The development of an organism from a fertilized egg into an individual is achieved by cell proliferation and differentiation. Cell proliferation promotes cell growth and increases the number of cells. Cell differentiation is an act of differentiation among cells.

Cell differentiation refers to the process of gradual differentiation in morphology, structure and physiological function among cells from fertilized egg to the individual. Beginning to synthesis of new specific proteins in the cell is the marker of cell differentiation. The synthesis of specific proteins by gene selective expression is the key of the cell differentiation. The results of cell differentiation is to produce cells with different forms, structures and functions, and then develop into the different tissues and organs of the individual.

I The morphology, structure and function of the differentiated cells are stable, including the location of differentiated cells in the body.

II Once a cell differentiates into a stable cell, it cannot reverse to the undifferentiated state. Such as highly differentiated mature red blood cells of mammals cannot reverse to normoblast or proerythroblast, even the state of bone marrow stem cells.

III The body must retain some of the undifferentiated pluripotent stem cells to prevent the possibility of losing highly differentiated cells, and stem cells will divide once needed. When the adult stem cell divides, due to the unequal division of cytoplasm, one cell is still stem cell, another one develops to specific function cell according to the developmental pathway.

Cell differentiation is a common biological phenomenon, which occurs in the whole process of life, but the most typical and frequent occurs in embryonic period.

I Cells of various tissues and organs in the body are all evolved from fertilized eggs. In the potential of development, zygotes and blastomeres (before eight-cell-stage) are totipotent cells with the potential to develop to be a complete individual.

II Many tridermic cells are pluripotent cells, and each the germ layer cells can only be limited to the areas in which they can differentiate. For example, the differentiation of the ectoderm into skin and nervous system; the differentiation of the mesoblast into muscle, skeleton and circulatory system; the differentiation of the endoderm into gastrointestinal and respiratory epithelium.

III Tissues and organs are differentiated from trilaminar, and the differentiation potential of these cells gradually constricts to become monoenergetic cell of one particular differentiation direction.

IV In the development of the individual, it is a universal law of cell differentiation from totipotency to pluripotency, and finally to unipotency.

Multicellular organisms not only have temporal differentiation, but also have spatial differentiation. Differentiation in time means that a cell can have different morphology, structure and function at different stages of development. Differentiation in space refers to the same source of cell having different morphological structure and function because of different space position.

The proerythroblast with a nuclear cannot synthesize hemoglobin, normoblast with a nuclear can synthesize hemoglobin, and mature erythrocytes lose nucleus and change to the concave disc morphology. The above manifests the differentiation on the “time”.

The ectoderm located at the surface develops and differentiates toward the direction of the epidermis, while neural tube evolved from the ectoderm invagination can develop to nervous tissue, manifesting the differentiation on the “space”.

The differentiated cells can lose their unique structure and function under the induction of specific conditions and be reversed to characteristic of undifferentiated cells, this phenomenon is called dedifferentiation. Through redifferentiation can regenerate a complete individual. For example, the regeneration of the salamander's limb is the dedifferentiation of salamander limb germ cells to form germ cells and then the proliferation and differentiation of germ cells into regenerating limb.

Under the special conditions, the phenomenon of cells from one differentiation state changes to another is known as transdifferentiation.

In the process of individual development, before the cell appears characteristic of recognized differentiation, it will make the choice of differentiation direction in advance.

I In the process of individual development, the developmental fate of cell in the future has been identified before occurring the identification of differentiation characteristics, and cells can only differentiate in a specific direction, this is called cell determination. Cell determination is prior to cell differentiation and restricts the direction of cell differentiation. After the cell determination, the direction of differentiation generally cannot be changed halfway. This will ensure that hundreds of cells orderly form the tissues, organs and systems. Gastrul stage has three germ layers. Although the cells of each germinal layer show no difference in morphology, but at this time areas reserved for all kinds of organs have been decided, they can only develop into specific tissues, organs and systems according to the certain rules.

II Cell decision has hereditary. That is to say cell which has been decided the direction can give this decision to its daughter cell.

The experiment of embryo transfer indicates that cell determination precedes cell differentiation during the development of individual.

