We are requesting support to test the hypothesis that fetal cells, acquired physiologically through pregnancy, and retained in the adult human female following abortion, miscarriage, or delivery, encompass a novel population of cells that we have termed the """"""""Pregnancy-Associated Progenitor Cell (PAPC)."""""""" To date, the controversy surrounding the plasticity of adult stem cells has virtually ignored the role of pregnancy in females. PAPCs, if shown to be true stem cells, would have the developmental advantages of being fetal in origin yet could be retrieved without ethical controversy from an adult female who has previously been pregnant. We have extensive preliminary data in the human adult, non-transfused female that fetal cells (identified on the basis of the Y chromosome as well as fetal-specific DNA polymorphisms), acquired through pregnancy, are detectable in peripheral blood and clinically diseased organs, and have multi-lineage capacity. Due to the necessity of obtaining clinical material from biopsy and/or autopsy specimens, these studies have been descriptive and not mechanistic. Our hypothesis will be tested in an animal model, a transgenic male mouse expressing either green fluorescent protein (GFP) or luciferase bred to wild-type female mice. This will allow us to control reproductive histories, and test multiple hypotheses regarding the plasticity and activity of fetal cells in the maternal body. The GFP and luciferase sequences are dominant transgenes. Half of the fetal pups will carry the transgene, and express the green fluorescent marker in some or all of their cells, depending on the construct. Fetal cells fluoresce green and can be identified and tracked in maternal tissues using a variety of techniques, including in vivo whole animal imaging, fluorescence microscopy, and real-time PCR amplification.
In specific aim 1 we will test the hypothesis that specific factors affect the development of fetal cell microchimerism (FCMC) in the mother.
In specific aim 2 we will use chemical, surgical, genetic, and ischemic models to determine if fetal cells are recruited in specific tissue injury scenarios and contribute to the repair of maternal injury by analyzing overall well being and longevity, target organ function, differences in wound healing, and differential gene expression.
In specific aim 3 we will examine the cell surface characteristics of the murine microchimeric fetal cells and perform microarray analysis to determine whether FCMC is due to 1 or multiple cell types.
In specific aim 4 we will test the hypothesis that fetal stem cells have an advantage over adult stem cells and contribute to prolonged survival or improved organ function. The long-term objective is to determine if pregnancy confers a long-term advantage to a female by resulting in the acquisition of unique cells that have therapeutic potential.
|Johnson, Kirby L; Stroh, Helene; Tadesse, Serkalem et al. (2012) Fetal cells in the murine maternal lung have well-defined characteristics and are preferentially located in alveolar septum. Stem Cells Dev 21:158-65|
|Pritchard, Stephanie; Wick, Heather C; Slonim, Donna K et al. (2012) Comprehensive analysis of genes expressed by rare microchimeric fetal cells in the maternal mouse lung. Biol Reprod 87:42|
|Pritchard, Stephanie; Bianchi, Diana W (2012) Fetal cell microchimerism in the maternal heart: baby gives back. Circ Res 110:3-5|
|Pritchard, Stephanie; Peter, Inga; Johnson, Kirby L et al. (2012) The natural history of fetal cells in postpartum murine maternal lung and bone marrow: a two-stage phenomenon. Chimerism 3:59-64|
|Pritchard, S; Hoffman, A M; Johnson, K L et al. (2011) Pregnancy-associated progenitor cells: an under-recognized potential source of stem cells in maternal lung. Placenta 32 Suppl 4:S298-303|
|Kallenbach, Lisa R; Bianchi, Diana W; Peter, Inga et al. (2011) Maternal background strain influences fetal-maternal trafficking more than maternal immune competence in mice. J Reprod Immunol 90:188-94|
|Kallenbach, Lisa R; Johnson, Kirby L; Bianchi, Diana W (2011) Fetal cell microchimerism and cancer: a nexus of reproduction, immunology, and tumor biology. Cancer Res 71:8-12|
|Johnson, Kirby L; Tao, Kai; Stroh, Helene et al. (2010) Increased fetal cell trafficking in murine lung following complete pregnancy loss from exposure to lipopolysaccharide. Fertil Steril 93:1718-1721.e2|
|Rust, Daniel W; Bianchi, Diana W (2009) Microchimerism in endocrine pathology. Endocr Pathol 20:11-6|
|Fujiki, Yutaka; Johnson, Kirby L; Peter, Inga et al. (2009) Fetal cells in the pregnant mouse are diverse and express a variety of progenitor and differentiated cell markers. Biol Reprod 81:26-32|
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