Embryonic stem cells (ESCs) are the cells of the
inner cell mass of a
blastocyst, formed prior to
implantation in the uterus. In
human embryonic development the
blastocyst stage is reached 4–5 days after
fertilization, at which time it consists of 50–150 cells. ESCs are
pluripotent and give rise during development to all derivatives of the three
germ layers:
ectoderm,
endoderm and
mesoderm. In other words, they can develop into each of the more than 200 cell types of the adult
body when given sufficient and necessary stimulation for a specific cell type. They do not contribute to the
extraembryonic membranes or to the
placenta. During embryonic development the cells of the inner cell mass continuously divide and become more specialized. For example, a portion of the ectoderm in the dorsal part of the embryo specializes as '
neurectoderm', which will become the future
central nervous system (CNS). Later in development,
neurulation causes the neurectoderm to form the
neural tube. At the neural tube stage, the anterior portion undergoes
encephalization to generate or 'pattern' the basic form of the brain. At this stage of development, the principal cell type of the CNS is considered a
neural stem cell. The neural stem cells self-renew and at some point transition into
radial glial progenitor cells (RGPs). Early-formed RGPs self-renew by symmetrical division to form a reservoir group of
progenitor cells. These cells transition to a
neurogenic state and start to divide
asymmetrically to produce a large diversity of many different neuron types, each with unique gene expression, morphological, and functional characteristics. The process of generating neurons from radial glial cells is called
neurogenesis. The radial glial cell, has a distinctive bipolar morphology with highly elongated processes spanning the thickness of the neural tube wall. It shares some
glial characteristics, most notably the expression of
glial fibrillary acidic protein (GFAP). The radial glial cell is the primary neural stem cell of the developing
vertebrate CNS, and its cell body resides in the
ventricular zone, adjacent to the developing
ventricular system. Neural stem cells are committed to the neuronal lineages (
neurons,
astrocytes, and
oligodendrocytes), and thus their potency is restricted. Human ESCs are grown on a feeder layer of mouse embryonic
fibroblasts and require the presence of basic fibroblast growth factor (bFGF or FGF-2). Without optimal culture conditions or genetic manipulation, embryonic stem cells will rapidly differentiate. A human embryonic stem cell is also defined by the expression of several transcription factors and cell surface proteins. The transcription factors
Oct-4,
Nanog, and
Sox2 form the core regulatory network that ensures the suppression of genes that lead to differentiation and the maintenance of pluripotency. The cell surface antigens most commonly used to identify hES cells are the glycolipids
stage specific embryonic antigen 3 and 4, and the keratan sulfate antigens Tra-1-60 and Tra-1-81. The molecular definition of a stem cell includes many more proteins and continues to be a topic of research. By using human embryonic stem cells to produce specialized cells like nerve cells or heart cells in the lab, scientists can gain access to adult human cells without taking tissue from patients. They can then study these specialized adult cells in detail to try to discern complications of diseases, or to study cell reactions to proposed new drugs. Because of their combined abilities of unlimited expansion and pluripotency, embryonic stem cells remain a theoretically potential source for
regenerative medicine and tissue replacement after injury or disease. However, there are currently no approved treatments using ES cells. The first human trial was approved by the US Food and Drug Administration in January 2009. However, the human trial was not initiated until October 13, 2010, in Atlanta for
spinal cord injury research. On November 14, 2011, the company conducting the trial (
Geron Corporation) announced that it will discontinue further development of its stem cell programs. Differentiating ES cells into usable cells while avoiding transplant rejection are just a few of the hurdles that embryonic stem cell researchers still face. Embryonic stem cells, being pluripotent, require specific signals for correct differentiation – if injected directly into another body, ES cells will differentiate into many different types of cells, causing a
teratoma. Many nations currently have
moratoria or limitations on either human ES cell research or the production of new human ES cell lines due to their ethical controversies. File:Mouse embryonic stem cells.jpg|
Mouse embryonic stem cells with fluorescent marker File:Human embryonic stem cell colony phase.jpg| Human embryonic stem cell colony on mouse embryonic fibroblast feeder layer The use of embryonic stem cells has generated significant ethical and political controversy. Central to the debate is the moral status of the human embryo, as deriving ES typically involves the destruction of early-stage embryos. Critics argue that this practice violates the sanctity of human life, and therefore is unacceptable.