I If a cell group (donor) that has not yet been decided the differentiation direction is transplanted to another embryo (hosts), this group of cells (donor) will follow the original direction of the host decision to differentiate.

II If a cell group (donor) that has already decided the differentiation direction is transplanted to another embryo (hosts), this group of cells (donor) will follow the original direction of the donor to differentiate.

Cell pluripotency is the ability of a single cell to develop into a complete individual. The essence of cellular pluripotency is the ability to express intact genome during development and to differentiate into all cell types of the individual.

I Totipotent cell is the cell that can develop into a complete individual. The zygote and the cleavage ball before 8 cell period of mammal are all have cell totipotency.

II The nucleus of differentiated somatic cells and the fertilized egg of the higher animals and all have the complete set of genome that have the potential to develop into a normal organism. Thus, the nuclei of the differentiated cells and fertilized egg are all called pluripotent nuclei.

In 1996, Bratin scientist Wilmut proved that the differentiated cell nuclei of higher animals had totipotency in his cloned sheep experiment. Cell nucleus of mamma lacteal gland cell which was belonged to specific cell from sheep A was taken and transplanted into denucleated egg cell of the sheep B. Reconstructed cell was cultured in vitro for six days and further implanted into the uterus of sheep C. After pregnancy for 148 days, the world's first clone sheep, named Dolly, was appeared. This experiment proved that nucleus of lacteal gland epithelial cell of sheep A has totipotency.

Tumor cells are variants of normal cells. Tumor cells show the characteristics of low differentiation and high proliferation. The tumor can be treated by inducing cell differentiation.

The marker of cell differentiation is the priority synthesis of intracellular specific proteins. The essence of cell differentiation is the change of gene expression. For example, the cells from mesoblast, some cells differentiate into red blood cells when synthesizing hemoglobin, other cells will differentiate into muscular cells when synthesis of myogram and myosin. The differences of proteins make different cell phenotypes. Protein synthesis is determined by gene and is the result of gene differential expression in the molecular level.

In the development of embryo, gene differential expression or sequential expression refers to that the emergence of new cell type is the result of differential expression of genes in a certain order.

Somatic cells contain the same genome as the fertilized egg. In theory, every cell should have ability to express any gene which in its gene base, that is totipotency. In fact, not all the genomes of the differentiated cells are simultaneously expressed. In multicellular organisms, the genes in their genomes are not all expressed in individual and cell differentiation. Normally, genes are expressed in certain spatial and temporal order. Differential expression occurs in different types of differentiated cells and in different developmental stages of the same cell. Within a certain time, some genes express, while the rest of the genes stay closed; at the other time, the genes which are originally open may continue to express, or may shut down. However, the genes shut down originally may be converted to open. No more than 10% gene in the entire genome of cells can express, others are in the closed state.

For example, differential expression of gene makes human hemoglobin have different types in different developmental stages. These differences reflect the different amounts of respiration required for embryos, fetuses and adult Hb at different developmental stages. Fetal hemoglobin (HbF) has a higher affinity for oxygen than adult hemoglobin (HbA).

According to the relationship of gene and cell differentiation, the gene can be divided into two classes:

I House-keeping gene

House-keeping gene refers to the gene that is necessary to maintain survive of the cell and active in all kinds of cells. tRNA, rRNA, mitochondrial protein, glycolytic enzymes, histone and so on, are all coded by house-keeping gene. The housekeeper gene has the following characteristics:

1. They are shared by all cells;

2. They can be expressed in any period;

3. Generally, it only gives assistance to the cell differentiation.

II Luxury gene

Luxury gene, also called tissue-specific gene, is the gene that can encode a specific protein (a luxury protein). The essence of cell differentiation is the result of luxury gene differential expression (sequential expression). The luxury gene has the following characteristics:

1. They express only in specific differentiated cells, such as epidermal cell (keratin), red cell (hemoglobin), muscular cell (actin and myosin) and so on;

2. They express only in specific period;

3. They have no direct impact on cell survival, but play a decisive role for cell differentiation.

The regulation of cell differentiation can occur at different levels, such as transcription, translation, protein formation, activity modification and so on, among which transcription regulation mediated by transcription factors is the most important.

