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Stem Cell Detailed Definitions

(reference sources – cellmedicine.com, Trizellion.com, wikipedia.com and unpublished data)

What are Stem Cells?

In explaining stem cells, it is important to clarify the nomenclature. The mere term “stem cell” has itself been widely misunderstood and, in many cases, inaccurately used. There are, in fact, a multitude of different types of stem cells, each one with clear and distinct characteristics.

Frequently, the names of these various types of stem cells are used interchangeably, and incorrectly so. The simple term “stem cell” is often casually employed in a generic sense, when what is usually meant, more correctly, is either “embryonic” stem cell or “adult” stem cell. As representatives of the National Institutes of Health (NIH) have stated,

“The terminology used to describe stem cells in the lay literature is often confusing or misapplied. Second, even among biomedical researchers, there is a lack of consistency in common terms to describe what stem cells are and how they behave in the research laboratory.” (From “Stem Cells: Scientific Progress and Future Research Directions,” available at http://stemcells.nih.gov).

Clearly, therefore, before one may understand the possible applications and related risks of stem cells, one must first understand the differences between the types of stem cells. Only then may one also be able to apply the correct terms in a correct manner. Herein, we shall offer a clarification of the various types of stem cells, their related terms and their differing characteristics.

In their first comprehensive report on stem cells, published in 2001 at the request of Tommy G. Thompson, then Secretary of Health and Human Services, The National Institutes of Health offered the following definition:

“Put simply, stem cells are self-renewing, unspecialized cells that can give rise to multiple types of all specialized cells of the body. The process by which dividing, unspecialized cells are equipped to perform specific functions – muscle contraction or nerve cell communication, for example – is called differentiation, and is fundamental to the development of the mature organism. It is now known that stem cells, in various forms, can be obtained from the embryo, the fetus, and the adult.” (From “Stem Cells: Scientific Progress and Future Research Directions,” available at http://stemcells.nih.gov).

The authors of this NIH report also add the observation that, “Like all fields of scientific inquiry, research on stem cells raises as many questions as it answers.”

Although this review is not intended to be exhaustive, we shall nevertheless address some fundamental questions about the 3 most basic types of stem cells. As listed above, these are:

  • Prenatal Stem Cells (embryonic + fetal stem cells)
  • Postnatal Sten Cells (umbilical cord + placental)
  • Adult Cells (post natal + full grown)

(“Full grown” stem cells are derived from various sites throughout the body, such as from fat, muscle, bone marrow, etc.).

The first pluripotent stem cells to be recognized were fetal stem cells, which were first isolated and grown in culture in 1998. (Ibid.) By this time, adult stem cells had already been in clinical use for nearly 40 years, although they were not yet believed to be pluripotent. Recent evidence, however, now suggests that some adult stem cells are capable of pluripotency. (These findings shall be addressed in more detail in the section on adult stem cells).

From an embryo that is 5 to 7 day old, it is possible to obtain “totipotent” human embryonic stem cells (hESC). From an embryo that is six weeks old or less, it is possible to obtain pluripotent human primordial germ cells (hEG). From fetal tissue (older than 8 weeks of development), one may obtain both pluripotent and multipotent human stem cells (hSC). From the umbilical cord and placenta, one may also obtain both pluripotent and multipotent stem cells. In the past, it was believed that, from adult stem cells, one may obtain only multipotent and monopotent stem cells. Now, however, as mentioned, new research has clearly demonstrated that even adult stem cells exhibit pluripotency.

At the beginning of any research involving embryonic or fetal stem cells, there is first a fertilized egg. Male and female gametes unite during fertilization, such that one cell divides into 2 cells, which in turn divide into 4 cells, which divide into 8 cells, etc. By continuous division and growth, the fertilized egg eventually matures into a recognizable organism. The fertilized egg may be said to be the ultimate stem cell, because it eventually becomes the whole body of a person. The fertilized egg is the only known occurrence of “totipotent” stem cells. (Please see the section on “Key Terms”).

Through differentiation into different tissues and organs, the fertilized egg develops into the embryo by the 14th day, which in turn develops into the fetus by the 8th week. Ultimately, a baby is born, and once birth has occurred, the stem cells present in the body are known exclusively as “adult stem cells”. As a newborn, each of us enjoyed a very high number of stem cells (namely, “adult” stem cells), the most we’ll ever have in our lives. After birth, the number of our stem cells then diminishes rapidly.

