Stem Cells

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Related Pages
Human Embryonic Stem (ES) Cells
Making transgenic animals using embryonic stem cells
Cloning mammals using somatic cell nuclei

Stem cells are cells that divide by mitosis to form either

How the choice is made is still unknown. However, several genes have been found whose activity prevents a daughter cell from differentiating.

Types of Stem Cells

Several adjectives are used to describe the developmental potential of stem cells; that is, the number of different kinds of differentiated cell that they can become.
  1. Totipotent cells. In mammals, totipotent cells have the potential to become

    The only totipotent cells are the fertilized egg and the first 4 or so cells produced by its cleavage (as shown by the ability of mammals to produce identical twins, triplets, etc.).

    In mammals, the expression totipotent stem cells is a misnomer — totipotent cells cannot make more of themselves.

  2. Pluripotent stem cells. These are true stem cells, with the potential to make any differentiated cell in the body (but probably not those of the placenta which is derived from the trophoblast).

    Three types of pluripotent stem cells occur naturally:

    All three of these types of pluripotent stem cells

    In mice and rats, embryonic stem cells can also:

    Using genetic manipulation in the laboratory, pluripotent stem cells can now be generated from differentiated cells. These induced pluripotent stem cells (iPSCs) are described below.

  3. Multipotent stem cells. These are true stem cells but can only differentiate into a limited number of types. For example, the bone marrow contains multipotent stem cells that give rise to all the cells of the blood but not to other types of cells. [Discussion]

    Multipotent stem cells are found in adult animals; perhaps most organs in the body (e.g., brain, liver, lungs) contain them where they can replace dead or damaged cells. These adult stem cells may also be the cells that — when one accumulates sufficient mutations — produce a clone of cancer cells.

Using Stem Cells for Human Therapy

The Dream

Many medical problems arise from damage to differentiated cells.

Examples:

The great developmental potential of stem cells has created intense research into enlisting them to aid in replacing the lost cells of such disorders.

While progress has been slow, some procedures already show promise.

Using multipotent "adult" stem cells.

Using differentiated cells derived from embryonic stem (ES) cells. Phase I clinical trials are underway to assess the safety of

The Immunological Problems

One major problem that must be solved before human stem cell therapy becomes a reality is the threat of rejection of the transplanted cells by the host's immune system (if the stem cells are allografts; that is, come from a genetically-different individual).
Link to discussions of

A Solution?

One way to avoid the problem of rejection is to use stem cells that are genetically identical to the host.

This is already possible in the rare situations when the patient has healthy stem cells in an undamaged part of the body (like the stem cells being used to replace damaged corneas).

But even where no "autologous" stems cells are available, there may be a solution: using somatic-cell nuclear transfer .

In this technique,

  1. An egg has its own nucleus removed and replaced by
  2. a nucleus taken from a somatic (e.g., skin) cell of the donor.
  3. The now-diploid egg is allowed to develop in culture to the blastocyst stage when
  4. embryonic stem cells can be harvested and grown up in culture.
  5. When they have acquired the desired properties, they can be implanted in the donor with no fear of rejection.

Using this procedure it possible to not only grow blastocysts but even have these go on to develop into adult animals — cloning — with a nuclear genome identical to that of the donor of the nucleus. The first successful cloning by SCNT was with amphibians [View procedure]. Later, mammals such as sheep (Dolly), cows, mice and others were successfully cloned. And in the 11 November 2007 issue of Science, researchers in Oregon reported success with steps 1–4 in rhesus monkeys (primates like us).

Their procedure:

This should reassure people who view with alarm the report in May 2013 by the same workers that they have finally succeeded in producing embryonic stem cells (ESCs) using SCNT from differentiated human tissue. The workers assure us that they will not attempt to implant these blastocysts in a surrogate mother to produce a cloned human. And their failure with monkeys suggests that they would fail even if they did try.

While cloning humans still seems impossible, patient-specific ESCs

Whether they will be more efficient and more useful than induced pluripotent stem cells [below] remains to be seen.

Questions that Remain to be Answered

Possible Solutions to the Ethical Controversy

Induced pluripotent stem cells (iPSCs)

A promising alternative to the use of embryonic stem cells in human therapy are recently-developed methods of genetically reprogramming the nuclei of differentiated adult cells so that they regain the pluripotency of embryonic stem (ES) cells.

In June 2007, three laboratories reported that introducing extra copies of only 4 genes into adult mouse skin cells (fibroblasts) enables them to regain the properties of ES cells. When these cells, named induced pluripotent stem cells (iPSCs for short), were placed in mouse blastocysts, they participated in building all the tissues of the chimeric mice that resulted. (When placed in tetraploid (4n) blastocysts — unable by themselves to develop normally — embryos were formed that thus were clones of the skin cell donor.) The four genes: c-Myc, Sox2, Oct3/4, Klf4.

By 2009, several labs had succeeded in producing fertile adult mice from iPSCs derived from mouse embryonic fibroblasts. This shows that iPSCs are just a capable of driving complete development (pluripotency) as embryonic stem cells.

Reprogramming works in humans, too! Using the same four genes, the Yamanaka lab in Japan reported on 20 November 2007, that they now had reprogrammed human skin cells to become induced pluripotent stem cells (iPSCs). And the Thomson lab in Wisconsin accomplished the same thing using SOX2, OCT4, NANOG, and LIN28.

Further evidence of the remarkable role played by these few genes is the finding that during normal embryonic development of the zebrafish, the same or similar genes (SoxB1, Oct4, Nanog) are responsible for turning on the genes of the zygote. Earlier in development of the blastula, all the genes being expressed (including these) are the mother's — mRNAs and proteins that the mother deposited in the unfertilized egg [More]. It makes sense that the same proteins that can reprogram a differentiated cell into a pluripotent state (iPSCs) are those that produce the pluripotent cells of the early embryo.

These achievements open the possibility of

Let us hope that what works in mice can someday be developed into a safe therapy that will work in humans. (In the case of Type 1 diabetes mellitus, however, even patient-derived beta cells will still be at risk of the same autoimmune rejection that caused the disease in the first place.)

Despite these successes, iPSCs may not be able to completely replace the need for embryonic stem cells and may even be dangerous to use in human therapy. Several groups have found that human iPSCs contain mutations as well as epigenetic patterns (e.g., methylation of their DNA) that are not found in embryonic stem cells. Some of the mutations are also commonly found in cancer cells.

Other approaches being explored

Applied to humans, none of the above procedures would involve the destruction of a potential human life.


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24 November 2013