Transcription factors are mainly proteins, which can interact with gene expression control region and regulate the gene expression. Transcription factors can be divided into general transcription factors and tissue specific transcription factors, of which the former regulate house-keeping gene expression, the later regulate luxury gene expression.

Specific transcription factors combine with various regulatory sites of specific genes to determine the temporal and spatial expression of genes.

The primary components of chromatin are DNA and protein. Covalent modifications include methylation, acetylation, phosphorylation, ubiquitin and so on.

I DNA methylation is associated with gene transcription suppression

Methylation of DNA is that, under the effect of methyltransgerase, cytosine in DNA molecule forms 5'-methylcytosine by methylation. It usually occurs in the CPG sequence site, also known as CPG island, located at the 5' junctions of some genes.

The role of DNA methylation: the methylation locus of DNA blocks the combination of transcription factors and inhibits transcription. The higher the degree of DNA methylation, the lower the DNA transcriptional activity. DNA methylation will promote chromatin condensation.

II Histone acetylation is conducive to gene transcription

Histone acetylation is that, under the effect of transacetylase, lysine in histone N-terminal tail pluses acetyl.

There are multiple sites on the nucleosomes that can be acetylated to make histone acetylation diversity. But the histone acetylation and deacetylation of a particular gene site is carried out in a non-random location-specific manner.

The effect of histone acetylation: it will reduce the affinity between histone and DNA, which is favorable for gene transcripition. Histone deacetylation inhibits gene transcription.

=== The differentiation and development blueprint of the anterior and posterior axis structures in homeobox genes

I Homeobox gene ===

Homeobox gene, which has 180bp the same DNA sequence, is very important in individual development. The function of homeobox gene is to plan the differentiation of antero posterior axis structure and regional organs. Its encoding homologous domain protein is an important transcription factor, for example, the Hox genes of human beings.

II Space and time order of homeobox gene expression

Human homeobox genes of Hox-A, Hox-B, Hox-C and Hox-D arrange in 7th, 17th, 12th and 2th chromosomes to form different gene clusters, respectively, and the orders of genes corresponds to their temporal and spatial sequential expression in vivo.

1. Time order of gene expression: the front-end gene preferentially expresses and the late-terminal gene expresses late.

2. Space order of gene expression: the front-end gene expresses in the front, and the back-end gene expresses in the back.

For example, homeobox Hox-A gene cluster contains genes of A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11 and A13, so space-time site of A1 gene expression should be the earliest and express in the front.

I The replicated karyoplasm can be equally divided into two daughter cells in each division of the fertilized egg, but the distribution of cytoplasm in fertilized eggs and the daughter cells is uneven. Cytoplasmic heterogeneity has decisive function in cell differentiation.

Mature egg cell stores 20,000-50,000 kinds of RNA, most of which are mRNA, and these mRNA do not conduct protein synthesis until after fertilization. Some of these mRNAs are unevenly distributed in the egg, some are distributed in the animal pole, and some are distributed in the vegetal pole, and they play a very important role in the decision of the fate of cell differentiation.

In general, the mRNAs that are polar distributed in the egg and are translated into the transcription factor and the translational regulatory protein play an important role in embryonic development after fertilization, which is called the maternal effect gene product (MEG).

For example, the grey crescent of frog's fertilized egg is very important for development. Artificially controlling cleavage of a fertilized egg, blastomere with grey crescent can develop into an individual, while blastomere without grey crescent cannot develop into an individual.

II In early embryonic cells, the heterogeneous cytoplasm contains a variety of transcription factors, namely cytoplasmic determinants, which can regulate the expression of nuclear genes and determine the direction of cell differentiation.

1. Uneven mammalian cytoplasm in early embryos can lead to the unequal distribution of cytoplasm in cell division and make cell choose different differentiation direction.

2. When human adult stem cell is divided into two cells, the cytoplasm is not equally divided. Because the cytoplasmic determinant of the two cells is different, one is still a stem cell, but the other is a differentiated cell.

3. Teratoma undergoes determinant and differentiation in wrong time and space. Undifferentiated stem cells desultorily aggregate and form unorganized lump. The behavior of continuous proliferates without differentiation like the early embryo, but teratoma unlimited growth eventually led to the death of the host.