When a stem cell divides, each “daughter” cell has the potential either to remain a stem cell or to differentiate into another type of cell with a more specialized function, such as a muscle cell, a heart cell, or a blood cell, etc.. Regardless of the name or the type of stem cell, however, they all share the same characteristic: stem cells are what manufacture the constituents of our bodies. Embryonic and fetal stem cells initially create, and adult stem cells continually regenerate throughout life, the cells of the body. Stem cells are constantly involved not only in the formation, but also in the maintenance, of life. They are needed in every organ and bone and tissue of the body throughout one’s entire life. Whether you cut your finger or break a bone, stem cells are responsible for healing wounds and injuries. Even without injury, every few hours, days and weeks, stem cells continuously renew the cells of our bodies, replenishing the constant turnover of blood, intestinal lining, skin and other tissue. As long as we are alive, we have stem cells in our bodies. Even people who live past the age of 100 still have their own stem cells, although to a lesser amount than they did when they were younger. And, whether we are one hour old or 100 years old, the stem cells which we have in our bodies are known as “adult” stem cells. Although they are introduced here for purposes of comparison, adult stem cells shall be addressed in more detail in a separate section.

Up until the end of the 2nd trimester, it is possible to perform surgery in utero, and the baby will be born without any scar from the surgery. This perfect, scarless healing of any surgical incision is the result of “fetal” stem cells, which are much more robust in their pluripotency than are adult stem cells. By contrast, there is no such thing as scarless surgery after birth. Additionally, the hyarluronic acid present in the amniotic fluid is of a special nature such that it allows the embryonic and fetal stem cells to continue replicating with very high efficiency (an advantage also absent in the internal milieu in which adult stem cells exist).

An important point often overlooked is the fact that teratocarcinomas (germ cell tumor cells capable of forming teratomas) may also be derived from embryonic stem cells (pluripotent ECs). The danger that such embryonic stem cells may cause cancer is a reality that has been well known since the very early days of stem cell research. Such a danger does not exist with adult stem cells.

In recent years, the media have given very little coverage of placental and umbilical cord stem cells, emphasizing instead the “advantages” of embryonic stem cells and the “disadvantages” of adult stem cells. Similarly, media reports have focused very little attention on the disadvantages of embryonic stem cells, or on the advantages of adult stem cells.

Herein, this review shall hopefully offer a more balanced, and scientifically complete, comparison of the various types of stem cells, and of the potential advantages, disadvantages and risks which all of them have to offer.

Bank Account Analogy

Everybody is born with a certain amount of stem cells, specifically, “adult stem cells.” This number may be thought of as a type of “bank account”, from which each person may make “withdrawals” throughout his or her lifetime, as needed.

However, not all bank accounts are created equal. To continue with the analogy, some people are born rich, while others are born poor. Most people, however, may be thought of as “middle class.” This fact helps to explain why some people are able to enjoy health and longevity despite very unhealthy lifestyles, while other people may enjoy neither robust health nor longevity despite healthy lifestyles. In other words, some people are able to “spend” their stem cells more extravagantly than others, simply because they have more to spend. Most of us, however, fall somewhere in the middle, where both the length and the quality of our lives may be influenced to some degree by our choice of lifestyle. Environmental factors also play a key role in determining how rapidly one’s “bank account” of (adult) stem cells is depleted. However, even under ideal circumstances, stem cells continually diminish with age.

Our stem cells exist in every part of the body to repair damage, such as from broken bones, a paper cut, radiological or chemical exposure, etc., all of which require stem cells for healing. You may draw on your bank account at any time, whenever you need to do so, until you run out of stem cells. As your “bank account” of stem cells approaches zero, physiological healing will become increasingly difficult, until finally it ceases altogether.

Utilizing stem cells is like going to the ATM machine. Depending upon how you live your life, and whether you were born with a large or a small bank account of stem cells, you either may or may not be able to withdraw from your account. If you were fortunate enough to be born with a large amount of stem cells, then you might possibly be able to smoke and drink and eat unhealthy food and never exercise, and still live to a ripe old age, because regardless of how many stem cells you expend, there are still more to be spent. On the other hand, if you were born at the opposite end of the spectrum, with a small amount of stem cells, then an unhealthy lifestyle will have a more immediate and detrimental impact upon the quality and length of your life. This is known as Nature’s Law of Conservancy: the less stem cells that exist in your “account”, the more stingy the ATM machine becomes in distributing the contents of that account. Most people, however, are born into the stem cell “middle class”, which is to say that lifestyle choices can often make a noticeable difference in determining health and longevity.

