http://maxweber.hunter.cuny.edu/eres/docs/eres/BIOL750_HENDERSON/501Weissman.pdf

Stem cells: units of development, units of regeneration, and units in evolution.

The discovery of mouse embryonic stem (ES) cells >20 years ago represented a major advance in biology and experimental medicine, as it enabled the routine manipulation of the mouse genome. Along with the capacity to induce genetic modifications, ES cells provided the basis for establishing an in vitro model of early mammalian development and represented a putative new source of differentiated cell types for cell replacement therapy. While ES cells have been used extensively for creating mouse mutants for more than a decade, their application as a model for developmental biology has been limited and their use in cell replacement therapy remains a goal for many in the field. Recent advances in our understanding of ES cell differentiation, detailed in this review, have provided new insights essential for establishing ES cell-based developmental models and for the generation of clinically relevant populations for cell therapy.

/pdf/embryonic-stem-cell-differentiation-emergence-of-a-new-era-36tt7979am.pdf

Embryonic stem cell differentiation: emergence of a new era in biology and medicine

Germ cell fate in mice is induced in pluripotent epiblast cells in response to signals from extraembryonic tissues. The specification of approximately 40 founder primordial germ cells and their segregation from somatic neighbours are important events in early development. We have proposed that a critical event during this specification includes repression of a somatic programme that is adopted by neighbouring cells. Here we show that Blimp1 (also known as Prdm1), a known transcriptional repressor, has a critical role in the foundation of the mouse germ cell lineage, as its disruption causes a block early in the process of primordial germ cell formation. Blimp1-deficient mutant embryos form a tight cluster of about 20 primordial germ cell-like cells, which fail to show the characteristic migration, proliferation and consistent repression of homeobox genes that normally accompany specification of primordial germ cells. Furthermore, our genetic lineage-tracing experiments indicate that the Blimp1-positive cells originating from the proximal posterior epiblast cells are indeed the lineage-restricted primordial germ cell precursors.

Blimp1 is a critical determinant of the germ cell lineage in mice

Stem cells are the natural units of embryonic generation, and also adult regeneration, of a variety of tissues. Recently, the list of tissues that use the model of differentiation from stem to progenitor to mature cell has increased from blood to include a variety of tissues, including both central and peripheral nervous systems and skeletal muscle; it is also possible that all organs and tissues are derived from, and still contain, stem cells. Because the number and activities of stem cells and their progeny are homeostatically regulated, clinical stem cell transplantation could greatly add to the physician's armamentarium against degenerative diseases.

https://science.sciencemag.org/content/sci/287/5457/1442.full.pdf

Translating stem and progenitor cell biology to the clinic: barriers and opportunities.

Early Lineage Segregation between Epiblast and Primitive Endoderm in Mouse Blastocysts through the Grb2-MAPK Pathway

Two distinct patterns of chimaerism were found in conceptuses produced by injecting dissociated 4.5-day inner cell mass cells into genetically dissimilar blastocysts. Pattern 1: donor cells were found in the endoderm layer of the visceral yolk sac, but not in the adjacent mesoderm layer of this organ or in the foetus itself. Pattern 2: donor cells were found in the mesoderm layer of the visceral yolk sac and/or foetus, but never in the yolk-sac endoderm as well. Primitive endoderm cells of donor inner cell masses are responsible for the first pattern and primitive ectoderm cells for the second. These results, together with those of previous studies, suggest that the entire foetus, including its endodermal components, is formed from the primitive ectoderm, and that primitive endoderm forms only extra-embryonic endoderm of the conceptus.

/pdf/investigation-of-the-fate-of-4-5-day-post-coitum-mouse-inner-2rtqlad7ig.pdf

Investigation of the fate of 4.5 Day post-coitum mouse inner cell mass cells by blastocyst injection.

Inner cell masses (ICMs) were dissected from 3 1/2- and 4 1/2-day mouse blastocysts and inserted into empty zonae before transfer to the oviducts of pseudopregnant mice. The ICMs survived in the oviduct for at least 2 days with little evidence of reduction in cell number. After 1 day, isolated 3 1/2-day ICMs were still viable, since they could form chimaeras when injected into 3 1/2-day blastocysts. However, no evidence of trophoblast formation could be detected in any of the isolated ICMs, despite exposure of some of their cells to 'outside' conditions. This is further evidence that ICM cells, although not overtly differentiated, are determined by 3 1/2 days. Although no trophoblast was formed, 3 1/2-day ICMs formed an outer endoderm layer after 1 day in the oviduct, as judged by light and electron microscopical evidence. It is suggested that cell position may be important in endoderm differentiation.

Investigation of the determinative state of the mouse inner cell mass. II. The fate of isolated inner cell masses transferred to the oviduct.

Inner cell masses (ICMs) were dissected from 3 1/2- and 4 1/2-day blastocysts and cultured in contact with 2 1/2-day morulae Blastocysts and morulae were homozygous for different electrophoretic variants of the enzyme glucose phosphate isomerase (GPI) Aggregation of ICMs and morulae was observed, and such aggregates were able to form blastocysts in vitro and morphologically normal foetuses in utero GPI analysis of these conceptuses revealed that most were chimaeric However, donor ICM-type isozyme was only detected in the embryonic and extra-embryonic fractions of the chimaeras and never in the trophoblastic fraction Thus, ICM cells appear unable to form trophoblast derivatives even when exposed to 'outside' conditions as experienced by developing trophoblast cells This is evidence that ICM cells, although not overtly differentiated, are determined by 3 1/2 days

J. Rossant

Papers

Investigation of the fate of 4.5 Day post-coitum mouse inner cell mass cells by blastocyst injection.

Investigation of the determinative state of the mouse inner cell mass. II. The fate of isolated inner cell masses transferred to the oviduct.

Investigation of the determinative state of the mouse inner cell mass. I. Aggregation of isolated inner cell masses with morulae.