Stem Cells

Introduction to Stem Cells

Stem cells are undifferentiated biological cells that can differentiate into specialized cells and can divide (through mitosis) to produce more stem cells.

Introduction to Stem Cells

What are Stem Cells?

Stem cells are undifferentiated biological cells that have the ability to differentiate into specialized cells. They are basically the initial building blocks of the body of a living organism. Furthermore, they can divide, through the process of mitosis, to produce more stem cells. They are found in most multicellular organisms. There are two broad types of stem cells in mammals: embryonic stem cells, which are isolated from the inner cell mass of blastocysts, and adult stem cells, which various tissues are endowed with.

Stem cells have the potential to develop into many other diverse types of cells found in the body. Additionally, in many developed tissues, they can serve as an internal repair system, dividing substantially without limit to replenish other cells as long as the organism lives.

Stem cells are distinguished from other cells by two important characteristics. Firstly, they are unspecialized cells that have the capacity of renewing themselves through cell division, sometimes even after extended periods of inactivity. Second, under certain physiologic or experimental conditions, they can be induced to develop into tissue-specific or organ-specific cells that contain special functions. In some organs, such as the bone marrow and the gut, stem cells routinely divide in order to repair and/or replace worn out or damaged tissues. In other organs, however, such as the heart and pancreas, stem cells only divide under certain special circumstances.

There are several reasons why stem cells are crucial for the proper functioning of living organisms. In the three- to five-day-old embryo called the blastocyst, the inner cell mass (ICM) can give rise to the complete body of the organism, which includes all of the varied specialized cell types and organs including the heart, skin, lungs, eggs, sperm as well as other tissues. In some adult tissues, such as the bone marrow, muscle, and brain, distinct populations of adult stem cells initiate and create replacements for the cells that have been lost through regular wear and tear, disease, or injury.

Whenever a stem cell divides, each new cell created has the potential to either remain as a stem cell or to become another type of cell with a more specialized function, such as a brain cell, a red blood cell, or a muscle cell.

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Microscopic view of a colony of undifferentiated human embryonic stem cells
Source: James Thomson's research lab, University of Wisconsin-Madison

 

Properties of Stem Cells

Plasticity, Differentiation, Self Renewal

Properties of Stem Cells

Plasticity

In the study of stem cells, the term "plasticity" refers to the capacity of stem cells in a particular tissue to display a phenotypic potential that extends beyond the differentiated cell phenotypes of their resident tissue. This basically means that stem cells are considered to have higher plasticity if they have the ability to generate other cell types, different from the one they currently reside in.

To understand this particular property of stem cells we need to learn about embryonic development. The human embryo in its early stages reaches a particular stage where the number of cells created through repeated multiplication is enough to divide them into there distinct layers - The ectoderm (which gives rise to the skin and neural cell lineages), the mesoderm (which possibly generates the blood, bone, muscle, cartilage, and fat tissues), and the endoderm (which contributes towards tissues of the respiratory and digestive tracts). Along with the cells assigned to each lineage undergo genetic modifications that commit them to their specific roles throughout adulthood which include mature cells, progenitor cells as well as stem cells (with very few exceptions, for example, neural crest cells). This is done in order to ensure that the cells do not cross tissue boundaries and maintain the body's homeostatic requirements. However recent experiments have shown that under certain circumstances the stem cells although committed to a particular lineage are able to differentiate into a variety of other cell types.

Originally it was believed that stem cells found in a particular tissue can only renew and differentiate into lineages of the tissue it resides in. But this statement has been disputed and it has been confirmed that tissue-specific stem cells have substantial plasticity and can propagate into cell types belonging to other lineages by overcoming the cross-lineage boundary and also lose their tissue-specific surface markers as well as functions. This property is also known as transdifferentiation. They are able to acquire the surface markers and functions of tissues they did not originally belong to. Many experiments have been conducted previously where scientists have been able to induce adult stem cells to propagate into cells of tissues they weren't originally isolated from such as brain stem cells that differentiate into blood cells or blood-forming cells that are able to give rise to muscle cells etc.

This has also prompted scientists to look into the matter of embryonic development wherein the splitting of germ layers may not be as clear cut as it was supposed to be. It has also opened the gates to potential research in the field of regenerative therapy.

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Source: www.cell.com

The mechanism by which the adult stem cells undergo transdifferentiation and have different levels of plasticity is highly variable. It may be due to the changes in the microenvironment, dormant differentiation programs, injury, presence of specific chemicals, etc.  The above diagram shows potential mechanisms and pathways for adult stem cell plasticity with Tissue-specific stem cells represented by orange or green circles, pluripotent stem cells represented by blue ovals, and differentiated cells of the “orange” lineage by red circles and of the “green” lineage by green hexagons.

Properties of Stem Cells

Differentiation

Differentiation is the process wherein unspecialized stem cells give rise to specialized cells with a deliberate switch from proliferation to specialization. Here unspecialized stem cells are those that have not been assigned a specific phenotype or role to play in the functioning of the living organism.
The stem cell, while differentiating, typically goes through several stages, becoming more and more specialized at each step. Each step bringing it closer to its function in the body accompanied by various alterations such as changes to cell morphology, metabolic activity, membrane potential, and responsiveness to certain signals. These signals may be composed of mostly growth factors, cytokines as well as epigenetic processes namely DNA methylation and chromatin remodeling. When embryonic stem cells undergo such differentiation they divide to give one duplicate stem cell (self-renewal) and one differentiated daughter cell becoming more and more mature as it moves downstream.

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Source: www.sigmaaldrich.com

The process of differentiation of the stem cell is tightly regulated by and prompted by internal and/or external signals.

