Cell potency

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Cell potency is a cell's ability to differentiate into other cell types.[1][2] The more cell types a cell can differentiate into, the greater its potency. Potency is also described as the gene activation potential within a cell which like a continuum begins with totipotency to designate a cell with the most differentiation potential, pluripotency, multipotency, oligopotency and finally unipotency. Potency is taken from the Latin term "potens" which means "having power."

File:Stem cells diagram.png
Pluripotent, embryonic stem cells originate as inner mass cells within a blastocyst. These stem cells can become any tissue in the body, excluding a placenta. Only the morula's cells are totipotent, able to become all tissues and a placenta.

Totipotency

Totipotency is the ability of a single cell to divide and produce all of the differentiated cells in an organism, and example totipotent cells are spores and zygotes.[3] In the spectrum of cell potency, totipotency represents the cell with the greatest differentiation potential. Toti comes from the Latin totus which means "entirely."

It is possible for a fully differentiated cell to return to a state of totipotency.[4] This conversion to totipotency is complex, not fully understood and the subject of recent research. Research in 2011 has shown that cells may differentiate not into a fully totipotent cell, but instead into a "complex cellular variation" of totipotency.[5]

The human development model is one which can be used to describe how totipotent cells arise.[6] Human development begins when a sperm fertilizes an egg and the resulting fertilized egg creates a single totipotent cell, a zygote.[7] In the first hours after fertilization, this zygote divides into identical totipotent cells, which can later develop into any of the three germ layers of a human (endoderm, mesoderm, or ectoderm), into cells of the cytotrophoblast layer or syncytiotrophoblast layer of the placenta. After reaching a 16-cell stage, the totipotent cells of the morula differentiate into cells that will eventually become either the blastocyst's Inner cell mass or the outer trophoblasts. Approximately four days after fertilization and after several cycles of cell division, these totipotent cells begin to specialize. The inner cell mass, the source of embryonic stem cells, becomes pluripotent.

Research on Caenorhabditis elegans suggests that multiple mechanisms including RNA regulation may play a role in maintaining totipotency at different stages of development in some species.[8] Work with zebrafish and mammals suggest a further interplay between miRNA and RNA binding proteins (RBPs) in determining development differences.[9]

In September 2013, a team from the Spanish national Cancer Research Centre were able for the first time to make adult cells from mice retreat to the characteristics of embryonic stem cells thereby achieving totipotency.[10]

Pluripotency

File:Human embryonic stem cells.png
A: Human embryonic stem cells (cell colonies that are not yet differentiated).
B: Nerve cells

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In cell biology, pluripotency (from the Latin plurimus, meaning very many, and potens, meaning having power)[11] refers to a stem cell that has the potential to differentiate into any of the three germ layers: endoderm (interior stomach lining, gastrointestinal tract, the lungs), mesoderm (muscle, bone, blood, urogenital), or ectoderm (epidermal tissues and nervous system).[12] However, cell pluripotency is a continuum, ranging from the completely pluripotent cell that can form every cell of the embryo proper, e.g., embyronic stem cells and iPSCs (see below), to the incompletely or partially pluripotent cell that can form cells of all three germ layers but that may not exhibit all the characteristics of completely pluripotent cells. In fact, there are variations and key differences even between cell populations that are considered "completely pluripotent".

Induced pluripotency

Template:Main Induced Pluripotent Stem Cells, commonly abbreviated as iPS cells or iPSCs are a type of pluripotent stem cell derived from a non-pluripotent cell, typically an adult somatic cell, by inducing a "forced" expression of certain genes and transcription factors.[13] These transcription factors play a key role in determining the state of these cells and also highlights the fact that these somatic cells do preserve the same genetic information as early embryonic cells. [14] This makes sense, as the DNA remains the same as an organism develops. The gene expression and epigenetic makeup of the DNA change, but reprogramming allows for the exogenous manipulation of these characteristics.

