Chapter 1: Stem Cells and Their Differentiation

Cell and Tissue Structure and Organization

Unity of plan everywhere lies hidden under the mask of diversity of structure—the complex is everywhere evolved out of the simple.

—Thomas Henry Huxley

A Lobster; or, the Study of Zoology (1861). In: Collected Essays, Vol. 8. 1894: 205–206.

The most basic and simple form of human life is the cell. Complex organisms, such as humans, are collections of these individual cells that have grown and differentiated to generate the organism itself. Each cell in an adult developed in a purposeful way from a precursor cell along a specific lineage to become organized structurally and according to its function. Be it a liver cell, a blood cell, a bone cell, or a muscle cell, it was derived from a stem cell generated soon after the organism’s conception. Hidden within the tiny stem cell is the vast capacity to develop into an array of diverse cell types that differentiate into efficient individual units that survive only within the context of the whole person.

Our discussion of cell and molecular biology therefore begins with an examination of stem cells, from which all other cells are generated. As we move deeper into this unit, we explore structural components of tissues including the extracellular matrix, which is produced by cells but resides outside the boundary of cell membranes. In considering cell structure, cell membranes serve as our starting point. As the outer limit of the cell, the plasma membrane protects the cell’s interior from the environment. Yet, it is also a dynamic structure that enables interactions with the environment and facilitates the cell’s function.

Within the confines of the plasma membrane, we find cytoskeletal proteins that not only organize the cytoplasm and provide a structural framework for the cell but also function in the intracellular movement of chromatin and organelles. The organelles are specialized centers within each cell that carry out functional processes, including energy extraction in the mitochondria, macromolecule digestion in the lysosomes, and DNA and RNA synthesis in the nucleus. While each organelle is a complex machine in its own right and has its own unique role within the cell, organelles are linked physically by the cytoskeleton and cooperate in completing their tasks with a unified purpose.

OVERVIEW

All cells within an organism are derived from precursor cells. Precursor cells divide along specific paths in order to produce cells that are differentiated to perform specialized tasks within tissues and organs. Cells with the capacity to give rise to the whole organism are referred to as stem cells. Stem cells are characterized by the ability to self-renew. They also generate many daughter cells committed to differentiate (change) into a diverse range of specialized cell types. A daughter cell with the ability to differentiate into a wide variety of cell types is pluripotent.

The human body is made up of about 200 different types of cells. The human genome is the same in all cell types, meaning that within an individual person, all cells have exactly the same DNA sequences and genes. Stem cells represent all the different ways that human genes are expressed as proteins. In order for different regions of the genome to be expressed in different cell types, the genome has to be reversibly modified. In fact, the organization of chromatin (a complex of specific proteins and DNA) varies between cell types and is made possible by reversible covalent modification of the proteins that are associated with DNA and sometimes the DNA itself (see also Chapter 6). These modifications are important to expose regions of the DNA to the proteins and enzymes that are required for transcription (DNA ? RNA), allowing for variation in gene expression as proteins (see also Chapter 8).

Different cell types arise from single precursor cells that proliferate (divide) and eventually differentiate into cells with unique structures, functions, and chemical composition. From specific proteins produced in the cells, a special type of cell division, and the microenvironment of the precursor cell, a progeny of cells is produced. This progeny can both sustain the organism as well as carry out specific functions in the body.

STEM CELLS

Stem cells exist in both early embryos and in adult tissues (Figure 1.1). The stem cells present in early embryos have an extensive capacity to differentiate into all cell types of the organism. Populations of stem cells exist in adults that can differentiate into various cells within a lineage but not outside that lineage. For example, a hematopoietic stem cell can differentiate into various types of blood cells but not into a hepatocyte (liver cell). However, researchers may have found new properties of adult stem cells.

FIGURE 1.1. Embryonic and adult stem cells.

Embryonic and adult stem cells.


  • Totipotency is the potential of a single cell to develop into a total organism (e.g., a fertilized egg and the four cell stage).
  • Pluripotency is a cell’s capacity to give rise to all cell types in the body but not to the supporting structures, such as the placenta, amnion, and chorion, all of which are needed for the development of an organism.
  • Unipotency is a cell’s capacity to give rise to only one cell type.
  • Multipotency is a cell’s capacity to give rise to a small number of different cell types.

Pluripotent stem cells

The most primitive, undifferentiated cells in an embryo are embryonic stem cells. These cells retain the ability to differentiate into a number of cell types. This ability to differentiate into multiple cell types is called plasticity.

