Cellular differentiation

In developmental biology, cellular differentiation is the process where a cell changes from one cell type to another.[2][3] Most commonly the cell changes to a more specialized type. Differentiation occurs numerous times during the development of a multicellular organism as it changes from a simple zygote to a complex system of tissues and cell types. Differentiation continues in adulthood as adult stem cells divide and create fully differentiated daughter cells during tissue repair and during normal cell turnover. Some differentiation occurs in response to antigen exposure. Differentiation dramatically changes a cell's size, shape, membrane potential, metabolic activity, and responsiveness to signals. These changes are largely due to highly controlled modifications in gene expression and are the study of epigenetics. With a few exceptions, cellular differentiation almost never involves a change in the DNA sequence itself. Thus, different cells can have very different physical characteristics despite having the same genome.

A specialized type of differentiation, known as 'terminal differentiation', is of importance in some tissues, for example vertebrate nervous system, striated muscle, epidermis and gut. During terminal differentiation a precursor cell formerly capable of cell division, permanently leaves the cell cycle, dismantles the cell cycle machinery and often expresses a range of genes characteristic of the cell's final function (e.g. myosin and actin for a muscle cell). Differentiation may continue to occur after terminal differentiation if the capacity and functions of the cell undergo further changes.

Among dividing cells, there are multiple levels of cell potency, the cell's ability to differentiate into other cell types. A greater potency indicates a larger number of cell types that can be derived. A cell that can differentiate into all cell types, including the placental tissue, is known as totipotent. In mammals, only the zygote and subsequent blastomeres are totipotent, while in plants many differentiated cells can become totipotent with simple laboratory techniques. A cell that can differentiate into all cell types of the adult organism is known as pluripotent. Such cells are called meristematic cells in higher plants and embryonic stem cells in animals, though some groups report the presence of adult pluripotent cells. Virally induced expression of four transcription factors Oct4, Sox2, c-Myc, and KIF4 (Yamanaka factors) is sufficient to create pluripotent (iPS) cells from adult fibroblasts.[4] A multipotent cell is one that can differentiate into multiple different, but closely related cell types.[5] Oligopotent cells are more restricted than multipotent, but can still differentiate into a few closely related cell types.[5] Finally, unipotent cells can differentiate into only one cell type, but are capable of self-renewal.[5] In cytopathology, the level of cellular differentiation is used as a measure of cancer progression. "Grade" is a marker of how differentiated a cell in a tumor is.[6]

Cell-count distribution featuring cellular differentiation for three types of cells (progenitor , osteoblast , and chondrocyte ) exposed to pro-osteoblast stimulus.[1]

Mammalian cell types

Three basic categories of cells make up the mammalian body: germ cells, somatic cells, and stem cells. Each of the approximately 37.2 trillion (3.72x1013) cells in an adult human has its own copy or copies of the genome except certain cell types, such as red blood cells, that lack nuclei in their fully differentiated state. Most cells are diploid; they have two copies of each chromosome. Such cells, called somatic cells, make up most of the human body, such as skin and muscle cells. Cells differentiate to specialize for different functions.[7]

Germ line cells are any line of cells that give rise to gametes—eggs and sperm—and thus are continuous through the generations. Stem cells, on the other hand, have the ability to divide for indefinite periods and to give rise to specialized cells. They are best described in the context of normal human development.

Development begins when a sperm fertilizes an egg and creates a single cell that has the potential to form an entire organism. In the first hours after fertilization, this cell divides into identical cells. In humans, approximately four days after fertilization and after several cycles of cell division, these cells begin to specialize, forming a hollow sphere of cells, called a blastocyst.[8] The blastocyst has an outer layer of cells, and inside this hollow sphere, there is a cluster of cells called the inner cell mass. The cells of the inner cell mass go on to form virtually all of the tissues of the human body. Although the cells of the inner cell mass can form virtually every type of cell found in the human body, they cannot form an organism. These cells are referred to as pluripotent.[9]

Pluripotent stem cells undergo further specialization into multipotent progenitor cells that then give rise to functional cells. Examples of stem and progenitor cells include:

A pathway that is guided by the cell adhesion molecules consisting of four amino acids, arginine, glycine, asparagine, and serine, is created as the cellular blastomere differentiates from the single-layered blastula to the three primary layers of germ cells in mammals, namely the ectoderm, mesoderm and endoderm (listed from most distal (exterior) to proximal (interior)). The ectoderm ends up forming the skin and the nervous system, the mesoderm forms the bones and muscular tissue, and the endoderm forms the internal organ tissues.


Dedifferentiated liposarcoma - intermed mag
Micrograph of a liposarcoma with some dedifferentiation, that is not identifiable as a liposarcoma, (left edge of image) and a differentiated component (with lipoblasts and increased vascularity (right of image)). Fully differentiated (morphologically benign) adipose tissue (center of the image) has few blood vessels. H&E stain.

