is a heterogenous group. Method of study An ethics-approved observational study was done to observe the effect of treatment on total blood lymphoid cells, and subsets of CD56+ blood lymphocytes including CD56+ CD3+ NKT cells determined by flow cytometry, and to correlate with pregnancy outcome. Fifteen fertile women with a history of successful pregnancy and thirty-one women suffering from repeated implantation failure or recurrent spontaneous abortion provided serial blood samples during one menstrual cycle or prior to and during treatment. IVIG was administered to the latter group with or without heparin/aspirin. Results Eight of thirty infertile women presented with high numbers of CD56+ CD3+ NKT cells, which declined after treatment with IVIG. The elevated NKT cell group with or without concomitant autoimmunity achieved a significantly higher successful pregnancy rate over the course of the study, as compared to women with average numbers of NKT cells and no evidence of autoimmunity ( P = 0.018). Elevated NKT levels alone was an independent predictor of success on treatment ( P = 0.003). Conclusion Elevated NKT cells in recurrent pregnancy loss or implantation failure can be ameliorated with IVIG treatment, and result in successful pregnancy. Assay of NKT cell numbers may idengif"y patients who are more likely to benefit from IVIG therapy and merits further examination in randomized phase II studies. [ABSTRACT FROM AUTHOR]

Cell therapy to prevent cardiac dysfunction after myocardial infarction (MI) is less effective in aged patients because aged cells have decreased regenerative capacity. Allogeneic transplanted stem cells (SCs) from young donors are usually rejected. Maintaining transplanted SC immunoprivilege may dramatically improve regenerative outcomes. The uterus has distinct immune characteristics, and we showed that reparative uterine SCs home to the myocardium post-MI. Here, we identify immunoprivileged uterine SCs and assess their effects on cardiac regeneration after allogeneic transplantation. We found more than 20% of cells in the mouse uterus have undetectable MHC I expression by flow cytometry. Uterine MHC I (neg) and MHC I (pos) cells were separated by magnetic cell sorting. The MHC I (neg) population expressed the SC markers CD34, Sca-1 and CD90, but did not express MHC II or c-kit. In vitro , MHC I (neg) and (pos) SCs show colony formation and endothelial differentiation capacity. In mixed leukocyte co-culture, MHC I (neg) cells showed reduced cell death and leukocyte proliferation compared to MHC I (pos) cells. MHC I (neg) and (pos) cells had significantly greater angiogenic capacity than mesenchymal stem cells. The benefits of intramyocardial injection of allogeneic MHC I (neg) cells after MI were comparable to syngeneic bone marrow cell transplantation, with engraftment in cardiac tissue and limited recruitment of CD4 and CD8 cells up to 21 days post-MI. MHC I (neg) cells preserved cardiac function, decreased infarct size and improved regeneration post–MI. This new source of immunoprivileged cells can induce neovascularization and could be used as allogeneic cell therapy for regenerative medicine. [ABSTRACT FROM AUTHOR]

Citation Burke SD, Barrette VF, Gravel J, Carter ALI, Hatta K, Zhang J, Chen Z, Leno-Durán E, Bianco J, Leonard S, Murrant C, Adams MA, Anne Croy B. Uterine NK cells, spiral artery modification and the regulation of blood pressure during mouse pregnancy. Am J Reprod Immunol 2010 Reproductive success in mammals involves coordinated changes in the immune and cardiovascular as well as in the neuroendocrine and reproductive systems. This review addresses studies that identify potential links for NK cells and T cells with the local and systemic cardiovascular adaptations of pregnancy. The studies reviewed have utilized immunohistochemisty and in vivo analyses of vascular parameters by ultrasound, chronic monitoring of hemodynamics via radiotelemetric recording and intravital microscopy. At the uterine level, functional subsets of uterine natural killer cells were identified. These included subsets expressing molecules important for vasoregulation, in addition to those previously identified for angiogenesis. Spiral arteries showed conducted responses that could account for conceptus control of vasoactivity and mouse gestational blood pressure 5-phase pattern. Vascular immunology is an emerging transdisciplinary field, critical for both reproductive immunology and cardiovascular disease. [ABSTRACT FROM AUTHOR]