Cell Renewal

Cell Division and Differentiation

Cell division is a pivotal biological process for the wellbeing of human beings. Cell division starts at the very early beginning of the individual life and never stops before death. The earliest cell division is the first cleavage division that immediately follows fertilization. This is followed by rapid successive cell divisions that give rise to embryo stages known as the morula and blastocyst. Thereafter cell divisions continue, accompanied by cell growth and differentiation, into the fetus stage.  After birth, all these three cellular processes continue until death.  

Fig. D1. Illustration showing cell divisions that follow fertilization of the ovum and embryonic developmental stages that follow.

Cell Division and Differentiation

Cells that are formed by the successive cell division that follow fertilization are undifferentiated cells. They are characterized by paucity of cytoplasmic organelles> They don’t perform any specific function such as secretion, contraction or impulse conduction.  During later stages of embryonic and fetal life and throughout the individual’s life, some of the body cells remain comparatively undifferentiated constituting stem cells and progenitor reserve cells; they retain their ability to divide and re-divide. The rest of the body cells differentiate into functional cells e.g. goblet cells, zymogen cells, hepatocytes, neurons and muscle cells, that perform specific functions. Some of these differentiated cells still retain their ability to divide, but most of the differentiated cells are incapable of undergoing cell division. Cell differentiation results from expressions of specific genes in specific cell types, for instance, expression of neuron specific genes yields neurons whereas expression of the epithelium specific genes yields epithelial cells.

Fig. D2. The illustration shows the role of gene expression in the process of differentiation of daughter cells from the same mother cell into two distinctly different functional cells.   

Cell Renewal

Cells of the body are continuously lost and are continuously replaced. The process of replacement of lost cells is called cell renewal. These renewal capabilities are not the same in all cells of the body. Different types of cells of the body have different renewal capabilities. Cell renewal capabilities reflect the ability of the body tissues to replace damaged and lost cells by new cells. Depending on their ability to renew themselves, cells of human body are classified into:

1. Populations that renew themselves continuously.

2. Populations that renew themselves when need arises.

3. Populations that cannot renew themselves at all.

Depending on the presence or absence of progenitors cells, functional cells of the body are classified into cells with progenitors and cells without progenitors.

Functional Cells that have progenitors

Many functional cells of the body (e.g. white blood cells, intestinal epithelial cells, keratinocytes of the skin) are short lived. Thus, they are continuously lost but are replaced throughout life by continuously dividing progenitor cells. These are known as continuously renewing cell populations.

Functional Cells that do not have progenitor

Some functional cells (e. g. hepatocytes) are long lived. They remain functional for long times but can divide when need arises. They have the potential for renewal. They are called stable cells, quiescent or facultative dividers. Some other functional cells (e.g. neurons and cardiac myocytes) are also long lived but have for no progenitor cells and have no capacity for self-renewal. They are called permanent cells. Progenitor cells can proliferate continuously and are known as labile cells.

Fig. D3. Illustration showing the cycling abilities of labile cells, stable cells and permanent cells. Labile cells are within the cycle all the time, stable cells are outside the cycle but can go back to the cycle when need arises. Permanent cells are out the cycle all the time; they can never go back to the cycle.

Progenitor Cells

Progenitor cells are relatively undifferentiated cells capable of dividing to give rise to two daughter cells of different potentialities. One of the daughter cells remains undifferentiated to replace the mother cell and the other one differentiates into a functional cell.  Thus, progenitor cells are capable of continuously dividing to renew themselves and to give rise to new functional cells. Progenitor cells are categorized as labile cells or continuously dividing cells. Some of the progenitor cells produce only one type of functional cells. Spermatogonia, for instance, produce only one type functional cells (the spermatozoa). This type of progenitor cell is called a unipotential progenitor cell. Some other progenitor cells give rise to more than one type of functional cell. The hemopoietic stem cells of the bone give rise to the different types of blood cells; they are categorized as multipotential progenitor cells. A progenitor stem cell which produces quite a large array of functional cells is known as a pluripotential cell. Example of this are cells of the inner mass of the blastocyst which give rise to all sorts of body cells.  The fertilized ovum (the zygote) gives rise to all cells of the body and also to cells of the extraembryonic membranes; it is a totipotential cell. The suffix potent is synonym with potential so we can say unipotent, multipotent, pluripotent and totipotent cells.