Dedifferentiation, or integration is a cellular process often seen in more basal life forms such as worms and amphibians in which a partially or terminally differentiated cell reverts to an earlier developmental stage, usually as part of a regenerative process.[13][14] Dedifferentiation also occurs in plants.[15] Cells in cell culture can lose properties they originally had, such as protein expression, or change shape. This process is also termed dedifferentiation.[16]

Some believe dedifferentiation is an aberration of the normal development cycle that results in cancer,[17] whereas others believe it to be a natural part of the immune response lost by humans at some point as a result of evolution.

A small molecule dubbed reversine, a purine analog, has been discovered that has proven to induce dedifferentiation in myotubes. These dedifferentiated cells could then redifferentiate into osteoblasts and adipocytes.[18]

Bischoff SR - Nuclear Reprogramming.pdf
Diagram exposing several methods used to revert adult somatic cells to totipotency or pluripotency.


Cell Differentiation
Mechanisms of cellular differentiation.

Each specialized cell type in an organism expresses a subset of all the genes that constitute the genome of that species. Each cell type is defined by its particular pattern of regulated gene expression. Cell differentiation is thus a transition of a cell from one cell type to another and it involves a switch from one pattern of gene expression to another. Cellular differentiation during development can be understood as the result of a gene regulatory network. A regulatory gene and its cis-regulatory modules are nodes in a gene regulatory network; they receive input and create output elsewhere in the network.[19] The systems biology approach to developmental biology emphasizes the importance of investigating how developmental mechanisms interact to produce predictable patterns (morphogenesis). (However, an alternative view has been proposed recently. Based on stochastic gene expression, cellular differentiation is the result of a Darwinian selective process occurring among cells. In this frame, protein and gene networks are the result of cellular processes and not their cause. See: Cellular Darwinism)

Signal transduction pathways
An overview of major signal transduction pathways.

A few evolutionarily conserved types of molecular processes are often involved in the cellular mechanisms that control these switches. The major types of molecular processes that control cellular differentiation involve cell signaling. Many of the signal molecules that convey information from cell to cell during the control of cellular differentiation are called growth factors. Although the details of specific signal transduction pathways vary, these pathways often share the following general steps. A ligand produced by one cell binds to a receptor in the extracellular region of another cell, inducing a conformational change in the receptor. The shape of the cytoplasmic domain of the receptor changes, and the receptor acquires enzymatic activity. The receptor then catalyzes reactions that phosphorylate other proteins, activating them. A cascade of phosphorylation reactions eventually activates a dormant transcription factor or cytoskeletal protein, thus contributing to the differentiation process in the target cell.[20] Cells and tissues can vary in competence, their ability to respond to external signals.[21]

Signal induction refers to cascades of signaling events, during which a cell or tissue signals to another cell or tissue to influence its developmental fate.[21] Yamamoto and Jeffery[22] investigated the role of the lens in eye formation in cave- and surface-dwelling fish, a striking example of induction.[21] Through reciprocal transplants, Yamamoto and Jeffery[22] found that the lens vesicle of surface fish can induce other parts of the eye to develop in cave- and surface-dwelling fish, while the lens vesicle of the cave-dwelling fish cannot.[21]

Other important mechanisms fall under the category of asymmetric cell divisions, divisions that give rise to daughter cells with distinct developmental fates. Asymmetric cell divisions can occur because of asymmetrically expressed maternal cytoplasmic determinants or because of signaling.[21] In the former mechanism, distinct daughter cells are created during cytokinesis because of an uneven distribution of regulatory molecules in the parent cell; the distinct cytoplasm that each daughter cell inherits results in a distinct pattern of differentiation for each daughter cell. A well-studied example of pattern formation by asymmetric divisions is body axis patterning in Drosophila. RNA molecules are an important type of intracellular differentiation control signal. The molecular and genetic basis of asymmetric cell divisions has also been studied in green algae of the genus Volvox, a model system for studying how unicellular organisms can evolve into multicellular organisms.[21] In Volvox carteri, the 16 cells in the anterior hemisphere of a 32-cell embryo divide asymmetrically, each producing one large and one small daughter cell. The size of the cell at the end of all cell divisions determines whether it becomes a specialized germ or somatic cell.[21][23]

Epigenetic control

Since each cell, regardless of cell type, possesses the same genome, determination of cell type must occur at the level of gene expression. While the regulation of gene expression can occur through cis- and trans-regulatory elements including a gene's promoter and enhancers, the problem arises as to how this expression pattern is maintained over numerous generations of cell division. As it turns out, epigenetic processes play a crucial role in regulating the decision to adopt a stem, progenitor, or mature cell fate. This section will focus primarily on mammalian stem cells.

In systems biology and mathematical modeling of gene regulatory networks, cell-fate determination is predicted to exhibit certain dynamics, such as attractor-convergence (the attractor can be an equilibrium point, limit cycle or strange attractor) or oscillatory.[24]

Importance of epigenetic control

The first question that can be asked is the extent and complexity of the role of epigenetic processes in the determination of cell fate. A clear answer to this question can be seen in the 2011 paper by Lister R, et al. [25] on aberrant epigenomic programming in human induced pluripotent stem cells. As induced pluripotent stem cells (iPSCs) are thought to mimic embryonic stem cells in their pluripotent properties, few epigenetic differences should exist between them. To test this prediction, the authors conducted whole-genome profiling of DNA methylation patterns in several human embryonic stem cell (ESC), iPSC, and progenitor cell lines.