Mesenchymal stem cells Mesenchymal stem cells (MSC) or mesenchymal stromal cells, also known as medicinal signaling cells are known to be multipotent, which can be found in adult tissues, for example, in the muscle, liver, bone marrow and adipose tissue. Mesenchymal stem cells usually function as structural support in various organs as mentioned above, and control the movement of substances. MSC can differentiate into numerous cell categories as an illustration of adipocytes, osteocytes, and chondrocytes, derived by the mesodermal layer. Where the mesoderm layer provides an increase to the body's skeletal elements, such as relating to the cartilage or bone. The term "meso" means middle, infusion originated from the Greek, signifying that mesenchymal cells are able to range and travel in early embryonic growth among the ectodermal and endodermal layers. This mechanism helps with space-filling thus, key for repairing wounds in adult organisms that have to do with mesenchymal cells in the dermis (skin), bone, or muscle. Mesenchymal stem cells are known to be essential for regenerative medicine. They are broadly studied in
clinical trials. Since they are easily isolated and obtain high yield, high plasticity, which makes able to facilitate inflammation and encourage cell growth, cell differentiation, and restoring tissue derived from immunomodulation and immunosuppression. MSC comes from the bone marrow, which requires an aggressive procedure when it comes to isolating the quantity and quality of the isolated cell, and it varies by how old the donor. When comparing the rates of MSC in the bone marrow aspirates and bone marrow stroma, the aspirates tend to have lower rates of MSC than the stroma. MSC are known to be heterogeneous, and they express a high level of pluripotent markers when compared to other types of stem cells, such as embryonic stem cells.
Cell cycle control Embryonic stem cells (ESCs) have the ability to divide indefinitely while keeping their
pluripotency, which is made possible through specialized mechanisms of
cell cycle control. Compared to proliferating
somatic cells, ESCs have unique cell cycle characteristics—such as rapid cell division caused by shortened
G1 phase, absent
G0 phase, and modifications in
cell cycle checkpoints—which leaves the cells mostly in
S phase at any given time. ESCs' rapid division is demonstrated by their short doubling time, which ranges from 8 to 10 hours, whereas somatic cells have doubling time of approximately 20 hours or longer. As cells differentiate, these properties change: G1 and G2 phases lengthen, leading to longer cell division cycles. This suggests that a specific cell cycle structure may contribute to the establishment of pluripotency. In human ESCs (hESCs), the duration of G1 is dramatically shortened. This has been attributed to high mRNA levels of G1-related Cyclin D2 and Cdk4 genes and low levels of cell cycle regulatory proteins that inhibit cell cycle progression at G1, such as
p21CipP1,
p27Kip1, and p57Kip2. Furthermore, regulators of Cdk4 and Cdk6 activity, such as members of the Ink family of inhibitors (p15, p16, p18, and p19), are expressed at low levels or not at all. Thus, similar to mESCs, hESCs show high Cdk activity, with Cdk2 exhibiting the highest kinase activity. Also similar to mESCs, hESCs demonstrate the importance of Cdk2 in G1 phase regulation by showing that G1 to S transition is delayed when Cdk2 activity is inhibited and G1 is arrest when Cdk2 is knocked down. However unlike mESCs, hESCs have a functional G1 phase. hESCs show that the activities of Cyclin E/Cdk2 and Cyclin A/Cdk2 complexes are cell cycle-dependent and the Rb checkpoint in G1 is functional. ESCs are also characterized by G1 checkpoint non-functionality, even though the G1 checkpoint is crucial for maintaining genomic stability. In response to
DNA damage, ESCs do not stop in G1 to repair DNA damages but instead, depend on S and G2/M checkpoints or undergo apoptosis. The absence of G1 checkpoint in ESCs allows for the removal of cells with damaged DNA, hence avoiding potential mutations from inaccurate DNA repair. Consistent with this idea, ESCs are hypersensitive to DNA damage to minimize mutations passed onto the next generation. ==Fetal==