Marcus O. Muench, PhD
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Developmental Hematopoiesis: The liver is a major site of hematopoiesis throughout much of fetal development and erythropoiesis is the dominant form of hematopoiesis in the fetal liver. We’re studying the environmental factors and cellular interactions that support erythropoiesis in the fetal liver. We are also examining the developmental changes that affect the growth and function of fetal stem cells and erythroid precursors. We are pursuing the hypothesis that a number of genes are differentially regulated between fetal and adult erythroid precursors to accommodate the distinct functions of fetal and adult erythrocytes. We are applying microarray technology to compare gene expression at different stages of fetal and adult erythroid development. This is being done by isolating erythroid precursors at varying stages of differentiation from fetal liver and adult bone marrow and then analyzing gene expression using microarray technology. Our aim is to profile the expression of genes during erythroid development and compare expression between adult and fetal erythrocytes. Additionally, we are studying the differentiation of embryonic stem cells into erythrocytes to determine if in vitro differentiation reconstitutes ontogeny by first generating cells with fetal gene expression before switching to an adult pattern of expression. There are a number of potential practical applications of knowledge gained from these studies. One is the further development of methods of prenatal diagnosis based on the detection of nucleated fetal erythrocytes that can be found in the maternal circulation. Improved methods of the isolation of these rare cell types would allow for non-invasive genetic diagnosis. Another application being studied is the ex vivo production of erythrocytes from stem cells for use as a source of red cells for transfusion. It has been shown feasible to grow and differentiate stem cells and progenitors from sources such as neonatal umbilical cord blood into mature enucleated erythrocytes. However, the efficiency of this process must be improved based on further research and understanding of the process of erythropoiesis before red cells grown in the laboratory can be used to augment the blood supply.
Liver Development. Both hematopoietic and hepatic tissues share the same organ during fetal development but are thought to arise from separate embryological tissues. Our goal is to identify and characterize hepatic stem cells in the fetal liver. We have identified several cell populations that may contain hepatic stem cells, which are being further studied to understand their position in the hierarchy of liver cell differentiation. Many genetic diseases could be cured or ameliorated by hepatic stem cell transplantation in utero. Identifying the hepatic stem cell population in the developing liver is a first step in the goal of using these cells for cellular therapy.
Fetal Transplantation. Fetal cellular therapy, the transplantation of cells into a fetus, has the potential of ameliorating or curing a large number of birth defects. However, the current practice of fetal stem cell transplantation has not been found effective in treating all hematopoietic disorders. Little is known about the developing fetal immune system and its potential to reject foreign cells. We are investigating the functional capacities of fetal NK- and T-cells to determine if they may contribute to graft rejection in the fetus. We are also studying the potential benefits of donor NK cells and T-cell subpopulations in aiding engraftment in utero. Our hypothesis is that certain mature cell populations can facilitate immune tolerance induction and stem cell engraftment when transplanted along with donor stem cells. We are studying the use of these cells in a murine model of in utero transplantation. One goal is to achieve tolerance induction in utero that will aid in subsequent post-natal transplant therapy.
Maternal Chimerism and Pediatric Disease. The barrier between a mother and her fetus is not absolute and cells can sometimes pass from one to the other. Research in the laboratory is focused on two aspects of this exchange in cells. One is the possibility of using fetal cells found in the mother’s circulation as a source of cells for prenatal diagnostic testing that doesn’t pose any threat to the fetus. The other aspect of the research concerns the possibility that in rare circumstances maternal cells that enter the fetus may be the cause of some childhood diseases. We are studying the possible role that maternal cells have in causing the pediatric diseases biliary atresia and inflammatory bowl disease. We have documented maternal chimerism in these illnesses and we’re studying the link between chimerism and the etiology of these diseases.
Suskind DL, Muench MO. Searching for common stem cells of the hepatic and hematopoietic systems in the human fetal liver: CD34+ cytokeratin 7/8+ cells express markers for stellate cells. J. Hepatol. 40:261-268, 2004.
Suskind DL, Rosenthal P, Heyman M, Kong D, Magrane G, Baxter-Lowe L-A, Muench MO. Maternal microchimerism in the livers of patients with biliary atresia. BMC Gastroenterol.4:14 (7 pages), 2004.
Muench MO. In utero transplantation: baby steps towards an effective therapy. Bone Marrow Transplant. 35:537-547, 2005.
Muench MO, Ohkubo T, Smith CA, Suskind DL, Bárcena A. Maintenance of proliferative capacity and retroviral transduction efficiency of human fetal CD38-CD34++ stem cells. Stem Cells Dev. 15:97-108, 2006.
Chen JC, Chang ML, Muench MO. Persistence of allografts in the peritoneal cavity after prenatal transplantation in mice. Transfusion (In Press), 2007.
Chen JC, Chang ML, Huang SF, Chang PY, Muench MO, Fu RH, Ou LS, Kuo ML. Prenatal tolerance induction: Relationship between cell dose, marrow T-cells, chimerism and tolerance. Cell Transplant. (In Press), 2007.