The ability to induce cells into a pluripotent state was initially pioneered using mouse fibroblasts and four transcription factors, Oct4, Sox2, Klf4 and c-Myc, in 2006.[15] For his work with reprogramming, Yamanaka received The Nobel Prize in Medicine in 2012 with John Gurdon.[16] Through the examination of gene expression and epigenetic patterns, Yamanaka et al.'s initial work with iPSCs suggested that the reprogramming of somatic cells might be "incomplete". [15] In other words, there were key differences between iPSCs and ESCs. Subsequent research was able to induce mouse iPSCs that appeared indistinguishable by epigenetics or differentiation potential. [17] [18] [19] However, without improved or repeated reprogramming methodologies, there still appears to be differences between the DNA methylation and gene expression patterns between the two pluripotent stem cells populations. [20]

The initial discovery was followed in 2007 with the successful induction of human iPSCs derived from human dermal fibroblasts using methods similar to those used for the induction of mouse cells.[21] These induced cells exhibit similar traits to those of embryonic stem cells (ESCs) but do not require the use of embryos. Some of the similarities between ESCs and iPSCs include pluripotency, morphology, self-renewal ability (a trait that implies that they can divide and replicate indefinitely) and gene expression.[22] However, as stated above, even with updated protocols, key differences in gene expression and epigenetic patterns suggest the two populations are not equivalent. [20]

These epigenetic differences are consequential. That is because Epigenetic factors are also involved in the reprogramming of somatic cells into pluripotent stem cells. Several epigenetic changes that occur in iPSCs include DNA methylation and histone modifications. These allow for the "opening up" of DNA; in other words, this allows for transcription to occur. Chromatin is thus reorganized in iPSCs, having a structure similar to chromatin found in ESCs, in which some loci become less condensed, making certain genes more accessible.[22]This aligns with the overall goal of reprogramming adult cells, as it allows them to express genes that may have been "turned off" along the differentiation pathway.

As stated above, recent studies have shown that epigenetic patterns, specifically DNA methylation, differ between iPSCs and ESCs, as well as between different iPSC lines.[23] This suggests a "memory" of iPSCs, as they appear to have different methylation based on their origin. [20] These epigenetic differences may cause iPSCs to behave differently than ESCs. As some iPSC lines retain somatic source-cell memory, they may be biased to differentiate into their source cell lineage.[24] Moreover, epigenetic patterns within iPSCs are transmitted to differentiated cells, which can alter the gene expression even in the differentiated progeny.[25] Some research groups have been able to reduce these epigenetic differences, thereby reducing epigenetic memory, through multiple passages or through differentiation and secondary reprogramming. <[20]

Despite this, ESCs and iPSCs are largely considered very similar. Due to this similarity, iPSCs have been of great interest to the medical and research community. iPSCs could potentially have the same therapeutic implications and applications as ESCs but without the controversial use of embryos in the process, a topic of great bioethical debate. In fact, the induced pluripotency of somatic cells into undifferentiated iPS cells was originally hailed as the end of the controversial use of embryonic stem cells. Induced Pluripotent Stem Cells even pose therapeutic advantages over ESCs, such as patient-specific lines. Some of the possible medical and therapeutic uses for iPSCs derived from patients include their use in cell and tissue transplants without the risk of rejection that is commonly encountered. iPSCs could also potentially replace animal models unsuitable as well as in-vitro models used for disease research.[26]

However, iPSCs were found to be potentially tumorigenic, and, despite advances, were never approved for clinical stage research in the United States.[13] Setbacks such as low replication rates and early senescence have also been encountered when making iPSCs, hindering their use as ESCs replacements.[27]

Transdifferentation

Additionally, it has been determined that the somatic expression of combined transcription factors can directly induce other defined somatic cell fates (transdifferentiation); researchers identified three neural-lineage-specific transcription factors that could directly convert mouse fibroblasts (skin cells) into fully functional neurons.[28] This result challenges the terminal nature of cellular differentiation and the integrity of lineage commitment; and implies that with the proper tools, all cells are totipotent and may form all kinds of tissue.


