טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentPaz Harel Gili
SubjectA Role for Myeloid Cells in Placental Angiogenesis
DepartmentDepartment of Medicine
Supervisors Dr. Ofer Fainaru
Professor Mordechai Hallak
Full Thesis textFull thesis text - English Version


Abstract

Immature myeloid cells (IMCs) differentiate into mature granulocytes, macrophages and dendritic cells (DCs) in the steady-state; however, their population expands in malignancy. In my dissertation we present a novel function of IMCs in pregnancy. We show that in mice, IMCs populate the placenta in mid-pregnancy promoting angiogenesis and then decrease throughout the latter part of pregnancy. Conversely, the DC population increases just before labor. These results indicate a reciprocal population shift between IMCs and DCs in the placenta during pregnancy.

The DC population in human pregnancies was higher in placentas derived from normal vaginal deliveries (NVD) compared to that derived from elective cesarean sections (CS). Accordingly, DC levels are higher in cesarean sections with contractions in comparison to elective CS without contractions and highest in term NVD. These results imply a role for DCs in the inflammatory process of labor.

Characterizing the myeloid cell populations during pregnancy complications, we found that in placentas derived from preeclampsia, IMC levels were significantly higher and DC levels were significantly lower than in placentas of normal pregnancies. In other pregnancy complications we did not detect significant myeloid cell population changes, as compared to healthy controls.

In order to define specific myeloid inflammatory populations, we compared them between mouse normal placentas to a mouse model for inflammatory bowel disease. We show that in similarity to the inflamed colon, the differentiation of monocytes into macrophages in the placenta is arrested throughout pregnancy, and other inflammatory cells, such as neutrophils are abundant. As expected, when inflammation aggravates labor is initiated.

Progesterone has an important role in the maintenance of pregnancy, and it is produced in high levels by the placenta. When progesterone action is disrupted, labor rapidly initiates. Our results in vitro show an overall increase in the IMC population in bone marrow cells cultured in the presence of progesterone, suggesting an inhibitory role for progesterone in IMC maturation. Additionally, the DC population decreases in the presence of progesterone, suggesting a role for progesterone in prevention of maturation of IMCs to DCs.

Placental IMCs were compared to IMCs derived from tumors. Go to:

The root cause of preeclampsia is the placenta. Preeclampsia begins to abate with the delivery of the placenta and can occur in the absence of a fetus but with the presence of trophoblast tissue with hydatidiform moles. In view of this, study of the placenta should provide insight into the pathophysiology of preeclampsia. In this presentation we examine placental pathological and pathophysiological changes with preeclampsia and fetal growth restriction (FGR). It would seem that this comparison should be illuminating as both conditions are associated with similarly abnormal placentation yet only in preeclampsia is there a maternal pathophysiological syndrome. Similar insights about early and late onset preeclampsia should also be provided by such information.

We report that the placental abnormalities in preeclampsia are what would be predicted in a setting of reduced perfusion and oxidative stress. However, the differences from FGR are inconsistent. The most striking differences between the two conditions are found in areas that have been the least studied. There are differences between the placental findings in early and late onset preeclampsia but whether these are qualitative, indicating different diseases, or simply quantitative differences within the same disease is difficult to determine.

We attempt to decipher the true differences, seek an explanation for the disparate results and provide recommendations that we hope may help resolve these issues in future studies.

Keywords: Preeclampsia, Fetal Growth Restriction, Placenta, Pathology, Morphology, Pathophysiology

A significant enrichment of the monocytic Ly6GintLy6Chi population was revealed in tumors compared to placentas, together with a significant decrease of the granulocytic Ly6GhiLy6Cint population. Additionally, differences in gene expression were detected. 732 and 420 genes were significantly up and down regulated in tumor IMCs compared to placental IMCs, respectively.

Gene Set Enrichment Analysis demonstrated tumor IMCs overexpressed genes that take part in cell cycle and proliferation whereas placental IMCs overexpressed genes were related to developmental processes, immune system development and leukocyte differentiation and maturation.

The possibility that the onset of labor and delivery is preceded by the maturation of IMCs into DCs is exciting. Our results indicate an involvement of these myeloid cell populations in the sterile inflammation in the placenta throughout pregnancy and specifically just before labor. The role of progesterone in the aspect of pregnancy maintenance in relation to its involvement in differentiation of IMCs to DCs is intriguing and warrants further studies.