Unipotent stem cells

Cells that reside within the adult tissues and retain the ability to generate cells for the tissue type to which they belong are unipotent stem cells. New information suggests that adult stem cells may actually be pluripotent. Adult stem cells have been identified for a number of different tissue types such as brain, bone marrow, peripheral blood, blood vessels, skeletal muscle, skin, and liver (Figure 1.2).

FIGURE 1.2. Stem cell plasticity.

Stem cell plasticity.

  1. Hematopoietic stem cells: This group of stem cells gives rise to all the types of blood cells, including red blood cells, B lymphocytes, T lymphocytes, natural killer cells, neutrophils, basophils, eosinophils, monocytes, macrophages, and platelets.
  2. Mesenchymal stem cells: Also called bone marrow stromal cells, mesenchymal cells give rise to a variety of cell types, including osteoblasts (bone cells), chondrocytes (cartilage cells), adipocytes (fat cells), and other kinds of connective tissue.
  3. Skin stem cells: These stem cells are found in the basal layer of the epidermis and also at the base of hair follicles. Epidermal stem cells give rise to keratinocytes, while the follicular stem cells give rise to both hair follicles and the epidermis.
  4. Neural stem cells: Stem cells in the brain give rise to its three major cell types: nerve cells (neurons) and two types of nonneuronal cells—astrocytes and oligodendrocytes.
  5. Epithelial stem cells: Located in the lining of the digestive tract, epithelial stem cells are found in deep crypts and give rise to several cell types, including absorptive cells, goblet cells, Paneth cells, and enteroendocrine cells.

STEM CELL COMMITMENT

Most stem cells give rise to intermediate progenitor cells (also known as transit amplifying cells), which then produce a differentiated population of cells. A good example of this stepwise process is illustrated by hematopoietic stem cells (HSCs). These cells are multipotent but undergo commitment into a particular pathway in a stepwise process. In the first step, they give rise to two different progenitors. The committed progenitors then undergo many rounds of cell division to produce a population of cells of a given specialized type. In this particular case, the HSCs give rise to one type that is capable of generating lymphoid cells and another type that results in the generation of myeloid cells (Figure 1.3).

FIGURE 1.3. Stem cells commit to different pathways in a stepwise process.

Stem cells commit to different pathways in a stepwise process.

The different steps of commitment happen due to changes in gene expression. Genes for a particular pathway are switched on, while access to other developmental pathways is shut off by specific proteins that act as transcription factors (see Chapter 10). These proteins are able to both activate the genes necessary for a particular pathway and shut down the expression of genes necessary for development along a different pathway.

STEM CELL PLURIPOTENCY

In order to maintain stable self-renewal of stem cells, mechanisms that prevent their differentiation and promote their proliferation must be transmitted to their daughter cells. While specific mechanisms by which stem cells retain their pluripotency remain largely unknown, studies with mouse embryonic stem cells suggest the importance of a self-organizing network of transcription factors. These factors play an important role in preventing the differentiation and promoting the proliferation of the stem cells (see below). Another alteration that facilitates this process is the epigenetic modification (change that affects the cell without directly affecting the DNA sequence) of DNA, histones, or the chromatin structure in such a fashion that it changes the accessibility to transcription factors.

Transcription factors

As mentioned above, transcription factors play an important role in this process. These proteins function through other effector proteins to activate specific signaling pathways that lead to both cell survival and entry into the cell cycle to facilitate cell division. Several transcription factors act as master regulators to maintain pluripotency (Figure 1.4).

FIGURE 1.4. Proteins involved in maintaining stem cell pluripotency.

Proteins involved in maintaining stem cell pluripotency.

Epigenetic mechanisms

When stem cells are induced to differentiate, their nuclei are strikingly different from the nuclei of undifferentiated stem cells. The chromatin is more relaxed in undifferentiated stem cells than in differentiated cells. This allows the low level expression of several genes that is characteristic of pluripotential cells. The open structure allows for the rapid regulation that is necessary for stem cells to respond to the needs of the organism. One group of proteins that is important in silencing the genome through its ability to modify histone proteins is the polycomb group of proteins. These proteins have been shown to play key roles in stem cell maintenance, but details regarding their mechanism of action in embryonic stem cells are not resolved.

STEM CELL RENEWAL

Development requires cells to commit to different fates. However, in the case of stem cells, there must be a mechanism in place to maintain their populations while also generating differentiated populations. This mechanism is called asymmetric cell division.

