Pregnancy associated progenitor cells migrate, integrate and contribute to maternal hematopoietic compartments in the murine model

Abstract

Cell migration between mother and fetus during pregnancy of placental animals is a commonly observed phenomenon. Fetal cells transferred to mothers are termed as Pregnancy Associated Progenitor Cells (PAPCs) and their presence in maternal tissues is known as fetomaternal microchimerism (FMM). FMM has been studied in mammalian animal model systems and PAPCs exhibited multilineage differentiation potential based on their ability to integrate and contribute to multiple maternal tissues and organs.

PAPCs have been extensively characterized in various maternal tissues by several groups in terms of quantification and phenotype. PAPCs have been previously found in the human small intestine, however, the presence of such cells in a murine model has not been demonstrated yet. In this research project, I sought to determine the presence of PAPCs in the murine small intestine and characterize these cells in more detail. Here, I show that PAPCs were detected in the small intestine in approximately 50% of the mothers. PAPCs were found as early as postnatal day 10 (P10) and could be detected at P210 demonstrating long-term engraftment of PAPCs to the intestine. PAPCs were predominantly found in the lamina propria and were non-proliferative. I also show that in the lamina propria, PAPCs were mainly of a hematopoietic phenotype as judged by the expression of B- and T- cell markers such as CD19, IgA, CD4, and CD8 and the myeloid marker CD11b. Furthermore, intestinal PAPCs expressed the intestinal specific marker IgA which signifies that they could express a tissue specific lymphoid phenotype.

Having identified PAPCs of hematopoietic origin in the small intestine, I further studied a potential source of PAPCs in the maternal peripheral blood. I demonstrate the novel long term engraftment of PAPCs up to 7 months postpartum in the maternal peripheral blood and show that PAPCs incorporate cell cycle marker EdU which is a first line of evidence for proliferation of PAPCs in the maternal system. I show that in the peripheral blood, PAPCs coexpressed the hematopoietic progenitor cell markers CD34 and CD45 as well as CD34 and c-Kit. This suggests the presence of a long term hematopoietic progenitor pool of fetal origin in the maternal blood. In addition, PAPCs express Qa-2, a mouse homologue of HLA-G, which may contribute to the PAPCs¿ ability to evade maternal immune response.

In the last part of my thesis, I show that PAPCs express integrin subunit complexes, a2, a4, a5, ß1, ß2 during postnatal stages. The expression of these subunits in combinations may aid the migration of PAPCs across the placental and endothelial barriers in the maternal tissues. Similarly, a subset of PAPCs in the maternal peripheral blood and in the small intestine expressed the a4ß7 integrin complex (LPAM-1) which might indicate an involvement of LPAM-1 in intestinal homing and migration of PAPCs.

Importantly, I identified the presence of major growth factor and chemokine receptors VEGFR1, c-Kit and CXCR4 on PAPCs during gestational and postpartum timepoints which may explain the migratory patterns of PAPCs to maternal tissues, injuries and neoplastic transformations. In addition, presence of VEGFR1+ CD34+ and VEGFR1+ CD133+ PAPCs in the maternal peripheral blood is highly indicative of hematopoietic progenitors of fetal origin. I was able to show that PAPCs express major growth factor/chemokine receptors and are able to migrate to Matrigel plug assays with ligands. VEGFR1+ and CXCR4+ PAPCs were specifically recruited to Matrigel plugs with placental growth factor (P¿GF) and stromal derived factor 1 (SDF1-a) during pregnancy.