Fetal cells in the adult female following pregnancy: an under-appreciated source of progenitor cells

s / Placenta 32 (2011) S326–S340 S327 FETAL CELLS IN THE ADULT FEMALE FOLLOWING PREGNANCY: AN UNDER-APPRECIATED SOURCE OF PROGENITOR CELLS D.W. Bianchi Tufts University School of Medicine, Boston, MA, USA As a result of pregnancy, all human females acquire progenitor cells from their fetuses. These cells and their progeny survive for decades postpartum in maternal blood and organs (Bianchi et al. PNAS 1996; 93: 7058). Significant knowledge gaps exist as to whether these fetal cells have characteristics of embryonic or adult stem cells, and whether they have positive, negative, or neutral effects on the health of the mother. This is important, because these fetal cells may have unique therapeutic properties in maternal organs. Furthermore, the long-term presence of fetal cells in women may have broader significance, in that they may be an important factor in diseases that manifest gender-related differences. The long-range goal of my laboratory is to understand the consequences of feto-maternal cell trafficking to determine if pregnancy results in longterm beneficial health effects for the mother. Our central hypothesis is that fetal cells have phenotypically and functionally unique properties that can be developed and applied for novel therapeutic purposes. We are specifically testing this hypothesis by examining whether fetal cells contribute to repair of or recovery from tissue injury in the maternal lung in a murine model system. This organ was selected on the basis of our significant and reproducible murine data that demonstrate that the lung is the maternal organ that contains the most fetal cells. We are currently in the process of determining key factors that distinguish fetal cells from adult cells in maternal organs using immunohistochemistry and gene expression studies. doi:10.1016/j.placenta.2011.07.033 TRANSLATING TRANSPLANTATION TOLERANCE IN THE CLINIC: WHERE ARE WE, WHERE DO WE GO? K. Wood Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK Strategies for the induction of specific unresponsiveness to donor alloantigens currently under investigation in the clinic take advantage of two of the major mechanisms for the induction of tolerance to self antigens – deletion and immunoregulation/suppression. Deletion of donor antigen reactive cells from the immune repertoire of the recipient will potentially prevent or reduce the risk of the transplanted organ or cells from being attacked and rejected. Whereas, active control of immune responsiveness to donor antigens after transplantation by regulatory/suppressor T cells will enable tight control of the response directed against the transplant throughout the post-transplant course. After exposure to alloantigen in vivo and in vitro, alloantigen reactive immunoregulatory activity is enriched in a population of CD4+ T cells that express high levels of CD25, the a chain of the interleukin-2 receptor, and the transcription factor Foxp3. In vivo, common mechanisms underpin the activity of CD25+CD4+ Treg in both naive and manipulated adult hosts. We have identified a unique role for IFNg in the functional activity of CD25+CD4+ alloantigen reactive Treg during the development of operational tolerance to donor alloantigens in vivo that is consistent with observations showing that tolerance to alloantigens cannot be induced in the absence of IFNg. The identification and characterisation of Treg that can control immune responsiveness to alloantigens has opened up exciting opportunities for new therapies in transplantation. These observations may have important implications for the design of clinical protocols to induce allograft tolerance in adult recipients. doi:10.1016/j.placenta.2011.07.034 IMMUNOMODULATION BY MESENCHYMAL STEM CELLS AND CLINICAL EXPERIENCE C. Gotherstrom Karolinska Institutet, CLINTEC, Karolinska University Hospital Huddinge, Stockholm, Sweden Finding a suitable cell source is one of the main challenges in tissue engineering. Besides fulfilling the function of the reconstructed tissue, low immunogenicity is advantageous. Promising candidates are multipotent mesenchymal stromal cells, also known as mesenchymal stem cell (MSC), because of their low immunogenicity, differentiation potential and their capacity to be extensively expanded in culture in combination with a low oncogeneic risk in vivo. They differentiate into several mesodermal cell types, such as bone, cartilage and fat, but also into nonconventional mesenchymal lineages such as myogenic, endothelic, hepatic and neurogenic. In immunocompetent allogeneic/xenogeneic animal models, MSC engraft widely and demonstrate site-specific differentiation. MSC also produce important cytokines, growth factors and extra cellular components. In vitro, MSC induce little, if any, proliferation of allogeneic lymphocytes. MSC also inhibit T-cell proliferation to alloantigens and mitogens and prevent the development of cytotoxic T-cells. In vivo, they prolong skin allograft survival and have several immunomodulatory effects. MSC preferentially seem to home to damaged tissue and therefore have therapeutic potential. Stem cells are present at various stages of development, from the inner cell mass through fetal and finally, adult sources. MSC from the adult bone marrow are widely used in therapy today, as for example in the treatment of therapy-resistant severe acute graft-versus-host disease, where they have much potential. The identification of MSC in the human fetus raises the possibility of using a more primitive MSC population for transplantation purposes. Fetal MSC, like adult MSC, escape recognition by the immune system in vitro suggesting that they are not inherently immunogenic. Fetal MSC differ from adult MSC in some aspects, which may be advantageous for transplantation. They demonstrate marked expansive capacity, and cycle faster than adult MSC, having a doubling time of 30 hours over 20 passages (50 population doublings) without expressing a differentiated phenotype. Like their adult counterparts, fetal MSC possess the ability to differentiate into at least 3 different mesenchymal tissues: bone, cartilage, fat. More recent work suggests that they are more primitive than adult MSC, having longer telomeres and expressing embryonic pluripotency markers such as nanog and Oct4, differentiating more readily into bone and outside conventional lineage boundaries into skeletal muscle, and oligodendrocytes. Finally, it has been shown that there is an engraftment advantage of fetal liver compared to adult bone marrow cells in fetal recipients. In utero transplantation of human fetal MSC has shown promising results in mouse models of osteogenesis imperfect and Duchenne muscular dystrophy. This characteristic of MSC is the basis for their extensive potential for tissue repair and in other indications like therapy-resistant severe acute graftversus-host disease, treatment of rejection of organ allografts and in autoimmune disorders. doi:10.1016/j.placenta.2011.07.035 REGULATORY T CELLS IN PREGNANCY A.G. Betz Medical Research Council, Cambridge, UK Regulatory T cells play a crucial role in maternal fetal tolerance. Immediately after conception, their number in the blood, spleen and uterusdraining lymph nodes substantially increases. Whilst this initial expansion is independent of exposure to paternal alloantigen, their accumulation in the gravid uterus appears to be constrained to alloantigen specific regulatory T cells. Clearly, the role of this shift in the composition