Cellular differentiation

"Cell differentiation" redirects here. For the journal, see Cell Differentiation (journal).

In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of tissues and cell types. Differentiation is a common process in adults as well: adult stem cells divide and create fully-differentiated daughter cells during tissue repair and during normal cell turnover. 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. 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 cell that is able to differentiate into all cell types of the adult organism is known as pluripotent. Such cells are called embryonic stem cells in animals and meristematic cells in higher plants. A cell that is able to 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. 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.

Mammalian cell types

See also: List of distinct cell types in the adult human body

SEVEN basic categories of cells make up the mammalian body: germ cells, somatic cells, spermy-awesome cells, chicken cells, soggy egg cells, beefy rice cells, and stem cells. Each of the approximately 100 trillion (10¹⁴) 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.

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. 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.

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

• Hematopoietic stem cells (adult stem cells) from the bone marrow that give rise to red blood cells, white blood cells, and platelets
• Mesenchymal stem cells (adult stem cells) from the bone marrow that give rise to stromal cells, fat cells, and types of bone cells
• Epithelial stem cells (progenitor cells) that give rise to the various types of skin cells
• Muscle satellite cells (progenitor cells) that contribute to differentiated muscle tissue

Dedifferentiation

Dedifferentiation 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. Dedifferentiation also occurs in plants. Cells in cell culture can lose properties they originally had, such as protein expression, or change shape. This process is also termed dedifferentiation.

Some believe dedifferentiation is an aberration of the normal development cycle that results in cancer, 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 were then able to redifferentiate into osteoblasts and adipocytes.

File:Dedifferentiation Methods (2010) - Bischoff, Steven R.tif

Dedifferentiation to totipotency or pluripotency: an overview of methods.'Various methods exist to revert adult somatic cells to pluripotency or totipotency. In the case of totipotency, reprogramming is mediated through a mature metaphase II oocyte as in somatic cell nuclear transfer (Wilmut et al., 1997). Recent work has demonstrated the feasibility of enucleated zygotes or early blastomeres chemically arrested during mitosis, such that nuclear envelope break down occurs, to support reprogramming to totipotency in a process called chromosome transfer (Egli and Eggan, 2010). Direct reprogramming methods support reversion to pluripotency; though, vehicles and biotypes vary considerably in efficiencies (Takahashi and Yamanaka, 2006). Viral-mediated transduction robustly supports dedifferentiation to pluripotency through retroviral or DNA-viral routes but carries the onus of insertional inactivation. Additionally, epigenetic reprogramming by enforced expression of OSKM through DNA routes exists such as plasmid DNA, minicircles, transposons, episomes and DNA mulicistronic construct targeting by homologous recombination has also been demonstrated; however, these methods suffer from the burden to potentially alter the recipient genome by gene insertion (Ho et al., 2010). While protein-mediated transduction supports reprogramming adult cells to pluripotency, the method is cumbersome and requires recombinant protein expression and purification expertise, and reprograms albeit at very low frequencies (Kim et al., 2009). A major obstacle of using RNA for reprogramming is its lability and that single-stranded RNA biotypes trigger innate antiviral defense pathways such as interferon and NF-kB-dependent pathways. In vitro transcribed RNA, containing stabilizing modifications such as 5-methylguanosine capping or substituted ribonucleobases, e.g. pseudouracil, is 35-fold more efficient than viral transduction and has the additional benefit of not altering the somatic genome (Warren et al., 2010).

Mechanisms

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 . 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)

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 . Cells and tissues can vary in competence, their ability to respond to external signals .

Induction refers to cascades of signaling events, during which a cell or tissue signals to another cell or tissue to influence its developmental fate . Yamamoto and Jeffery investigated the role of the lens in eye formation in cave- and surface-dwelling fish, a striking example of induction. Through reciprocal transplants, Yamamoto and Jeffery 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.

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 segregation of cytoplasmic determinants or because of signaling . 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 . In Volvox carteri, the 16 cells in the anterior hemisphere of a 32-celled 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 .