Abstract
Experiments were conducted to redirect mouse Embryonic Stem (ES) cells from a tumorigenic phenotype to a normal mammary epithelial phenotype in vivo. Mixing LacZ-labeled ES cells with normal mouse mammary epithelial cells at ratios of 1∶5 and 1∶50 in phosphate buffered saline and immediately inoculating them into epithelium-divested mammary fat pads of immune-compromised mice accomplished this. Our results indicate that tumorigenesis occurs only when normal mammary ductal growth is not achieved in the inoculated fat pads. When normal mammary gland growth occurs, we find ES cells (LacZ+) progeny interspersed with normal mammary cell progeny in the mammary epithelial structures. We demonstrate that these progeny, marked by LacZ expression, differentiate into multiple epithelial subtypes including steroid receptor positive luminal cells and myoepithelial cells indicating that the ES cells are capable of epithelial multipotency in this context but do not form teratomas. In addition, in secondary transplants, ES cell progeny proliferate, contribute apparently normal mammary progeny, maintain their multipotency and do not produce teratomas.
Highlights
In earlier publications, we demonstrated that dispersed mouse testicular, neural, bone-marrow-derived cells and mouse and human cancer cells were redirected to normal mammary epithelial cell fates when inoculated into epithelium-cleared mammary fat pads with normal mouse mammary epithelial cells (MEC’s) [1,2,3,4,5]
MECs direct Embryonic Stem (ES) cells to adapt a mammary cell fate When ES cells are transplanted into the cleared fat pad of nude mice, teratomas formed in all cases (Table 1, Fig. 1)
To test whether this effect was manifest in mixtures of tumorigenic totipotent ES cells and mouse mammary epithelial cells, we utilized mouse embryonic stem cells that constitutively express E. coli beta-galactosidase
Summary
We demonstrated that dispersed mouse testicular, neural, bone-marrow-derived cells and mouse and human cancer cells were redirected to normal mammary epithelial cell fates when inoculated into epithelium-cleared mammary fat pads with normal mouse mammary epithelial cells (MEC’s) [1,2,3,4,5]. Mouse embryonic stem cells (referred to as ES cells in these experiments), are derived from the inner cell mass of the blastocyst before germ layer formation occurs in the early embryo and are capable of forming all cell types of the developing and adult mouse [6] Because of this unique potential, they can be used to identify developmentally relevant signals that pattern the embryo to form tissues and organs. Studies by G Barry Pierce showed that only the undifferentiated cells in these tumors give rise to teratomas, the differentiated cells do not [6,7,9] Utilizing these undifferentiated cells allows evaluation of the mammary microenvironment’s ability to reprogram embryonic cells that have not yet committed to a cell fate, and test the mammary gland’s capacity to alter the teratoma-forming capability of mouse ES cells. We demonstrate that the mammary microenvironment is sufficient to suppress ES cell induced tumorigenesis and to provide signals necessary to induce differentiation of ES cells to a mammary cell fate
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