Female adipose cells, lung fibroblasts, and foreskin fibroblasts were reprogrammed into induced pluripotent state with the OCT4, SOX2, KLF4, and MYC genes. Patterns of DNA methylation in ESCs, iPSCs, somatic cells were compared. Lister R, et al. observed significant resemblance in methylation levels between embryonic and induced pluripotent cells. Around 80% of CG dinucleotides in ESCs and iPSCs were methylated, the same was true of only 60% of CG dinucleotides in somatic cells. In addition, somatic cells possessed minimal levels of cytosine methylation in non-CG dinucleotides, while induced pluripotent cells possessed similar levels of methylation as embryonic stem cells, between 0.5 and 1.5%. Thus, consistent with their respective transcriptional activities,[25] DNA methylation patterns, at least on the genomic level, are similar between ESCs and iPSCs.

However, upon examining methylation patterns more closely, the authors discovered 1175 regions of differential CG dinucleotide methylation between at least one ES or iPS cell line. By comparing these regions of differential methylation with regions of cytosine methylation in the original somatic cells, 44-49% of differentially methylated regions reflected methylation patterns of the respective progenitor somatic cells, while 51-56% of these regions were dissimilar to both the progenitor and embryonic cell lines. In vitro-induced differentiation of iPSC lines saw transmission of 88% and 46% of hyper and hypo-methylated differentially methylated regions, respectively.

Two conclusions are readily apparent from this study. First, epigenetic processes are heavily involved in cell fate determination, as seen from the similar levels of cytosine methylation between induced pluripotent and embryonic stem cells, consistent with their respective patterns of transcription. Second, the mechanisms of de-differentiation (and by extension, differentiation) are very complex and cannot be easily duplicated, as seen by the significant number of differentially methylated regions between ES and iPS cell lines. Now that these two points have been established, we can examine some of the epigenetic mechanisms that are thought to regulate cellular differentiation.

Mechanisms of epigenetic regulation

Pioneer factor|Pioneering factors (Oct4, Sox2, Nanog)

Three transcription factors, OCT4, SOX2, and NANOG – the first two of which are used in induced pluripotent stem cell (iPSC) reprogramming, along with Klf4 and c-Myc – are highly expressed in undifferentiated embryonic stem cells and are necessary for the maintenance of their pluripotency.[26] It is thought that they achieve this through alterations in chromatin structure, such as histone modification and DNA methylation, to restrict or permit the transcription of target genes. While highly expressed, their levels require a precise balance to maintain pluripotency, perturbation of which will promote differentiation towards different lineages based on how the gene expression levels change. Differential regulation of Oct-4 and SOX2 levels have been shown to precede germ layer fate selection.[27] Increased levels of Oct4 and decreased levels of Sox2 promote a mesendodermal fate, with Oct4 actively suppressing genes associated with a neural ectodermal fate. Similarly, Increased levels of Sox2 and decreased levels of Oct4 promote differentiation towards a neural ectodermal fate, with Sox2 inhibiting differentiation towards a mesendodermal fate. Regardless of the lineage cells differentiate down, suppression of NANOG has been identified as a necessary prerequisite for differentiation.[27]

Polycomb repressive complex (PRC2)

In the realm of gene silencing, Polycomb repressive complex 2, one of two classes of the Polycomb group (PcG) family of proteins, catalyzes the di- and tri-methylation of histone H3 lysine 27 (H3K27me2/me3).[26][28][29] By binding to the H3K27me2/3-tagged nucleosome, PRC1 (also a complex of PcG family proteins) catalyzes the mono-ubiquitinylation of histone H2A at lysine 119 (H2AK119Ub1), blocking RNA polymerase II activity and resulting in transcriptional suppression.[26] PcG knockout ES cells do not differentiate efficiently into the three germ layers, and deletion of the PRC1 and PRC2 genes leads to increased expression of lineage-affiliated genes and unscheduled differentiation.[26] Presumably, PcG complexes are responsible for transcriptionally repressing differentiation and development-promoting genes.

Trithorax group proteins (TrxG)

Alternately, upon receiving differentiation signals, PcG proteins are recruited to promoters of pluripotency transcription factors. PcG-deficient ES cells can begin differentiation but cannot maintain the differentiated phenotype.[26] Simultaneously, differentiation and development-promoting genes are activated by Trithorax group (TrxG) chromatin regulators and lose their repression.[26][29] TrxG proteins are recruited at regions of high transcriptional activity, where they catalyze the trimethylation of histone H3 lysine 4 (H3K4me3) and promote gene activation through histone acetylation.[29] PcG and TrxG complexes engage in direct competition and are thought to be functionally antagonistic, creating at differentiation and development-promoting loci what is termed a "bivalent domain" and rendering these genes sensitive to rapid induction or repression.[30]

