Investigating the role of hemaotopoietic plasticity for normal mouse development

Abstract

Hematopoietic cells have been reported to convert into several non-hematopoietic cell types after transplantation. This raises the possibility that differentiation plasticity of hematopoietic cells is important for normal mammalian development. Here, we this question by non-invasive lineage tracing, using hepatocytes and endothelial cells as paradigms. To this end, we developed a transgenic mouse model, in which Cre recombinase under control of promoter elements of the vav gene catalyzes the irreversible activation of a reporter gene in blood cells, thereby establishing a cellular memory. Analysis of the hematopoietic system of such vav ancestry mice revealed essentially complete labeling of fetal and adult HSCs as well as mature hematopoietic cells such as tissue macrophages. Thus, vav ancestry mice allow tracing hematopoietic plasticity throughout development.;The analysis of hepatocytes in vav ancestry mice revealed a frequency of about 1:100,000 labeled cells in 3 month old mice, which increased to about 1:50,000 in 12 month old animals. Similar frequencies were found in lysozyme ancestry mice, a lineage tracing model in which all tissue macrophages and a small subset of all other hematopoietic cells, including HSCs, are labeled. This indicates ongoing, but very rare, macrophage to hepatocyte conversions in unperturbed mice. Such conversions occur exclusively after fetal and early postnatal phases of liver growth, since no large clusters of labeled hepatocytes were found. The induction of liver injury suggested a link between prolonged liver inflammation and the induction of macrophage to hepatocyte conversions but the overall frequency of such conversions remained too low to be significant for liver regeneration. In contrast to hepatocytes, no endothelial cells of hematopoietic origin were found by the comparative analysis of vav and lysozyme ancestry mice. This finding held also true after bone marrow transplantation. Furthermore, no evidence for significant hematopoietic contributions to cell types such as neurons, lung epithelial cells, skeletal myotubes and cardiomyocytes was found. Thus, our work shows that hematopoietic cells are tightly restricted in their differentiation potential in the mouse embryo and that hematopoietic plasticity plays no significant role in organ formation and maintenance.