Naive vs. Primed Pluripotency States

Recent findings with respect to epiblasts before and after implantation have produced proposals for classifying pluripotency into two distinct phases: "naive" and "primed." [29]The baseline stem cells commonly used in science that are referred as Embryonic stem cells (ESCs) are derived from a pre-implantation epiblast; such epiblast is able to generate the entire fetus, and one epiblast cell is able to contribute to all cell lineages if injected into another blastocyst. On the other hand, several marked differences can be observed between the pre- and post-implantation epiblasts, such as their difference in morphology, in which the epiblast after implantation changes its morphology into a cup-like shape called the "egg cylinder" as well as chromosomal alteration in which one of the X-chromosomes undergoes random inactivation in the early stage of the egg cylinder, known as X-inactivation. [30] During this development, the egg cylinder epiblast cells are systematically targeted by Fibroblast growth factors, Wnt signaling, and other inductive factors via the surrounding yolk sac and the trophoblast tissue [31], such that they become instructively specific according to the spatial organization. [32] Another major difference that was observed, with respect to cell potency, is that post-implantation epiblast stem cells are unable to contribute to blastocyst chimeras [33], which distinguishes them from other known pluripotent stem cells. Cell lines derived from such post-implanation epiblasts are referred to as epiblast-derived stem cells which were first derived in laboratory in 2007; it should be noted, despite their nomenclature, that both ESCs and EpiSCs are derived from epiblasts, just at difference phases of development, and that pluripotency is still intact in the post-implantation epiblast, as demonstrated by the conserved expression of Nanog, Fut4, and Oct-4 in EpiSCs [34], until somitogenesis and can be reversed mid-way through induced expression of Oct-4. [35]

Multipotency

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File:Hematopoiesis (human) diagram.png
Hematopoietic steam cell is an example of multipotency. When it differentiate in myeloid or linphoid progenitor cell, it loss potency and become pluripotential cell with ability to give arise to all cells of its lineage.

Multipotency describes progenitor cells which have the gene activation potential to differentiate into multiple, but limited cell types. For example, a multipotent blood stem cell is a hematopoietic cell — and this cell type can differentiate itself into several types of blood cell types like lymphocytes, monocytes, neutrophils, etc., but cannot differentiate into brain cells, bone cells or other non-blood cell types.

New research related to multipotent cells suggests that multipotent cells may be capable of conversion into unrelated cell types. In one case, fibroblasts were converted into functional neurons.[28] In another case, human umbilical cord blood stem cells were converted into human neurons.[36] Research is also focusing on converting multipotent cells into pluripotent cells [37]

Multipotent cells are found in many, but not all human cell types. Multipotent cells have been found in adipose tissue,[38] cardiac cells,[39] bone marrow, and mesenchymal stromal cells (MSCs) which are found in the third molar.[40]

MSCs may prove to be a good, reliable source for stem cells because of the ease in collection of molars at 8–10 years of age and before adult dental calcification. MSCs can differentiate into osteoblasts, chondrocytes, and adipocytes.[41]

Oligopotency

In biology, oligopotency is the ability of progenitor cells to differentiate into a few cell types. It is a degree of potency. Examples of oligopotent stem cells are the lymphoid or myeloid stem cells.[1] A lymphoid cell specifically, can give rise to various blood cells such as B and T cells, however, not to a different blood cell type like a red blood cell.[42] Examples of progenitor cells are vascular stem cells that have the capacity to become both endothelial or smooth muscle cells.

Unipotency

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In cell biology, a unipotent cell is the concept that one stem cell has the capacity to differentiate into only one cell type. It is currently unclear if true unipotent stem cells exist. Hepatoblasts, which differentiate into hepatocytes (which constitute most of the liver) or cholangiocytes (epithelial cells of the bile duct), are bipotent.[43] A close synonym for unipotent cell is precursor cell.

See also

References

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