DNA methylation

Regulation of gene expression is further achieved through DNA methylation, in which the DNA methyltransferase-mediated methylation of cytosine residues in CpG dinucleotides maintains heritable repression by controlling DNA accessibility.[30] The majority of CpG sites in embryonic stem cells are unmethylated and appear to be associated with H3K4me3-carrying nucleosomes.[26] Upon differentiation, a small number of genes, including OCT4 and NANOG,[30] are methylated and their promoters repressed to prevent their further expression. Consistently, DNA methylation-deficient embryonic stem cells rapidly enter apoptosis upon in vitro differentiation.[26]

Nucleosome positioning

While the DNA sequence of most cells of an organism is the same, the binding patterns of transcription factors and the corresponding gene expression patterns are different. To a large extent, differences in transcription factor binding are determined by the chromatin accessibility of their binding sites through histone modification and/or pioneer factors. In particular, it is important to know whether a nucleosome is covering a given genomic binding site or not. This can be determined using a chromatin immunoprecipitation (ChIP) assay.[31]

DNA-nucleosome interactions are characterized by two states: either tightly bound by nucleosomes and transcriptionally inactive, called heterochromatin, or loosely bound and usually, but not always, transcriptionally active, called euchromatin. The epigenetic processes of histone methylation and acetylation, and their inverses demethylation and deacetylation primarily account for these changes. The effects of acetylation and deacetylation are more predictable. An acetyl group is either added to or removed from the positively charged Lysine residues in histones by enzymes called histone acetyltransferases or histone deacteylases, respectively. The acetyl group prevents Lysine's association with the negatively charged DNA backbone. Methylation is not as straightforward, as neither methylation nor demethylation consistently correlate with either gene activation or repression. However, certain methylations have been repeatedly shown to either activate or repress genes. The trimethylation of lysine 4 on histone 3 (H3K4Me3) is associated with gene activation, whereas trimethylation of lysine 27 on histone 3 represses genes[32][33][34]

During differentiation, stem cells change their gene expression profiles. Recent studies have implicated a role for nucleosome positioning and histone modifications during this process.[35] There are two components of this process: turning off the expression of embryonic stem cell (ESC) genes, and the activation of cell fate genes. Lysine specific demethylase 1 (KDM1A) is thought to prevent the use of enhancer regions of pluripotency genes, thereby inhibiting their transcription.[36] It interacts with Mi-2/NuRD complex (nucleosome remodelling and histone deacetylase) complex,[36] giving an instance where methylation and acetylation are not discrete and mutually exclusive, but intertwined processes.

Role of signaling in epigenetic control

A final question to ask concerns the role of cell signaling in influencing the epigenetic processes governing differentiation. Such a role should exist, as it would be reasonable to think that extrinsic signaling can lead to epigenetic remodeling, just as it can lead to changes in gene expression through the activation or repression of different transcription factors. Little direct data is available concerning the specific signals that influence the epigenome, and the majority of current knowledge about the subject consists of speculations on plausible candidate regulators of epigenetic remodeling.[37] We will first discuss several major candidates thought to be involved in the induction and maintenance of both embryonic stem cells and their differentiated progeny, and then turn to one example of specific signaling pathways in which more direct evidence exists for its role in epigenetic change.

The first major candidate is Wnt signaling pathway. The Wnt pathway is involved in all stages of differentiation, and the ligand Wnt3a can substitute for the overexpression of c-Myc in the generation of induced pluripotent stem cells.[37] On the other hand, disruption of ß-catenin, a component of the Wnt signaling pathway, leads to decreased proliferation of neural progenitors.

Growth factors comprise the second major set of candidates of epigenetic regulators of cellular differentiation. These morphogens are crucial for development, and include bone morphogenetic proteins, transforming growth factors (TGFs), and fibroblast growth factors (FGFs). TGFs and FGFs have been shown to sustain expression of OCT4, SOX2, and NANOG by downstream signaling to Smad proteins.[37] Depletion of growth factors promotes the differentiation of ESCs, while genes with bivalent chromatin can become either more restrictive or permissive in their transcription.[37]

Several other signaling pathways are also considered to be primary candidates. Cytokine leukemia inhibitory factors are associated with the maintenance of mouse ESCs in an undifferentiated state. This is achieved through its activation of the Jak-STAT3 pathway, which has been shown to be necessary and sufficient towards maintaining mouse ESC pluripotency.[38] Retinoic acid can induce differentiation of human and mouse ESCs,[37] and Notch signaling is involved in the proliferation and self-renewal of stem cells. Finally, Sonic hedgehog, in addition to its role as a morphogen, promotes embryonic stem cell differentiation and the self-renewal of somatic stem cells.[37]

The problem, of course, is that the candidacy of these signaling pathways was inferred primarily on the basis of their role in development and cellular differentiation. While epigenetic regulation is necessary for driving cellular differentiation, they are certainly not sufficient for this process. Direct modulation of gene expression through modification of transcription factors plays a key role that must be distinguished from heritable epigenetic changes that can persist even in the absence of the original environmental signals. Only a few examples of signaling pathways leading to epigenetic changes that alter cell fate currently exist, and we will focus on one of them.

Expression of Shh (Sonic hedgehog) upregulates the production of BMI1, a component of the PcG complex that recognizes H3K27me3. This occurs in a Gli-dependent manner, as Gli1 and Gli2 are downstream effectors of the Hedgehog signaling pathway. In culture, Bmi1 mediates the Hedgehog pathway's ability to promote human mammary stem cell self-renewal.[39] In both humans and mice, researchers showed Bmi1 to be highly expressed in proliferating immature cerebellar granule cell precursors. When Bmi1 was knocked out in mice, impaired cerebellar development resulted, leading to significant reductions in postnatal brain mass along with abnormalities in motor control and behavior.[40] A separate study showed a significant decrease in neural stem cell proliferation along with increased astrocyte proliferation in Bmi null mice.[41]

A alternative model of cellular differentiation during embryogenesis is that positional information is based on mechanical signalling by the cytoskeleton using Embryonic differentiation waves. The mechanical signal is then epigenetically transduced via signal transduction systems (of which specific molecules such as Wnt are part) to result in differential gene expression.

In summary, the role of signaling in the epigenetic control of cell fate in mammals is largely unknown, but distinct examples exist that indicate the likely existence of further such mechanisms.

Effect of matrix elasticity

In order to fulfill the purpose of regenerating a variety of tissues, adult stems are known to migrate from their niches, adhere to new extracellular matrices (ECM) and differentiate. The ductility of these microenvironments are unique to different tissue types. The ECM surrounding brain, muscle and bone tissues range from soft to stiff. The transduction of the stem cells into these cells types is not directed solely by chemokine cues and cell to cell signaling. The elasticity of the microenvironment can also affect the differentiation of mesenchymal stem cells (MSCs which originate in bone marrow.) When MSCs are placed on substrates of the same stiffness as brain, muscle and bone ECM, the MSCs take on properties of those respective cell types.[42] Matrix sensing requires the cell to pull against the matrix at focal adhesions, which triggers a cellular mechano-transducer to generate a signal to be informed what force is needed to deform the matrix. To determine the key players in matrix-elasticity-driven lineage specification in MSCs, different matrix microenvironments were mimicked. From these experiments, it was concluded that focal adhesions of the MSCs were the cellular mechano-transducer sensing the differences of the matrix elasticity. The non-muscle myosin IIa-c isoforms generates the forces in the cell that lead to signaling of early commitment markers. Nonmuscle myosin IIa generates the least force increasing to non-muscle myosin IIc. There are also factors in the cell that inhibit non-muscle myosin II, such as blebbistatin. This makes the cell effectively blind to the surrounding matrix.[42] Researchers have obtained some success in inducing stem cell-like properties in HEK 239 cells by providing a soft matrix without the use of diffusing factors.[43] The stem-cell properties appear to be linked to tension in the cells' actin network. One identified mechanism for matrix-induced differentiation is tension-induced proteins, which remodel chromatin in response to mechanical stretch.[44] The RhoA pathway is also implicated in this process.

See also


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Adipogenesis is the process of cell differentiation by which pre-adipocytes become adipocytes. Adipogenesis has been one of the most intensively studied models of cellular differentiation.


Anaplasia (from Ancient Greek: ἀνά ana, "backward" + πλάσις plasis, "formation") is a condition of cells with poor cellular differentiation, losing the morphological characteristics of mature cells and their orientation with respect to each other and to endothelial cells. The term also refers to a group of morphological changes in a cell (nuclear pleomorphism, altered nuclear-cytoplasmic ratio, presence of nucleoli, high proliferation index) that point to a possible malignant transformation.Such loss of structural differentiation is especially seen in most, but not all, malignant neoplasms. Sometimes, the term also includes an increased capacity for multiplication. Lack of differentiation is considered a hallmark of aggressive malignancies (for example, it differentiates leiomyosarcomas from leiomyomas). The term anaplasia literally means "to form backward". It implies dedifferentiation, or loss of structural and functional differentiation of normal cells. It is now known, however, that at least some cancers arise from stem cells in tissues; in these tumors failure of differentiation, rather than dedifferentiation of specialized cells, account for undifferentiated tumors.

Anaplastic cells display marked pleomorphism (variability). The nuclei are characteristically extremely hyperchromatic (darkly stained) and large. The nuclear-cytoplasmic ratio may approach 1:1 instead of the normal 1:4 or 1:6. Giant cells that are considerably larger than their neighbors may be formed and possess either one enormous nucleus or several nuclei (syncytia). Anaplastic nuclei are variable and bizarre in size and shape. The chromatin is coarse and clumped, and nucleoli may be of astounding size. More important, mitoses are often numerous and distinctly atypical; anarchic multiple spindles may be seen and sometimes appear as tripolar or quadripolar forms. Also, anaplastic cells usually fail to develop recognizable patterns of orientation to one another (i.e., they lose normal polarity). They may grow in sheets, with total loss of communal structures, such as gland formation or stratified squamous architecture. Anaplasia is the most extreme disturbance in cell growth encountered in the spectrum of cellular proliferations.

Artificial development

Artificial development, also known as artificial embryogeny or computational development, is an area of computer science and engineering concerned with computational models motivated by genotype-phenotype mappings in biological systems. Artificial development is often considered a sub-field of evolutionary computation, although the principles of artificial development have also been used within stand-alone computational models.

