The literature is full of the nomenclature of ESC subtypes which are obtained from blastocysts by either changing culture conditions or isolation from different original parent cell peri-implantation as opposed to preimplantation. These sources of stem cells are not pluripotent although they may share some features of ESCs and are not considered ESCs. For instance, EpiSCs can originate from epiblast of peri-implantation ICM or other stem cell (SC) lines from the trophoblast (TS) or extraembryonic endoderm (XEN), and they are not pluripotent. The ICM and epiblast of the mouse embryo, and presumably the human analogies, are dynamic cell populations whose interactions with the extraembryonic tissues surrounding them are crucial for cell-fate determination. Also, the facile interconversions of stem cells types may reflect an underlying heterogeneity within mouse ESC and EpiSC populations.

Different types of ESCs have a very plastic phenotype although a commonly shared genetic network of transcription factors maintains the pluripotent state. The analysis of human ESC cultures shows that they have high heterogeneity and there are subpopulations identified by flow cytometry. Cells with the greatest capacity to renew themselves express the highest level of pluripotency genes and are at the top of the pluripotency hierarchy [9]. Many cells can co-express both lineage-specific genes and pluripotency genes; however, those with pluripotency genes only are at the top of pluripotency hierarchy. Importantly in stem cell biology, it is the balance of transcription factors which maintains the cell in the “stem state” capable of pluripotency. Extracellular signaling, propagated through intracellular signal-transduction pathways, maintains the genetic network that controls the “on and off” switch for pluripotency [10, 11]. The key signaling systems that maintain stem cells in their pluripotent state include transforming growth factor β (TGFβ), growth factors that signal through receptor tyrosine kinases (RTKs), WNTs, leukemia inhibitory factor (LIF), and JAK-STAT [12]. The key signal in maintaining pluripotency is LIF/STAT3; conversely, it is the FGF/MAPK/TGFb/activin pathway that has been shown to induce differentiation and drive lineage and cellular commitment [12].

Stem cell plasticity is critical to enable the body to respond to adapt to cellular loss or changing demands in cell production, tissue maintenance, remodeling, or regeneration in adults. Experimentally, data from mouse models differ from human stem cell discovery, since distinct phenotypic stem cells are experimentally accessible from all states of murine embryogenesis, suggesting that pluripotency is a continuum versus a transient window of time (Table 11.1). The various states of mouse stem cells suggest that these cells have reached different stages of developmental potential. There is more developmental equivalence demonstrated between human ESCs and mouse EpiSCs than other pluripotent cell types derived from the mouse embryo (Table 11.1). Unlike mouse ESCs, both human ESCs and mouse EpiSCs (1) require nodal or activin signals to maintain their pluripotent state, (2) neither requires LIF to maintain the pluripotent state, and (3) both grow poorly after dissociation into single cells. Notably there are differences in their cell-surface marker expression and gene expression.

The most studied stem cells are the ESCs, and the knowledge obtained from their discovery has directed the subsequent investigation of various types of nonembryonic stem cells, so a discussion of the definition of “stemness” is critical.

Investigators need to prove the following essential features to confirm “stemness” which includes the following properties and functional characteristics: