There are approximately 200 different cell types in the body - each differing in their morphology (size, shape), and the contribution they make to the functioning of the body as a whole. This specialization of cell structure and function is called differentiation.

Cellular differentiation reflects variations in patterns of gene expression from one specialized cell to another. While all cells of the body (other than spermatozoa and ova) contain exactly the same complement of genes, not all of these genes are active in every cell. Some genes may be switched on in one cell type, and switched off in another. For example, even though all cells in the body contain genes which can potentially code for hemoglobin, it is only red blood cells, specializing in oxygen transport, that synthesize this molecule. Likewise only skin cells produce keratin, and antibodies are synthesized only by certain cells of the immune system. The process of differentiation begins shortly after conception and continues throughout life, regulated by a hierarchy of genes that determine the developmental pathway that a particular cell will follow.

Cellular differentiation allows the body to divide the many physiologic tasks of life among many cells - allowing the body to function more efficiently. However, differentiation is also associated with a cost to individual cells. The more specialized cells become, the more limited they are when it comes to performing maintenance functions, providing for their energy needs, and adapting to physiologic stresses. Additionally, specialized cells lose some of their ability to replicate themselves.

Most of the differentiated cells of the body are organized into cooperative groups called tissues . Despite its complexity, the human body is composed of only four basic types of tissue: Epithelia, Connective Tissue, Muscle, and Nervous Tissue. The cells that make up these four categories of tissues share certain structural, biochemical, and functional characteristics that distinguish one tissue type from another. These four tissues are also combined in various combinations to form organs . The cells in tissues and organs are usually in contact with a complex network of secreted macromolecules (proteins and complex carbohydrates) called the extracellular matrix. This matrix helps hold cells together and provides a medium through which cells can communicate with one another in order to function as a unit.

Biologic Characteristics of Normal Tissue

The normal tissues of the body have a number of structural and functional characteristics in common that help distinguish them from certain disease states such as cancer.

• Uniformity and regularity of cellular architecture - Microscopic examination of almost all normal tissues reveals a remarkable uniformity in cell size, shape, and spatial organization. This uniformity even extends to the numbers and distribution of intracellular organelles. Tissues are most commonly organized into broad sheets of single or multiple layers of cells (e.g., skin, intestinal mucosa, pleura, peritoneum, etc.) - or into tubular structures (e.g., glandular structures, blood and lymphatic vessels, renal tubules, etc.)

• Ordered cellular growth and development
  • Growth factor dependence - Cell replication is a tightly regulated event in normal tissues (see below). Normal cells are not autonomous - they only divide and grow when they are stimulated by an external biochemical signal called a growth factor. For example, red blood cell production is dependent on the availability of a growth factor called erythropoietin. Without this substance, adequate numbers of red blood cells can not be produced.

  • Stable numbers of cells - The numbers of cells in normal tissues remain relatively constant over time. The rate of cell regeneration is equal to the rate at which old cells are lost to injury or normal attrition. This homeostatic mechanism is designed to keep organs at a standard size. Even a small but persistent imbalance between the rate of cell production and the rate of cell death could create problems. For example, if only 2% of the cells in a particular organ divided each week but only 1% died, the organ would grow to exceed the weight of the rest of the body within eight years.

  • Anchorage dependent growth - With the exception of blood cells, most other cells of the body have to be physically attached to the extracellular matrix in order to grow and differentiate normally. Anchorage dependent growth is particularly important for orienting and stabilizing cells during the formation of tissues and organs. In epithelial tissues (skin, glands, etc.), the cellular anchorage is called the basement membrane (or basal lamina).

  • Contact inhibition - With only a few exceptions, normal cells do not grow over or around other cells. When a migrating or dividing cells come in contact with other cells, further motility or cell division is inhibited. This helps to contribute to the orderly arrangement of cells in tissues.

• Programmed Cell Death: The cells of normal tissues have a genetically programmed life span. Specialized cells typically perform their functions for a limited period of time and then they die. This genetically determined cell death is a kind of "cell suicide" called apoptosis. In this process, the nucleus of a dying cell condenses and, along with the cytoplasm, breaks up into small fragments which are engulfed and digested by neighboring cells. In some cases, apoptotic cells may persist instead of being reabsorbed (e.g., the keratin layer of the skin, the crystalline structure of the lens), or if they line a body cavity or surface, they may be sloughed off (e.g., loss of endometrial cells during menses).

Embryology of Tissue Development

Embryologic development of humans and other vertebrates is usually divided into three overlapping phases. (1) During the first few weeks following fertilization of the ovum, the zygote rapidly divides forming a mass of cells that will eventually develop into the specialized cells of the body. (2) In the second phase, rudiments of various organs are formed such as the limbs, eyes, heart, etc. - a process called organogenesis. (3) In the third phase, organs mature and grow to their adult size. We will focus on the first phase of embryologic development during which the embryo becomes organized into the three primary germ cell layers and the process of cellular differentiation begins.

• Week 1: The fertilized ovum (zygote) undergoes several rapid mitotic divisions as it migrates through the uterine (Fallopian) tube. After reaching a size of approximately 120 cells, the fluid-filled blastocyst reaches the uterine cavity and attaches to the endometrium (a process called implantation). The blastocyst consists of an outer cell layer called the trophoblast, and an inner cluster of cells called the embryoblast.