Within evolutionary computation, the need for artificial development techniques was motivated by the perceived lack of scalability and evolvability of direct solution encodings (Tufte, 2008). Artificial development entails indirect solution encoding. Rather than describing a solution directly, an indirect encoding describes (either explicitly or implicitly) the process by which a solution is constructed. Often, but not always, these indirect encodings are based upon biological principles of development such as morphogen gradients, cell division and cellular differentiation (e.g. Doursat 2008), gene regulatory networks (e.g. Guo et al., 2009), degeneracy (Whitacre et al., 2010), grammatical evolution (de Salabert et al., 2006), or analogous computational processes such as re-writing, iteration, and time. The influences of interaction with the environment, spatiality and physical constraints on differentiated multi-cellular development have been investigated more recently (e.g. Knabe et al. 2008).

Artificial development approaches have been applied to a number of computational and design problems, including electronic circuit design (Miller and Banzhaf 2003), robotic controllers (e.g. Taylor 2004), and the design of physical structures (e.g. Hornby 2004).

Biological process

Biological processes are the processes vital for a living organism to live. Biological processes are made up of many chemical reactions or other events that are involved in the persistence and transformation of life forms. Metabolism and homeostasis are examples.

Regulation of biological processes occurs when any process is modulated in its frequency, rate or extent. Biological processes are regulated by many means; examples include the control of gene expression, protein modification or interaction with a protein or substrate molecule. Mamel

Homeostasis: regulation of the internal environment to maintain a constant state; for example, sweating to reduce temperature

Organization: being structurally composed of one or more cells – the basic units of life

Metabolism: transformation of energy by converting chemicals and energy into cellular components (anabolism) and decomposing organic matter (catabolism). Living things require energy to maintain internal organization (homeostasis) and to produce the other phenomena associated with life.

Growth: maintenance of a higher rate of anabolism than catabolism. A growing organism increases in size in all of its parts, rather than simply accumulating matter.

Adaptation: the ability to change over time in response to the environment. This ability is fundamental to the process of evolution and is determined by the organism's heredity, diet, and external factors.

Response to stimuli: a response can take many forms, from the contraction of a unicellular organism to external chemicals, to complex reactions involving all the senses of multicellular organisms. A response is often expressed by motion; for example, the leaves of a plant turning toward the sun (phototropism), and chemotaxis.

Reproduction: the ability to produce new individual organisms, either asexually from a single parent organism or sexually from two parent organisms.

Interaction between organisms. the processes by which an organism has an observable effect on another organism of the same or different species.

Also: cellular differentiation, fermentation, fertilisation, germination, tropism, hybridisation, metamorphosis, morphogenesis, photosynthesis, transpiration.


Compaction may refer to:

Soil compaction, for mechanically induced compaction near the ground surface

Compaction (geology), part of the process of lithification involving mechanical dewatering of a sediment by progressive loading under several km of geomaterial

Waste compaction, related to garbage

Cold compaction, powder compaction at low temperatures

Data compaction, related to computers

Curve-fitting compaction

Compactor, a device that performs compaction

Compaction, a cellular differentiation process during early embryogenesis, which occurs during the cleavage stage of human embryogenesis

Embryonic development

Embryonic development also embryogenesis is the process by which the embryo forms and develops. In mammals, the term refers chiefly to early stages of prenatal development, whereas the terms fetus and fetal development describe later stages.

Embryonic development starts with the fertilization of the egg cell (ovum) by a sperm cell, (spermatozoon). Once fertilized, the ovum is referred to as a zygote, a single diploid cell. The zygote undergoes mitotic divisions with no significant growth (a process known as cleavage) and cellular differentiation, leading to development of a multicellular embryo.

Although embryogenesis occurs in both animal and plant development, this article addresses the common features among different animals, with some emphasis on the embryonic development of vertebrates and mammals.

Grading (tumors)

In pathology, grading is a measure of the cell appearance in tumors and other neoplasms. Some pathology grading systems apply only to malignant neoplasms (cancer); others apply also to benign neoplasms. The neoplastic grading is a measure of cell anaplasia (reversion of differentiation) in the sampled tumor and is based on the resemblance of the tumor to the tissue of origin. Grading in cancer is distinguished from staging, which is a measure of the extent to which the cancer has spread.

Pathology grading systems classify the microscopic cell appearance abnormality and deviations in their rate of growth with the goal of predicting developments at tissue level (see also the 4 major histological changes in dysplasia).

Cancer is a disorder of cell life cycle alteration that leads (non-trivially) to excessive cell proliferation rates, typically longer cell lifespans and poor differentiation. The grade score (numerical: G1 up to G4) increases with the lack of cellular differentiation - it reflects how much the tumor cells differ from the cells of the normal tissue they have originated from (see 'Categories' below). Tumors may be graded on four-tier, three-tier, or two-tier scales, depending on the institution and the tumor type.

The histologic tumor grade score along with the metastatic (whole-body-level cancer-spread) staging are used to evaluate each specific cancer patient, develop their individual treatment strategy and to predict their prognosis. A cancer that is very poorly differentiated is called anaplastic.