In the process of cell differentiation, more and more gene products are produced and added to the cytoplasmic components. This makes the gene expression environment constantly change, and the status of gene expression in the nucleus is continually adjusted, so that the embryonic cells can gradually decide and differentiate.

Embryo induction and differentiation inhibition occur in a short distance among adjacent cells, which is accomplished by cell signaling system. Mechanism: The chemical signals (paracrine factors) released by tissue are applied to adjacent tissue and regulate gene expression by signal transduction to induce or inhibit neighboring tissue differentiation.

Embryonic induction, also called differentiation induction, refers to the positive role of promoting differentiation in blastoderm during embryonic development. Studies have shown that the interaction between cells is hierarchical. In the three germ layers, the mesoderm firstly becomes independent and conducts differentiation, and promotes the differentiation of endoderm and ectoderm toward their respective tissues and organs. For example, during the development of eyes, mesoderm independently differentiates firstly, and then produces differentiation induction of endoblast and ectoderm.

Mesodermat notochord induces ectoderm

↓differentiation

Neutral tube (primary induction)

↓

The front-end of neutral tube develops into brain and erupts ocular cup in both side

↓induction

Ectoderm of ocular cup external surface differentiates into lens, and ocular cup forms retina and iris (the secondary induced)

↓induction

Ectoderm of lens external surface forms cornea (three stage induction)

Differentiation inhibition refers to the negative feedback regulation of the differentiated cells inhibit the adjacent cells from differentiation to the same direction in the process of embryonic development. For example, after the formation of heart (or eyes), it will inhibit other cells from forming the heart (or eyes) again. If relieving this inhibition, multiple parts of the body will develop into heart (or eyes).

The interaction among long-distant cells is achieved by hormones. Hormonal regulation mainly occurs in the late stage of embryonic development, and cells have decided at this time. Hormones are signaling molecules secreted by secretory cells and act on the long-range target cells through the blood circulation. They can influence leptocyte differentiation through a series of signal transmission process.

Various factors in the environment can regulate or influence cell differentiation and the developmental direction of the organism, such as physical, chemical, biological factors, etc. Exposure to high doses of radiation in the early development of embryo can cause 50% of infants with congenital malformation. Incubation temperatures can determine the sex of certain reptiles (such as crocodile).

Stem cell, which exists in various stages of the tissues and organs during the individual development, has the ability of self-regeneration and potential of differentiation. Stem cells are the initial source of all sorts of differentiated cells or specialized cells, among which embryonic stem cells constitute the source of cells for human embryonic development, and adult stem cells are the cellular basis for the regeneration of human metabolic tissues and the repair of necrotic tissues.

1. They are circular or oval with relatively large nucleochylema; 2. Telomerase activity of them is high; 3. They have special markers; 4. Their proliferation is slow; 5. Their cell number is constant.

ES cells are present in early embryos and can be induced to differentiate into all cell types of the organism.

1. They are highly undifferentiated cells; 2. They self-renew for a long time; 3. They have the development of totipotency.

Adult somatic stem cells, also called tissue-specific stem cells, exist in adult tissues and organs and can be induced to differentiate into apart of tissue cells, such as, hematopoietic stem cells, neural stem cells, mesenchymal stem cells, etc.

1. They are the undifferentiated cells in the differentiated tissue; They have been decided, but un-differentiate; 2. They can self-renew; 3. They have multipotent or specialized.

Totipotential stem cell. Embryonic stem cells can proliferate indefinitely and differentiate into about 200 types of cell, and further to form all tissues and organs of body.

Pluripotential stem cell. They have the potential to differentiate into a variety of cellular tissues, but lose their ability to develop into complete individual. For example, hematopoietic stem cell (HSC) can differentiate at least 12 types of blood cells, but it can't differentiate into other cells that do not belong to hematopoietic system.

Limited potential stem cell. Basal epithelial stem cells can only differentiate into one or two close types of cells.

Stem cells are seed cells for cell therapy. Stem cells are used to develop tissue engineering organs. Stem cells can be used as evaluation model for drug toxicity and efficacy.

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