Stem cell research 101

Defining stem cells

Stem cells have two properties that distinguish them from other cells.

• First, stem cells self-renew. When a stem cell divides, it creates two “daughter” cells, one of which is an exact replica of itself. Thus, the population of stem cells remains plentiful and stem cells are considered to be “immortal.”

• Second, an embryonic stem cell is “undifferentiated ”—it has not committed to become any particular type of cell, such as a neuron or skin cell. Through a series of divisions, the stem cell can generate any cell in the human body. When it divides, the second daughter cell embarks on a journey toward becoming a terminally differentiated cell, such as a white blood cell. Once a cell has reached a terminally differentiated state, it cannot reproduce (renew) itself.

Under the proper conditions, stem cells isolated from early embryos are capable of producing all of the specific cell types within the body and are thus termed “pluripotent.” Once an organism has passed the embryonic stage of development, its stem cells lose their unlimited potential to differentiate into all cell types (their pluripotency) and are able to become only certain cell types.

Adult stem cells, such as those that reside in the bone marrow and are capable of generating the dozen or so differentiated cells in the blood, are termed multipotent. Adult stem cells within a tissue that can only generate several specialized cell types within that particular tissue are called oligopotent.

Patterns of human stem cell division

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Types of stem cells

Embryonic stem cells
Pluripotent early embryonic stem cells can only be found to occur naturally in embryos that are several days old. As embryonic development proceeds, the descendants of these embryonic stem cells soon become committed to enter into one or another lineage of differentiated cell types and as such, lose their pluripotency.

Hence, during embryonic development, the versatility of most stem cells in the body to generate diverse types of differentiated descendants becomes progressively narrowed, until these stem cells ultimately become limited to generating a relatively small number of distinct cell types.

In 2006, the lab of Shinya Yamanaka at Kyoto University demonstrated the creation of embryonic-stem-cell-like “induced pluripotent stem” (IPS) cells in mice. These were made by taking a tail cell from an adult mouse and over-expressing four genes—without the use of an embryo or an egg. The following year, several labs, including Rudolf Jaenisch’s lab at Whitehead, confirmed and extended this work. Since then, hundreds of researchers worldwide have been working to improve the process of IPS cell creation and to apply it to medical conditions.

Adult stem cells

Among primitive species, once an organism’s body is fully formed from its embryonic precursors, stem cells are no longer found in that organism’s tissues. However, in higher organisms such as humans, the cells in most specialized tissues are continually lost and are replaced by newly minted, differentiated cells. This turnover of cells is enormous, such that during a human lifespan more than 100 times more cells are eventually formed (and destroyed) than actually reside in the body at any one time.

This ongoing cell replenishment and tissue renewal requires that many of the stem cell types that participated initially in embryonic development continue to function in the adult, thereby ensuring the maintenance of functional tissues and organs. Consequently, such adult stem cells operate by the same basic biological principles that govern stem cell types in the developing embryo. However, because these adult stem cells can give rise only to certain types of types of cells (not all cells, as with embryonic stem cells), they are referred to not as pluripotent but rather as “multipotent.”

Examples of multipotent adult stem cells include liver stem cells, muscle stem cells, nerve stem cells, intestinal stem cells, and hematopoietic (blood-forming) stem cells. All adult stem cells are extremely rare making their identification and isolation significant research challenges.

Cancer stem cells

Recent research with both blood cells and certain solid tumors suggests that at least some cancer cell populations are composed of a combination of self-renewing, less differentiated stem cells and more differentiated, specialized cells that have little if any capacity to proliferate.

In this model, undifferentiated so-called cancer stem cells are thought to drive tumor growth (by giving rise to the differentiated cells that form the bulk of the tumor) and initiate metastasis. Such cancer stem cells also appear resistant to conventional radiation and chemotherapy, which could help explain why many tumors recur after courses of standard treatment.

The promise of stem cell research

Recent successes in stem cell research have raised dozens of new possibilities for biomedical research and clinical medicine. The most obvious of these lie in the area of regenerative medicine. A diverse array of medical conditions, ranging from age-related wasting of muscle tissue, Parkinson’s disease, diabetes, and AIDS, to certain types of senile dementia, are now thought to reflect the progressive depletion of functional, specialized cell types in various tissues.

This depletion is attributable to the inability of naturally occurring stem cells to repopulate affected tissues and organs with adequate numbers of functional, differentiated cells. Accordingly, an ability to create stem cells that are committed to specific tissue lineages should allow the reversal of these otherwise progressive degenerative diseases.

In theory then, the reversal of a variety of disease states should be possible. Thus, heart muscle damaged by heart attacks might be replaced by new muscle cells. The loss of highly specialized dopamine producing brain cells in Parkinson’s disease might be reversed by the infusion of new, fully functional brain cells. The diffuse loss of neurons in the brain during aging might be reversed by infusions of fresh neuronal precursor cells that might take up residence in appropriate sides in the brain and assume differentiated functions. And tissues that suffer because of in-born genetic defects may be restored through the introduction of fully functional cells that do not suffer from these genetic defects.

Since 2006, work in induced pluripotent stem (IPS) cells has created heightened excitement. These cells can be generated from adult cells, without destroying an embryo or an egg in the process as is required with true embryonic stem cells. Years in the future, the hope is that medical personnel can take a few cells from a patient, reprogram them to an IPS state, modify them genetically to generate the kind of new cells that are needed, and finally reintroduce them into the patient, where they can aid in treating a given condition.

While the opportunities to develop novel therapeutic applications are clear, many obstacles remain. Many of these require solving the basic science of stem cells in order to enable the design of rational approaches to stem cell therapies. Without that scientific underpinning, progress in designing medical applications will continue to be an inexact science.