Human embryonic development

Human embryonic development, or human embryogenesis, refers to the development and formation of the human embryo. It is characterised by the process of cell division and cellular differentiation of the embryo that occurs during the early stages of development. In biological terms, the development of the human body entails growth from a one-celled zygote to an adult human being. Fertilisation occurs when the sperm cell successfully enters and fuses with an egg cell (ovum). The genetic material of the sperm and egg then combine to form a single cell called a zygote and the germinal stage of development commences. Embryonic development in the human, covers the first eight weeks of development; at the beginning of the ninth week the embryo is termed a fetus.

Human embryology is the study of this development during the first eight weeks after fertilisation. The normal period of gestation (pregnancy) is nine months or 38 weeks.

The germinal stage refers to the time from fertilization through the development of the early embryo until implantation is completed in the uterus. The germinal stage takes around 10 days. During this stage, the zygote begins to divide, in a process called cleavage. A blastocyst is then formed and implanted in the uterus. Embryogenesis continues with the next stage of gastrulation, when the three germ layers of the embryo form in a process called histogenesis, and the processes of neurulation and organogenesis follow.

In comparison to the embryo, the fetus has more recognizable external features and a more complete set of developing organs. The entire process of embryogenesis involves coordinated spatial and temporal changes in gene expression, cell growth and cellular differentiation. A nearly identical process occurs in other species, especially among chordates.

Mammalian embryogenesis

Mammalian embryogenesis is the process of cell division and cellular differentiation during early prenatal development which leads to the development of a mammalian embryo.


Maturation is the process of becoming mature; the emergence of individual and behavioral characteristics through growth processes over time.

It can also refer to any of the following:

Foetal development

Developmental biology

In petroleum geology, the maturation of a rock is a measure of its state in terms of hydrocarbon generation.

Psychological development

Physical maturation of any biological life form – see individual articles for maturation of different life forms.

In research, a threat to internal validity in which subjects change during the course of the experiment or even between measurements and the researcher may not be able to determine if the cause of the discrepancy is due to time or the independent variable.

The final stages of cellular differentiation of cells, tissues, or organs.

The process of storing alcoholic beverages in wooden cylindrical containers intended to impart a change in flavour and colouring.

Any process that develops a finished product that is different from its beginning stage through processes that involve the passing of time, often resulting in a more desired or effective product. Such processes can encompass things such as cheese or other food fermentations, and mature technology.


Morphallaxis is the regeneration of specific tissue in a variety of organisms due to loss or death of the existing tissue. The word comes from the Greek allazein, which means to exchange.

The classical example of morphallaxis is that of the Cnidarian hydra, where when the animal is severed in two (by actively cutting it with, for example, a surgical knife) the remaining severed sections form two fully functional and independent hydra. The notable feature of morphallaxis is that a large majority of regenerated tissue comes from already-present tissue in the organism. That is, the one severed section of the hydra forms into a smaller version of the original hydra, approximately the same size as the severed section. Hence, there is an "exchange" of tissue.

Researchers Wilson and Child showed circa 1930 that if the hydra was pulped and the disassociated cells passed through a sieve, those cells then put into an aqueous solution would shortly reform into the original organism with all differentiated tissue correctly arranged.Morphallaxis is often contrasted with epimorphosis, which is characterized by a much greater relative degree of cellular proliferation. Although cellular differentiation is active in both processes, in morphallaxis the majority of the regeneration comes from reorganization or exchange, while in epimorphosis the majority of the regeneration comes from cellular differentiation. Thus, the two may be distinguished as a measure of degree.

Epimorphosis is the regeneration of a part of an organism by proliferation at the cut surface. For example, in Planaria neoblasts help in regeneration.


Morphogenesis (from the Greek morphê shape and genesis creation, literally, "beginning of the shape") is the biological process that causes an organism to develop its shape. It is one of three fundamental aspects of developmental biology along with the control of cell growth and cellular differentiation, unified in evolutionary developmental biology (evo-devo).

The process controls the organized spatial distribution of cells during the embryonic development of an organism. Morphogenesis can take place also in a mature organism, in cell culture or inside tumor cell masses. Morphogenesis also describes the development of unicellular life forms that do not have an embryonic stage in their life cycle, or describes the evolution of a body structure within a taxonomic group.

Morphogenetic responses may be induced in organisms by hormones, by environmental chemicals ranging from substances produced by other organisms to toxic chemicals or radionuclides released as pollutants, and other plants, or by mechanical stresses induced by spatial patterning of the cells.

Nucleated red blood cell

All vertebrate organisms have hemoglobin-containing cells in their blood, and with the exception of mammals, all of these red blood cells contain a nucleus. Mammals represent ~5,500 named species out of ~66,000 vertebrate species, and within this ~8% subgroup, red blood cells are known as erythrocytes or RBCs and have no cell nucleus in mature organisms. In contrast, a nucleated red blood cell (NRBC), also known by several other names, is a mammalian RBC that contains a cell nucleus. NRBCs occur in normal development as progenitor cells in the erythropoietic lineage and in pathological states.

