Stem cells refer to the cells that have two fundamental properties that define their “stemness” characteristics: self-renewal and multipotency. During development, stem cells and resulting progenitor cells are responsible for generating all the tissues and cells of an organism. In adult, stem cells exist in many tissues throughout life and may play critical roles in tissue regeneration and repair. Mammalian embryonic stem cells (ESCs) derived from the inner mass of the embryonic blastocyst are pluripotent, which means that they have the ability to generate all types of cells in an adult animal. Tissue-specific stem cells have limited ability for differentiation and generally are committed to create the mature cells in the tissues where they reside. For example, neural stem cells (NSCs) could give rise to major cell types in the central nervous system (CNS), including neurons, astrocytes, and oligodendrocytes, whereas hematopoietic stem cells (HSCs) have the potential to produce all lineages of blood cells, such as Erythrocytes, B-lymphocytes, T-lymphocytes.
The development of a mammalian organism begins from the zygote (fertilized egg). The zygotye is totipotent, which means that it has the potential to develop into a complete organism, as well as extra embryonic tissues. The first visible cell differentiation in a developing zygote is the formation of the blastocyst that consists of trophoblasts, inner cell mass, and blastocyst cavity [1
]. ESCs are experimentally derived from inner cell mass of blastocysts by following specific in vitro culture conditions. The closest resemblance, but not identical counter part, of ESCs in vivo is epiblasts that appear at E6-6.5 (embryonic day) in mice. Under an optimal in vitro maintenance condition, ESCs are pluripotent with the ability to generate stem cells and subsequent differentiated cells of all three germ layers, ectoderm, mesoderm, and endoderm both in culture dishes and upon transplantation into developing embryos [1
]. Unlike the zygote, ESCs can not differentiate into extra-embryonic tissues such as yolk sac [2
]. ESCs are ideal stem cells for both research and cell-based therapies both because that they can be cultured almost indefinitely without altering their stem cell properties and because that they have the potential to regenerate all types of cells and organs in an adult animal or a human being. However, despite great public interest and significant scientific advances in understanding ESCs, many critical questions remain. How do ESCs maintain their pluripotency? During ESC differentiation, how are those genes essential for pluripotency silenced, while other genes specific for differentiated cells activated? How do some of the genes essential for pluripotency become silenced during fetal development but are expressed again in the next generation germ cells? These are some of the most critical questions that need to be answered in ESC field.
Neurogenesis is defined as the process of generating new neurons from NSCs, which consists of the proliferation and fate determination of NSCs, migration and survival of young neurons, and maturation and integration of newly matured neurons [3
]. To date, it is well accepted that adult mammalian brains have two regions with persistent neurogenic capabilities: one is the subventricular zone (SVZ) in the lateral ventricle and another one is the subgranular zone (SGZ) in the dentate gyrus of the hippocampus. The presence of neurogenesis in these two regions have been demonstrated in many species including primates [5
] and humans [7
]. Due to a lack of NSC-specific marker, the identity of true NSCs in vivo is still unclear. Experimental evidence suggests that adult NSCs may have originated from neuroepithelial cells or radial glia during initial neurogenic phase of embryos. These cells evolve into a subset of astrocytes that preserve their stem cell properties in the neurogenic niche of adult brains [9
]. Recent advances have revealed that many mechanisms are involved in the regulation of neurogenesis: physiological activities including running, learning and memory, and enriched environment [10
]; hormones [11
]; growth factors such as Fgf and Vegf [12
]; transcription factors such as Tlx [14
], Bmi-1 [15
], and Sox2 [16
]; and diseases including epilepsy [19
] and stroke [20
One fundamental question in understanding neurogenesis is why the adult brain has such limited neurogenic potential compared to that in the embryonic brain. The reason might be that adult neurogenesis is mechanistically different from embryonic neurogenesis. For adult neurogenesis, multipotent NSCs are in intimate contact with the surrounding glia and the fate of NSCs is affected by their microenvironment (so-called “stem niche”) [22
]. For example, mice lacking sonic hedgehog [26
], Tlx [14
], Bmi-1 [15
], and Mbd1 [27
] have profound deficits in postnatal neurogenesis but not in embryonic neural development. In addition, adult NSCs also process different intrinsic properties as compared to their embryonic counterparts. For example, isolated embryonic NSCs can generate much more diverse types of neurons than adult NSCs upon transplantation into embryonic brains [28
]. This is likely due to the differences in the genetic and epigenetic programs between adult and embryonic NSCs. Consistent with this, we found that Mbd1−/−
adult NSCs expressed abnormally higher levels of basic fibroblast growth factor (Fgf-2) and exhibited increased aneuploidy while NSCs isolated from Mbd1−/−
embryonic day 14 (E14) or neonate (P1) brains did not [27
]. Understanding the molecular mechanism of adult neurogenesis and adult NSCs is a critical step towards their therapeutic applications.
Although significant advances have been achieved concerning the biology of stem cells, how stem cells maintain their “stemness” remains to be answered. Recently, epigenetic regulations of development and cell fate determination have come to the center stage of stem cell biology and we will review how epigenetic mechanisms could determine ‘stem cells signature’ and play crucial roles in regulating gene expression and stem cell functions.