• Week 2: The blastocyst becomes completely embedded in the uterine wall and trophoblastic cells tap into the maternal blood supply. At this point in time the embryoblast has evolved into a disk-like structure, two cell layers thick - called the embryonic disc. The two layers of the embryonic disc, the epiblast and hypoblast, divide the blastocyst into two chambers - the amniotic cavity and yolk sac. The amnion is a fluid filled chamber that cushions the developing embryo/fetus and helps maintain fetal body temperature at a constant level. Later in gestation, amniotic fluid circulates between the fetus and the mother. The fetus swallows amniotic fluid which is absorbed by the primitive digestive system into the fetal blood stream. Eventually, it passes into the maternal circulation across the placenta carrying metabolic waste products. Part of the yolk sac gets incorporated into the gut during later development. It is also the site of early blood cell formation. Another chamber known as the extraembryonic coelom forms around the amnion, yolk sac and developing embryo. The walls of this chamber are derived from the cells of the trophoblast and will later become the chorionic sac and placenta.
  

• Week 3: The process of gastrulation takes place during which the two-layered embryo is transformed into three layers of cells known as the primary germ cells (ectoderm, mesoderm, and endoderm). These three groups of embryonic cells will evolve into the specialized cells, tissues, and organs of the body.

  Near the caudal ("tail") end of the epiblast, a few cells form a slightly thickened, furrowed cell mass called the primitive streak which begins to extend towards the cranial ("head") end of the embryonic disc. Eventually, a few cells near the advancing edge of the primitive streak begin to pull apart slightly to form an open pit. Cells bordering the pit then migrate under their neighbors - between the epiblast and hypoblast - creating a layer called the mesoderm . Cells from the epiblast also invade and displace the hypoblast creating another cell layer called the endoderm . The hypoblast eventually recedes and is not incorporated into the developing embryo. The epiblast, on the amniotic side of the embryonic disk, now becomes known as ectoderm. At this point, the embryonic disc is three cell layers thick. The process of gastrulation also establishes the craniocaudal (head to tail) orientation and bilateral symmetry that will characterize the fully developed body.

What becomes of the primary germ cells?

• Endoderm - Forms the lining of the primitive digestive tract and its associated glandular structures. Portions of the liver, pancreas, trachea, and lungs also arise from endoderm.

• Mesoderm - Initially, the mesoderm is composed of a loose aggregate of cells called mesenchyme. Within a short time, these cells begin to organize into distinct regions within the mesoderm and evolve into the vertebral column, skeletal muscle, ribs, skull, and the dermis of the skin. Tubular structures such as the urogenital system, heart, and blood vessels also develop from mesenchymal cells as do blood cells, and the lining of the pericardial, pleural, and peritoneal cavities.

• Ectoderm - Later develops into the epidermis of the skin. Part of the ectoderm becomes the brain and spinal cord. The sensory receptors for vision, hearing, and smell, along with cells of the future autonomic nervous system and adrenal medulla also arise from ectoderm.

Cell Renewal and Tissue Regeneration

Throughout life, normal cells are regularly injured or are lost to programmed cell death. To maintain normal tissue and organ functions these cells have to be replaced on a regular basis. However, normal cells vary in their ability to regenerate; some cells replicate frequently, while others rarely divide.

• Renewing Cell Populations: Most tissues have renewable cells that closely resemble embryonic germ cells. These cells are called stem cells and have the ability to divide and replace cells lost to normal attrition or injury. When a stem cell divides, one daughter cell remains a stem cell available for future cell renewal, while the other divides one or more times and develops into mature, non-dividing, differentiated cells. Stem cells are long-lived and can divide without limit for the life span of the individual. Examples of tissues that use stem cells to regenerate tissues include the epidermis of the skin, epithelial lining of the digestive tract, and blood cells.

• Static Cell Populations: Not all tissues are capable of renewal. Some tissues contain highly specialized cells that have lost the ability to divide (or divide very rarerly) and contain no functional stem cells. The cells in these tissues usually persist for the lifespan of the individual. These "static" cells are also sometimes referred to as permanent cells. When permanent cells are injured and lost, they are gone forever. Examples include neurons and heart muscle (myocardium).

• Stable Cell Populations: Other tissues contain cells that are "partially differentiated". As part of their normal development, these cells enter a dormant rest phase of the cell division cycle before they fully mature and retain the ability to divide. These cells are called stable cells. When stable cells are injured or lost, other stable cells are stimulated to divide in order to replace them. Examples of stable cells include the functional cells of the liver (hepatocytes), the cells that form blood vessels (endothelial cells), cells in the skin (fibroblasts) that produce scar tissue in response to tissue injury, and the periosteum of bone.

THE CELL DIVISION CYCLE: Cell replication is a complex process that involves a highly regulated sequence of biochemical events. It can be divided into two stages - mitosis (visible, active cell division), and the interphase (the biochemical preparation for mitosis). Interphase is further divided into three phases G1, S, and G2. G1 represents the period after mitosis during which the cell actively synthesizes proteins and matures into a functional cell. S phase represents active DNA synthesis and replication of the cell's chromosomes so that the two daughter cells resulting from mitosis will have the same genes. G2 represents the period following active DNA synthesis and before mitosis. The cell typically accumulates energy stores and synthesizes the microtubular apparatus necessary for mitosis. After mitosis, many dividing cells enter a modified G1 phase called G0. These cells are in an arrested phase of development and are relatively dormant. They are essentially reserve cells that can later be recruited into the active stages of cell division if needed.