Stem Cells Research
 

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Index to this page
bulletTypes of Stem Cells
bullet Using Stem Cells for Human Therapy - The Dream
bullet The Problems
bulletThe Solution?
Related Pages
Culturing Human Embryonic Stem (ES) Cells
Making transgenic animals using embryonic stem cells
Cloning mammals using somatic cell nuclei


 

Stem cells are cells that divide to form

bulletone daughter that goes on to differentiate, and
bulletone daughter that retains its stem-cell properties.

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
    bulletany type in the adult body;
    bulletany cell of the extraembryonic membranes (e.g., placenta).

    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: these cells fail to meet the second criterion they 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 cannot contribute to making the extraembryonic membranes (which are derived from the trophoblast).

     

    Three types of pluripotent stem cells have been found
    bulletEmbryonic Stem (ES) Cells. These can be isolated from the inner cell mass (ICM) of the blastocyst the stage of embryonic development when implantation occurs. For humans, excess embryos produced during in vitro fertilization (IVF) procedures are used. Harvesting ES cells from human blastocysts is controversial because it destroys the embryo, which could have been implanted to produce another baby (but often was simply going to be discarded).
    bulletEmbryonic Germ (EG) Cells. These can be isolated from the precursor to the gonads in aborted fetuses.
    bulletEmbryonic Carcinoma (EC) Cells. These can be isolated from teratocarcinomas, a tumor that occasionally occurs in a gonad of a fetus. Unlike the other two, they are usually aneuploid.

    All three of these types of pluripotent stem cells
    bulletcan only be isolated from embryonic or fetal tissue;
    bulletcan be grown in culture, but only with special methods to prevent them from differentiating.


     

  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) 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:

bulletInsulin-dependent diabetes mellitus (IDDM) where the beta cells of the pancreas have been destroyed by an autoimmune attack;
bulletParkinson's disease; where dopamine-secreting cells of the brain have been destroyed;
bulletspinal cord injuries leading to paralysis of the skeletal muscles; [View]
bulletischemic stroke where a blood clot in the brain has caused neurons to die from oxygen starvation;
bullet multiple sclerosis with its loss of myelin sheaths around axons.
bulletblindness caused by damage to the cornea.

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 some success has been achieved with laboratory animals, not much has yet been achieved with humans.

One exception: culturing human epithelial stem cells and using their differentiated progeny to replace a damaged cornea. This works best when the stem cells are from the patient (e.g. from the other eye). Corneal cells from another person (an allograft) are always at risk of rejection by the recipient's immune system.

Using Stem Cells for Human Therapy - The Problems

So 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
bullet the problems
bullet the immunological basis of them

The 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 transplantation (but with no goal of attempting to implant the resulting blastocyst in a uterus).

In this technique,

bulletA human egg has its own nucleus removed and replaced by
bulleta nucleus taken from a somatic (e.g., skin) cell of the patient.
bulletThe now-diploid egg is allowed to develop in culture to the blastocyst stage when
bulletembryonic stem cells can be harvested and grown up in culture.
This much has now been achieved with humans - Link
bulletWhen they have acquired the desired properties, they can be implanted in the patient with no fear of rejection.

While an exciting prospect, there are still problems with the method that must be solved.

bulletImprinted Genes.

Sperm and eggs each contain certain genes that carry an "imprint" identifying them later in the fertilized egg as being derived from the father or mother respectively.

Link to discussion of gene imprinting.

Creating an egg with a nucleus taken from an adult cell may not allow a proper pattern of imprinting to be established.

When the diploid adult nucleus is inserted into the enucleated egg (at least those of sheep and mice), the new nucleus becomes "reprogrammed". What reprogramming actually means still must be learned, but perhaps it involves the proper methylation and demethylation of imprinted genes. For example, the inactive X chromosome in adult female cells must be reactivated in the egg, and this actually seems to happen.

bulletAneuploidy.

In primates (in contrast to sheep, cattle, and mice), the process of removing the resident nucleus causes molecules associated with the centrosome to be lost as well. Although injecting a donor nucleus allows mitosis to begin, spindle formation may be disrupted, and the resulting cells fail to get the correct complement of chromosomes (aneuploidy).

bulletSomatic Mutations. This procedure also raises the spectre of amplifying the effect(s) of somatic mutations. [Link to discussion]

In other words, mutations that might be well-tolerated in a single somatic cell of the adult (used to provide the nucleus) might well turn out to be quite harmful when they become replicated in a clone of cells injected later into the patient.

bulletPolitical Controversy.

The goal of this procedure (which is often called "therapeutic cloning" even though no new individual is produced) is to culture a blastocyst that can serve as a source of ES cells.

But that same blastocyst could theoretically be implanted in a human uterus and develop into a baby that was genetically identical to the donor of the nucleus. In this way, a human would be cloned.

And in fact, Dolly and other animals are now routinely cloned this way. Link to a description.

The spectre of this is so abhorrent to many that they would like to see the procedure banned despite its promise for helping humans.

In fact, many are so strongly opposed to using human blastocysts even when produced by nuclear transfer that they would like to limit stem cell research to adult stem cells (even though these are only multipotent).

One possible solution: It now appears that ES cells can be derived from a single cell removed from a human morula an earlier stage in embryonic development. Removing a single cell from the morula does not destroy it [link to evidence].

Jose Cibelli and his team at Advanced Cell Technology report in the 1 February 2002 issue of Science that they have succeeded in
bulletstimulating monkey oocytes to begin dividing without completing meiosis II (therefore still 2n)
bulletgrowing these until the blastocyst stage, from which they were able to harvest
bulletES cells.

If this form of cloning by parthenogenesis works in humans, it would have

bulletthe advantage that no babies could be produced if the blastocyst should be implanted (two identical genomes cannot produce a viable mammal probably because of incorrect imprinting);
bulletthe disadvantage that it will only help females (because only they can provide an oocyte!)


 

In the 12 March 2004 issue of Science, a group of Korean scientists (such government-funded work is currently forbidden in the US) reported that they had created human ES cells from blastocysts produced following somatic cell nuclear transfer (SCNT). In each case, the donor nucleus came from the same woman who provided the enucleated egg.

When injected into SCID mice, these cells formed teratomas; tumors containing a mix of differentiated human cell types, including cells characteristic of ectoderm, mesoderm, and endoderm.

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