Asymmetric cell division occurs when two daughter cells are produced that differ in fate. In the case of the stem cell, it is the capacity to produce one cell similar to itself (i.e., to continue being a stem cell) and also generate another daughter cell that can proceed on a different pathway and differentiate (Figure 1.5).

FIGURE 1.5. Asymmetric cell division.

Asymmetric cell division.

Several mechanisms exist within stem cells that determine whether asymmetric cell division will take place. One such mechanism is cell polarity. Polarity is a stable feature in early embryos but may be a transient feature in tissue stem cells. External signals transmitted by seven transmembrane receptors are involved in this process (see Chapter 17).

STEM CELL NICHE

If stem cells have to be maintained as stem cells and not differentiate into a particular cell type, mechanisms must exist to guarantee their continued presence. The microenvironment that controls the self-renewal and maintenance of stem cells is termed the “stem cell niche.” The niche saves stem cells from depletion, while protecting the host from overproduction of stem cells. It performs as a basic tissue unit integrating signals that allow for a balanced response of stem cells to the needs of the organism. Progress has been made in the understanding and identification of niches for various types of tissue stem cells and in elucidating the role of the niche in regulating the asymmetric stem cell division. The choice of fate is determined by both extrinsic signaling and intrinsic mechanisms (see also Chapters 17 and 18).

Extrinsic signaling

While the cues that control proliferation and renewal of stem cells are not yet well defined, extracellular matrix interactions are known to play an important role (see also Chapter 2 for information regarding the extracellular matrix). Studies have highlighted the requirement for E-cadherin– and ?-catenin–containing junctions between stem cells and cells that support their “stemness” (see also Chapter 2 for information about cell adhesion molecules and cell junctions).

This is best understood with HSCs that associate with certain osteoblasts in the bone microenvironment that supports them. Signaling pathways that are engaged through adherens junctions have been found to be important in HSC renewal and proliferation. Cells outside of the direct contact with osteoblasts will differentiate, while the ones associated with this subpopulation of osteoblasts will remain as stem cells (Figure 1.6).

FIGURE 1.6. Extrinsic pathways maintaining HSC stem cell niche.

Extrinsic pathways maintaining HSC stem cell niche.

Intrinsic mechanisms

The mechanism of asymmetric cell division in mammalian cells is not completely understood. Different mechanisms may result in asymmetric cell division. One such mechanism may rely on specific proteins to subdivide the cell into different domains before mitosis (cell division) so that an axis of polarity is generated. Segregation of certain cell-fate–determining molecules into only one of the two daughter cells will help maintain one as a stem cell and allow the other to differentiate (Figure 1.7).

FIGURE 1.7. Differential segregation of cellular constituents during asymmetric cell division.

Differential segregation of cellular constituents during asymmetric cell division.

STEM CELL TECHNOLOGY

Pluripotent stem cells offer the possibility of a renewable source of replacement cells and tissues to treat a number of diseases and conditions.

  • Parkinson, where the brain cells secreting dopamine are destroyed.
  • Type 1 diabetes mellitus, where the ? cells of the pancreas are destroyed.
  • Alzheimer disease, where neurons are lost due to the accumulation of protein plaques in the brain.
  • Stroke, where a blood clot causes loss of brain tissue oxygenation.
  • Spinal cord injuries, leading to paralysis of skeletal muscles.
  • Other conditions such as burns, heart disease, osteoarthritis, and rheumatoid arthritis, where lost cells can be replaced using stem cells.

Induced pluripotent stem cells (iPS cells). It has been possible to reprogram adult cells into a pluripotent state by introducing extra copies of key genes that control pluripotency. In these cases, a cocktail of three to four genes appeared to do the trick. These genes code for specific transcription factors such as c-myc, Sox2, Oct3/4, Nanog, etc. While such research is in its infancy, the potential of iPS cells in the treatment of the above mentioned disorders is enormous (Figure 1.8).

FIGURE 1.8. Stem cell–based therapy.

Stem cell–based therapy.

STEM CELL DISEASES

It is possible that stem cell abnormality is the basis for several diseases and conditions.

Metaplasia is a switch that occurs in tissue differentiation that converts one cell type to another. It is often seen in lung disease (e.g., pulmonary fibrosis) and intestinal disorders (e.g., inflammatory bowel disease, Crohn disease). This represents a change that might be brought about by stem cells rather than terminally differentiated cells.

It is likely that many cancers, particularly of continuously renewing tissues, such as blood, gut, and skin, are in fact diseases of stem cells. Only these cells persist for a sufficient length of time to accumulate the requisite number of genetic changes for malignant transformation (see Chapter 22).