Fig. D4. Illustration showing classification of cells differentiation potency.

Fig. D5. Illustration showing classification of cells according to their ability to undergo cell division, into continuously dividing (labile) cells, facultative dividers (Stable cells) and terminally differentiated (permanent) Cells.

The Cell Cycle

  The cell cycle is the period between the end of a cell division and the end of the succeeding division. The cell cycle consists of two main phases:

1.      Interphase

2.      Mitotic phase

Fig.D6. Showing events of the cell cycle (left) and its two main phases (right).  

Interphase of the Cell cycle

Interphase is that part of the cell cycle where the cell is not dividing. Cells in the interphase show their normal characteristics features and perform their normal functions (e.g. secretion). The interphase comprises three stages: G1, S and G2. Each of stages (phases) has its characteristic features and events

Fig.D7. Illustration showing the three phases of the interphase (G1, S, G2) and the interphase

G1, S and G2 of Interphase: These three phases (G1, S and G2) cannot be identified in ordinary histological sections. In all of them the cell shows its characteristic microscopic features for both the nucleus and the cytoplasm. G1 is the longest of the three phases. The nucleus has an ordinary DNA complement (2n). The S phase is the phase where DNA is synthesized. During S phase the amount of DNA is doubled increasing from 2n to 4n. G2 is the shortest phase with the nucleus appearing normal but having a 4n DNA complement.

Fig. D8. Appearance of the interphase nucleus. In the illustration on the left, the nucleus clearly shows its normal three components, the nuclear envelope, the nucleolus and chromatin. A pair of centrioles are present adjacent to the nucleus. The micrograph on the right shows the normal appearance of the interphase nucleus under light microscope (nucleolus, euchromatin, heterochromatin.  

Mitotic Phase (M-Phase)

The mitotic phase (M-phase) is that part of the cell cycle where the cell is actually dividing by mitosis. Mitosis is that type of cell division whereby a somatic (body) cell produces two daughter cells genetically identical to each other and to the mother cell.  It comprises four phases: the prophase, metaphase, anaphase and telophase. Each of thse four phases of mitosis has its characteristic features and events.

Fig. D9. The illustration shows the process of mitosis and its four phases: prophase, metaphase, anaphase and telophase. Each phase has unique features. The end result is the production of two daughter cells identical to each other and to the mother cell.

Phases of Mitosis

At the beginning of prophase, the nuclear chromatin condenses and gradually transforms into fine thread-like structures; these are the chromosomes beginning to appear as individual entities. Meanwhile, the two centrioles organize microtubules around themselves in a radiating manner, forming what are known as aster rays. The aster ray microtubules transform into the mitotic spindle. Concurrently, the nuclear envelope gradually disintegrates and disappears. In metaphase the chromosome, which now appear thicker and discrete, arrange themselves in the equatorial plane of the cell. The chromosomes are arranged as individual chromosomes (46 chromosomes) without pairing of the homologous chromosomes. Close examination shows that each chromosome is made of two sister chromatids attached to each other at the centromere. The mitotic spindle is now fully formed consisting of the two centrioles occupying opposite poles of the cell and the spindle microtubules (fibers) extending between them. There are two types of spindle microtubules; continuous microtubules and chromosomal microtubules. Continuous microtubules extend between the two centrioles at opposite poles of the cell, whereas chromosomal microtubules extend between each of the centrioles and the chromosomes arranged in the cell equator. The point of attachment of the microtubule to the chromatid is called the kinetochore.

Fig. D10. Showing prophase and metaphase in illustrations above and micrographs below.

Fig. D11. Showing arrangement of the metaphase chromosomes (black colour) at the equator of the cell as seen by the transmission electron microscope. The spindle is complete made of two centrioles (R) and microtubules (M). Arrows are pointing to kinetochores.

In anaphase the sister chromatids are pulled apart from each other due to contraction (shortening) of the chromosomal spindle microtubules and concurrent elongation of the continuous spindle microtubules. The two sets of chromatids (now known as chromosomes) are pulled towards the centrioles at opposite poles of the cell. Each set consists of 46 single chromatids / chromosomes. They appear >-shaped or <-shaped because they are pulled from their centromeres.  