When someone has a large number of stem cells in the bank, the ATM works very quickly and efficiently. But when the bank account is almost empty, which ordinarily happens in the latter years of life, the ATM machine does not distribute the stem cells as readily. In biological terms, this is because the division rate of the cells has slowed considerably. Simply changing the doubling time of stem cells from 24 hours to 72 hours can make a 90 day difference in the amount of time required to reach a “critical mass” of cells that are required to heal a wound. Michael Andreeff, M.D., Ph.D., a professor in the Departments of Blood and Marrow Transplantation and Leukemia Cancer at M.D. Anderson, has described cancer as a “never healing wound”; in some cases, the doubling time of the stem cells may never be fast enough to “catch up” and heal the wound. This is why the incidence of cancer increases with age. After childhood cancers (which arise due to genetic factors or to overwhelming environmental exposure), the incidence of cancer drops significantly until around the age of 40, when it starts to increase, shooting up dramatically around the age of 50, and then falling again around the age of 65.

When someone has fully depleted his or her stem cell reserve, the only possible way to get more stem cells is from an alternate source. This is where stem cell therapy comes into play. In the remaining sections of this review, we shall evaluate the different options which the various types of stem cells therapies may offer.

Salamanders are a supreme example of stem cell billionaires. Salamanders have a seemingly unlimited supply of stem cells, as their “bank accounts” are virtually incapable of being depleted. If you were to look at the blood of a salamander under a microscope, you would see that all of the red blood cells (RBCs) are nucleated. In other words, all RBCs of a salamander contain nuclei, unlike human RBCs, which are not nucleated. This is why salamanders can regenerate entire limbs and humans cannot: every RBC in a salamander is a functional stem cell, floating around everywhere throughout the salamander’s body. In humans, by contrast, our RBCs cannot replicate themselves once they have migrated out of our bone marrow. As long as the salamander is still alive, its ATM machine is fast and generous in distributing as many stem cells as may be needed for any task.

Although humans are not salamanders, the ability to regenerate entire limbs nevertheless offers a powerful example of the possible applications and implications of stem cells. Practically as well as theoretically, an enormous, mostly untapped, potential exists in the field of stem cell therapy. (The reader is referred to the section on “Regeneration”).

Key Terms

Totipotency: This is the ability of a stem cell to differentiate into all possible types of cells in the body. Its potential is total (from the Latin “totus”, meaning “total”). Only the fertilized egg (zygote) is considered to be totipotent. The term “totipotency” in regard to plants (which is the ability to grow an entire plant from a shoot or cutting) has been used for many years, but only with the advent of stem cell therapy has the term entered the biomedical lexicon. It is believed that, at least theoretically, all living cells have the potential for totipotency, since all living cells carry the necessary genetic information; but the exact mechanisms by which totipotency is “triggered” remain unknown.

Pluripotency: After the fertilized egg has developed into an embryo, its totipotency has yielded to pluripotency. Pluripotent stem cells are able to develop into all possible types of cells in the body, except those needed to develop a fetus. Embryonic, fetal, and post-natal (umbilical plus placental) stem cells are pluripotent. Usually isolated from embryos a few days old, embryonic stem cells are used to create pluripotent stem cell “lines”, grown in the laboratory. Pluripotent stem cell lines have also been developed from fetal tissue (older than 8 weeks of development in gestation). As authors of the previously cited NIH report have written, “A single pluripotent stem cell has the ability to give rise to types of cells that develop from the three germ layers (mesoderm, endoderm, and ectoderm), from which all the cells of the body arise.” The 2001 NIH report also states that, “The only known sources of human pluripotent stem cells are those isolated and cultured from early human embryos and from fetal tissue that was destined to be part of the gonads.” As we shall see in a later section, the known sources of human pluripotent stem cells are today, in 2005, more than they were in 2001.

Multipotency: After birth, most of the adult stem cells that are present no longer exhibit pluripotency, but instead exhibit multipotency. Multipotent stem cells are capable of differentiating into multiple types of cells, but not all possible types. Most adult stem cells have been previously believed to be either multipotent or monopotent, and this has constituted the crux of the argument against the therapeutic use of adult stem cells. As we shall later see in more detail, this argument is not always valid.

Monopotency: Many types of adult stem cells exhibit “monopotency”, meaning that they are capable of differentiating into only one particular type of cell. This “specialized” feature has typically been considered one of the major drawbacks of adult stem cells.

Of all the various types of stem cells, the NIH has stated that,

“Pluripotent stem cells offer the greatest possibility of a renewable source of replacement cells and tissues to treat a myriad of diseases, conditions and disabilities, including Parkinson’s and Alzheimer’s diseases, spinal cord injury, stroke, burns, heart disease, diabetes, osteoarthritis and rheumatoid arthritis.” (From “The Promise of Stem Cells”, available at http://stemcells.nih.gov).

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