 

The stem cell's DNA can acquire epigenetic marks that restrict DNA expression of the cell through the interactions of these signals during differentiation. This information can be further passed down to daughter cells.

The mechanisms involved in differentiation, especially those of embryonic stem cells is being widely studied by scientists especially with regards to debilitating diseases such as Parkinson's disease and cancer.

Properties of Stem Cells

Self renewal

Self-renewal is the ability of stem cells to divide in order to make more stem cells, growing the stem cell pool throughout the lifespan of the living organism. Self-renewal is the division of the stem cell along with the maintenance of the undifferentiated state so that the body does not run out of the essential stem cells. Any defects in the mechanisms of self-renewal can cause developmental disorders, premature aging phenotypes, and/or cancer. understanding the complexities of self-renewal mechanisms provides the potential for fundamental insights into development, cancer, and aging. Stem cells remain quiescent unless there great physiological need at which point they divide to create daughter cells that have the same developmental potential as their mother cell. In this way, it is different in nature to general cell proliferation.

This requires control of the cell cycle and often the maintenance of potency (the capacity of the stem cell to divide into different cell types), depending on the stem cell.

The balance of proto-oncogenes (that promote self-renewal), gate-keeping tumor suppressor genes (that limit self-renewal), and care-taking tumor suppressor genes (that maintain genomic integrity) is crucial in the self-renewal of stem cells.
These intrinsic mechanisms of the cell are regulated by signals originating from the niche, which is the microenvironment surrounding the stem cells that maintains and regulates their function in tissues.

In response to the dynamic tissue demands, stem cells can undergo changes in their cell cycle condition and developmental potential over time, necessitating particular self-renewal programs at different stages of life.

During aging, the stem cell function and tissue regenerative capacity are reduced. This is caused by changes in self-renewal programs that amplify tumor suppression. Cancer can arise from mutations that inappropriately activate self-renewal programs.

Regulation of Self-renewal in Pluripotent Stem Cells

Embryonic Stem cells (ESC) have unique transcriptional and cell cycle regulation which leads to properties of unlimited self-renewal potential and pluripotency. Oct4, the POU domain transcription factor is critical for the pluripotency of the inner cell mass of the blastocyst as well as ESCs in culture. Sox2, the SRY-related HMG-box transcription factor is also needed in order to maintain the pluripotency of the embryo and of ESCs in culture. Both these factors coordinate in order to activate the expression of a group of genes whose role is to regulate pluripotency. Nanog is a homeodomain protein that is also required for the maintenance of pluripotency. This Oct4-Sox2-Nanog network is finely regulated by positive and negative signals because even the slightest hyper- or hypoactivation of some of these factors can disrupt pluripotency. Besides these factors, there are epigenetic regulators as well that also promote the maintenance of pluripotency.

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Diagram depicting the Oct4-Sox2-Nanog regulatory network. This also shows that ESCs inhibit differentiation in order to self-renew.

 

Potency of Stem Cells

Stem cells can be classified based on their degree of plasticity. Different types of stem cells vary in their degree of developmental versatility. Stem cells can be described best in terms of their level of commitment to becoming any specific type of cell.

Potency of Stem Cells

Classification of Stem Cells Based on Potential

Stem Cell potency is the ability of stem cells to be able to differentiate into specialized cell types. Cells with higher potency are able to generate more varied cell types than those with lower potency.

Totipotent stem cells have the highest versatility amongst the stem cell types. When a sperm and an ovum unite, they form a one-celled zygote. This cell is considered to be totipotent, which means that it has the potential to give rise to any and all cells of the entire body, such as the brain, skin, blood, etc. It has the ability to give rise to an entire functional organism through differentiation and self-renewal. The first few cell divisions of the zygote during embryonic development produce the most number of totipotent cells. After the fourth day of embryonic development, the cells start to specialize and become pluripotent stem cells.

Pluripotent stem cells are similar to totipotent stem cells in that they can produce all types of tissues. But unlike totipotent stem cells, they cannot generate the body of an entire organism. On the fourth day of development, the cells of the embryo arrange themselves into two distinct layers, an outer layer which will become the placenta, and an inner mass that will form the tissues and eventually the organs of the human body. Though they can form nearly any human tissue, these inner cells, cannot do so without the presence of the outer cell layer; hence they are not considered totipotent but are pluripotent in nature. As these pluripotent stem cells continue to divide and differentiate, they begin to specialize giving further cell types.

Multipotent cells have less plasticity and are more differentiated than pluripotent stem cells. They can divide to produce a limited range of cells that belong to a particular type of tissue. The daughter cells of the pluripotent cells will eventually become the progenitors of cell lines such as blood cells, nerve cells, and skin cells. At this stage, they can give rise to one of several types of cells within a given organ and/or tissue. For instance, multipotent blood stem cells can give rise to many types of cells present in the blood such as red blood cells, white blood cells or platelets. These type of stem cells are also referred to as oligopotent stem cells.

An adult stem cell can either be a unipotent progenitor stem cell, which means that it can give rise to cells belonging to a single specific lineage or a specialized multipotent stem cell that can produce cells of a very limited type. in adult humans, these kinds of stem cells are used to replace cells that have either died or lost their function. They are undifferentiated cells present in a microenvironment of differentiated tissue known as a stem cell niche. They can renew themselves and can specialize to yield all cell types present within the tissue niche. Thus far, adult stem cells have been isolated from many tissue types such as the hematopoietic (blood), neural, endothelial, muscle, mesenchymal, gastrointestinal, and epidermal cells, etc.