Fig. D12. Showing an illustration (on the left) and a light micrograph (on the right) of a cell in anaphase of mitosis. The chromatids (now known as chromosomes) have been pulled apart by the centrioles and the chromosomal microtubules.

In telophase the two sets of chromosomes settle at opposite poles of the cell, mitotic spindle disintegrates, the nuclear envelope reappears, and the chromosomes elongate into slender thread-like structures that intermingle to form chromatin, and thus two nuclei are formed within the cell, each containing 26 chromosomes i.e. 23 pairs (2N).  Cytokinesis takes place towards the end of telophase. It is the division of the cytoplasm of the mother cell into two parts, resulting in the formation of two daughter cells. The process begins with a circular equatorial furrow at the cell surface. Actin filaments play a significant role in this process. They form a ring under the cell membrane in the equator and contracts pulling the cell surface inwards forming a cleavage furrow that deepens, ultimately dividing the cell into two identical daughter cells.   

Fig. D13. Telophase of mitosis as illustrated diagrammatically (on the left) and as seen under the fluorescent microscope (on the right). The two daughter nuclei are almost completely formed, the mitotic spindle has disappeared, and distinct cleavage farrow is seen at the cell equator (arrows).

Thus, the cell cycle comprises seven phases, which are: G1, S, G2, prophase, metaphase, anaphase and telophase. The time duration of these phases varies depending on several different factors. However, in more 95% of the time the cell is in the interphase. The duration of interphase varies considerably in different types of cells.  

 The Mitotic Index (MI)

The mitotic index is the proportion of cells of a certain tissue undergoing mitosis in a given time. It is calculated by counting dividing and non-dividing cells under the microscope with or without utilization of immunoperoxidase or autoradiography techniques specific for demonstrating proliferating cells. A cell identified under the microscope to be in any phase of mitosis is known as a mitotic figure. Mitotic figures are more easily identified in smears than in histological sections, because whole cells are seen in smears.

Fig. D14. A light micrograph showing several mitotic figures pointed to by arrows. 

Proliferation and Growth

Cell proliferation and growth are influenced by several substances produced by a variety of cells, which include macrophages, endothelial cells, T-cells and blood platelets. These substances are either produced locally (paracrine) or brought in by blood. They include:

1.      The epidermal growth factor (EGF), which promotes mitosis in fibroblasts and epithelial cells.

2.      The vascular endothelial growth factor (VEGF), which promotes angiogenesis.

3.      The fibroblast growth factors (FGFs), which promote angiogenesis.

Apoptosis

During embryonic development and physiological involution (e.g. atresia of follicles, involution of the uterus and mammary glands) cells undergo apoptosis. Apoptosis is programmed cell death. Apoptotic cells show a condensed nucleus, followed by karyorrhexis and fragmentation of the acidophilic cytoplasm. Fragments are quickly phagocytosed

Fig. D15. An illustration showing the interrelations between certain biomolecules and cell growth, cell division (mitosis), differentiation and apoptosis

Fig. D16. An illustration showing cyclins and cyclin kinases and sites of their action in the cell cycle. 

Control of the Cell Cycle

The cell cycle is controlled by cytoplasmic proteins that include Cyclins (G1 cyclins, S-phase cyclins, M-phase cyclins), and cyclin-dependent Kinases (G1 CDKs S-phase CDKs M-phase CDKs). Cyclin dependent kinases bind with the appropriate cyclin. There are also cycle promoting factors (PF) that include S-phase promoting factors, M-phase promoting factors and anaphase promoting factors.

Fig. D17. An illustration showing cyclins and cyclin kinases and sites of their action in the cell cycle. 

Safeguards (Checkpoints)

Checkpoints can interrupt the cell cycle if something goes wrong; they include the genes p53 and p27. In S phase, the presence of Okazaki fragments on the lagging strand during DNA replication can interrupt the cycle. The DNA damage checkpoints sense DNA damage and interrupt the cycle. Spindle checkpoints detect failure of spindle fibers to attach to kinetochores and arrest the cell in metaphase. Checkpoints trigger apoptosis if the damage is irreparable.

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