Normally, nucleated RBCs are found only in the circulation of fetuses and newborn infants. After infancy, RBCs normally only contain a nucleus during the very early stages of the cell's life, and the nucleus is ejected as a normal part of cellular differentiation before the cell is released into the bloodstream. Thus, if NRBCs are seen on an adult's peripheral blood smear, it suggests that there is a very high demand for the bone marrow to produce RBCs, and immature RBCs are being released into circulation. Possible pathologic causes include anemia, myelofibrosis, thalassemia, miliary tuberculosis, cancers involving bone marrow (myelomas, leukemias, lymphomas), and in chronic hypoxemia.


PRC2 (polycomb repressive complex 2) is one of the two classes of polycomb-group proteins or (PcG). The other component of this group of proteins is PRC1 (Polycomb Repressive Complex 1).

This complex has histone methyltransferase activity and primarily trimethylates histone H3 on lysine 27 (i.e. H3K27me3), a mark of transcriptionally silent chromatin. PRC2 is required for initial targeting of genomic region (PRC Response Elements or PRE) to be silenced, while PRC1 is required for stabilizing this silencing and underlies cellular memory of silenced region after cellular differentiation. PRC1 also mono-ubiquitinates histone H2A on lysine 119 (H2AK119Ub1). These proteins are required for long term epigenetic silencing of chromatin and have an important role in stem cell differentiation and early embryonic development. PRC2 are present in all multicellular organisms.

The mouse PRC2 has four subunits: Suz12 (zinc finger), Eed, Ezh1 or Ezh2 (SET domain with histone methyltransferase activity) and RbAp48 (histone binding domain). PRC2 can bind to H3K27me3 and repress neighboring nucleosomes, thus spreading the repression.

PRC2 has a role in X chromosome inactivation, in maintenance of stem cell fate, and in imprinting. Aberrant expression of PRC2 has been observed in cancer.The PRC2 is evolutionarily conserved, and has been found in mammals, insects, and plants.

Pregnancy (mammals)

In mammals, pregnancy is the period of reproduction during which a female carries one or more live offspring from implantation in the uterus through gestation. It begins when a fertilized zygote implants in the female's uterus, and ends once it leaves the uterus.


A prolymphocyte is a white blood cell with a certain state of cellular differentiation in lymphocytopoiesis. In the 20th century it was believed that a sequence of general maturation changed cells from lymphoblasts to prolymphocytes and then to lymphocytes (the lymphocytic series), with each being a precursor of the last. Today it is believed that the differentiation of cells in the lymphocyte line is not always simply chronologic but rather depends on antigen exposure, such that, for example, lymphocytes can become lymphoblasts.The size is between 10 and 18 μm.

Small GTPase

Small GTPases (EC, also known as small G-proteins, are a family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate (GTP). They are a type of G-protein found in the cytosol that are homologous to the alpha subunit of heterotrimeric G-proteins, but unlike the alpha subunit of G proteins, a small GTPase can function independently as a hydrolase enzyme to bind to and hydrolyze a guanosine triphosphate (GTP) to form guanosine diphosphate (GDP). The best-known members are the Ras GTPases and hence they are sometimes called Ras subfamily GTPases.

A typical G-protein is active when bound to GTP and inactive when bound to GDP (i.e. when the GTP is hydrolyzed to GDP). The GDP can be then replaced by free GTP. Therefore, a G-protein can be switched on and off. GTP hydrolysis is accelerated by GTPase activating proteins (GAPs), while GTP exchange is catalyzed by guanine nucleotide exchange factors (GEFs). Activation of a GEF typically activates its cognate G-protein, while activation of a GAP results in inactivation of the cognate G-protein.

Guanosine nucleotide dissociation inhibitors (GDI) maintain small GTP-ases in the inactive state.

Small GTPases regulate a wide variety of processes in the cell, including growth, cellular differentiation, cell movement and lipid vesicle transport.

Swarming motility

Swarming motility is a rapid (2–10 μm/s) and coordinated translocation of a bacterial population across solid or semi-solid surfaces, and is an example of bacterial multicellularity and swarm behaviour. Swarming motility was first reported by Jorgen Henrichsen and has been mostly studied in genus Serratia, Salmonella, Aeromonas, Bacillus, Yersinia, Pseudomonas, Proteus, Vibrio and Escherichia.

This multicellular behavior has been mostly observed in controlled laboratory conditions and relies on two critical elements: 1) the nutrient composition and 2) viscosity of culture medium (i.e. % agar). One particular feature of this type of motility is the formation of dendritic fractal-like patterns formed by migrating swarms moving away from an initial location. Although the majority of species can produce tendrils when swarming, some species like Proteus mirabilis do form concentric circles motif instead of dendritic patterns.

Wellcome Trust Centre for Stem Cell Research

The Wellcome Trust Centre for Stem Cell Research (CSCR) at the University of Cambridge is a research centre for the nature and potential medical uses of stem cells. It is located on Tennis Court Road in central Cambridge, England.

The Centre is funded by the Wellcome Trust and the Medical Research Council.

The main areas of study include pluripotent and neural stem cells, as well as epidermal stem cells. Key advances in stem cell science at the centre include the elucidation of the role of the nanog protein in pluripotency and work on inhibiting cellular differentiation. It also conducts human embryo work as approved by the Human Fertilisation and Embryology Authority.

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