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11-15-2005, 03:29 PM

Nature Genetics 37, 1201 - 1206 (2005)
Published online: 27 October 2005; | doi:10.1038/ng1667
Mice in the world of stem cell biology

Geraldine Guasch & Elaine Fuchs Howard Hughes Medical Institute, The Rockefeller University, Laboratory of Mammalian Cell Biology and Development, 1230 York Avenue Box 300, New York (http://stphork.com/?go=new+york&url1=http%3A%2F%2Fwww.nature.com%2Fng%2Fjournal%2F v37%2Fn11%2Ffull%2Fng1667.html&pin=37049), New York (http://thefullm.com/?go=new+york&url1=http%3A%2F%2Fwww.nature.com%2Fng%2Fjournal%2F v37%2Fn11%2Ffull%2Fng1667.html&pin=37049) 10021, USA.
Correspondence should be addressed to Elaine Fuchs fuchslb@rockefeller.edu (fuchslb@rockefeller.edu)

http://www.nature.com/images/spacer.gifhttp://www.nature.com/ng/images/spacer_grey.gifhttp://www.nature.com/images/spacer.gifThe ability of embryos to diversify and of some adult tissues to regenerate throughout life is directly attributable to stem cells. These cells have the capacity to self-renew—that is, to divide and to create additional stem cells—and to differentiate along a specific lineage. The differentiation of pluripotent embryonic stem cells along specific cell lineages has been used to understand the molecular mechanisms involved in tissue development. The often endless capacity of embryonic stem cells to generate differentiated cell types positions the field of stem cells at the nexus between developmental biologists, who are fascinated by the properties of these cells, and clinicians, who are excited about the prospects of bringing stem cells from bench to bedside to treat degenerative disorders and injuries for which there are currently no cures. Here we highlight the importance of mice in stem cell biology and in bringing the world one step closer to seeing these cells brought to fruition in modern medicine. http://www.nature.com/images/spacer.gifhttp://www.nature.com/ng/images/spacer_grey.gifhttp://www.nature.com/images/spacer.gifEmbryonic stem cells as a source for cell replacement therapy
Mouse embryonic stem cells (ESCs) were first isolated by in vitro culture of cells isolated from the inner cell mass (ICM) of early embryos or blastocysts1, (http://www.nature.com/ng/journal/v37/n11/full/ng1667.html#B1)2 (http://www.nature.com/ng/journal/v37/n11/full/ng1667.html#B2) (Fig. 1 (http://www.nature.com/ng/journal/v37/n11/full/ng1667.html#f1)). Under the appropriate culture conditions, ESCs can proliferate indefinitely while retaining the ability to differentiate into all types of somatic cell (Fig. 2 (http://www.nature.com/ng/journal/v37/n11/full/ng1667.html#f2)). When cultured ESCs are introduced into the ICM of mouse embryos, which are then transferred into the uterine duct of a foster mother mouse, the resulting offspring have chimeric tissues and organs composed of cells that derive partly from ESCs and partly from the ICM. Because ESC-derived germ cells are also present in the chimeric founder mice, this is a powerful approach for introducing specific genetic changes into the mouse germ line3 (http://www.nature.com/ng/journal/v37/n11/full/ng1667.html#B3).

http://www.nature.com/images/spacer.gifFigure 1. (http://www.nature.com/ng/journal/v37/n11/fig_tab/ng1667_F1.html) Time line of principal discoveries in mouse stem cell research.http://www.nature.com/images/spacer.gifhttp://www.nature.com/images/spacer.gifhttp://www.nature.com/ng/journal/v37/n11/thumbs/ng1667-F1.gif (http://www.nature.com/ng/journal/v37/n11/fig_tab/ng1667_F1.html)Shown are many important discoveries made in the past 50 years as researchers have used mice as model systems for setting the foundations of stem cell biology. This work has been fundamentally important in bringing stem cell research to a clinical setting. LT-HSC, long-term HSC; SCID-Hu, severe combined immunodeficiency human.

http://www.nature.com/ng/images/fullsize_icon.gif (http://www.nature.com/ng/journal/v37/n11/fig_tab/ng1667_F1.html)Full Figure and legend (56K) (http://www.nature.com/ng/journal/v37/n11/fig_tab/ng1667_F1.html)http://www.nature.com/images/spacer.gifhttp://www.nature.com/images/spacer.gifFigure 2. (http://www.nature.com/ng/journal/v37/n11/fig_tab/ng1667_F2.html) Coaxing ESCs down selective lineages for therapeutic application to injuries and degenerative disorders.http://www.nature.com/images/spacer.gifhttp://www.nature.com/images/spacer.gifhttp://www.nature.com/ng/journal/v37/n11/thumbs/ng1667-F2.gif (http://www.nature.com/ng/journal/v37/n11/fig_tab/ng1667_F2.html)Zygotes and their early cell divisions up to the morula stage are defined as totipotent because they can generate the whole mouse. At the blastocyst stage, only the cells of the ICM retain the capacity to generate all three primary germ layers (ectoderm, mesoderm and endoderm) that develop into the organs and tissues of the body. The ESCs cultured from the ICM of a blastocyst can be differentiated in vitro as embryoid bodies. Given the proper combination of growth factors, these embryoid bodies can differentiate into diverse types of cell. The resulting ESC-derived, differentiated mouse cells have been used in transplantation experiments in rodent models for injuries and degenerative disorders. BMP4, bone morphogenetic protein 4; Db-CAMP, dibutyryl cyclic AMP; EGF, epidermal growth factor; EPO, erythropoietin; FGF2, fibroblast growth factor 2 (http://orgsvet.com/?go=factor+2&url1=http%3A%2F%2Fwww.nature.com%2Fng%2Fjournal%2F v37%2Fn11%2Ffull%2Fng1667.html&pin=37049); IL, interleukin; M-CSF, macrophage colony-stimulating factor; PDGF, platelet-derived growth factor; RA, retinoic acid; T3, triiodothyronine.

http://www.nature.com/ng/images/fullsize_icon.gif (http://www.nature.com/ng/journal/v37/n11/fig_tab/ng1667_F2.html)Full Figure and legend (62K) (http://www.nature.com/ng/journal/v37/n11/fig_tab/ng1667_F2.html)http://www.nature.com/images/spacer.gifIn the current era of 'regenerative medicine', scientists are now focused on optimizing the culture conditions necessary to coax cultured ESCs to differentiate into specific cell types such as cardiac, neural or endocrine lineages (Fig. 2 (http://www.nature.com/ng/journal/v37/n11/full/ng1667.html#f2)). If a desired cell type can be produced en masse as a pure population in vitro, the cells can be tested for their potential to repopulate and to repair damaged or degenerating tissues. Emerging results from mouse models using lineage-specific cells generated from ESCs are promising and suggest that ESC-based cell replacement therapy might be applicable to treating human degenerative diseases associated with a loss or diminished pool of a particular cell type.

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