Clinical uses of stem cells: Which way are we heading?

Where our knowledge begins 

Stem cell biology and research has roots dating back at least 40 years.1, 2 Studies on cells from early embryos (ie, during their first week of development) provide much of our present knowledge about the cell cycle, cellular growth and development, and cellular differentiation into primitive ectoderm and endoderm. The cell culture techniques used in these investigations, as well as in related research on chimeras, were instrumental in developing the techniques of in vitro fertilization (IVF) and embryonic growth and, later, in the development of cloning processes.

Gene control studies of specific developmental systems were also fundamental to stem cell research. The advanced and optimally composed culture media used in today's IVF clinics owe credit to the various matrices and conditioned media developed much earlier in experiments on how to support the growth of embryonic stem cells.

Types of stem cells 

There are four major types of stem cells, each with distinct applications.

•Adult stem cells have been in clinical use for a long time, predominantly for treating hematologic disorders.

•Cord blood stem cells (which could perhaps be called juvenile stem cells) have recently become of economic interest in the Western world because of expectations relating to the banking of cord blood, though the future of this application is still relatively uncertain.

•Fetal stem cells, isolated predominantly from brain tissue obtained from legal abortions, have been used in the treatment of Parkinson's disease.3

•Embryonic stem cells may perhaps have the greatest clinical application, and they certainly have been at the center of the stem cell controversy (see Figure 1). Formation of these stem cells from the inner cell mass (ICM) of early embryos has long been recognized, but it was not until 1998 that human blastocysts were used for this purpose,4 sparking a fierce ethical, religious, and legal debate around the globe (see “The stem cell controversy and its consequences”).

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Figure 1. Human embryonic stem cell colony (approximately 5,000 cells) grown on human feeder cells. Photo courtesy of Lars Hamberger, MD

Embryonic stem cells favored 

At this point, we lack the research to fully characterize the different types of stem cells and thus the ability to make a fair comparison concerning their clinical advantages and disadvantages. Recently, however, and after years of disagreement, a group of scientists working with adult stem cells admitted that dedifferentiation of these cells had profound limitations and risks and that adult stem cells could not in all situations replace the use of embryonic stem cells.5 This is an extremely important statement from an ethical and legal point of view.

Embryo availability and quality 

Worldwide, the number of surplus human embryos has increased enormously in the last few years because of an ambition among IVF clinics to replace fewer embryos, combined with the use of improved freezing techniques. The effect of these changes is to have more (and better quality) embryos available to be donated for research. According to the latest US National Report, published in 2002 by the Centers for Disease Control and Prevention, the United States alone holds 391,666 embryos in storage. Of these, 11,000 (or 3%) are already donated for research, and this figure will likely rise rapidly.

Improved culture techniques will produce greater numbers of embryos in advanced stages (5–7 days old), the ideal time for separating the ICM from the trophectoderm, the first critical step in the formation of human embryonic stem (hES) cell lines. Some promising data:

An estimated 150 to 200 hES cell lines are available worldwide for research today. This accomplishment represents the work of some 1,500 researchers, who must contend with the numerous steps and obstacles required to form these lineages (see Table 1).

TABLE 1. Factors in the development of hES cell lines

	Technical/scientific
	Formation of blastocysts and isolation of the inner cell mass
	Characterization of hES
	Differentiation of hES
	Expansion of hES
	Establishment of hES cell lines
	Freeze preservation and registration of hES cell lines
	Economic
	External collaboration
	Research support and funding
	Ethical/legal
	Donation of embryos for research
	Clinical application
	hES, human embryonic stem cell.

A related issue is the production of genetically abnormal hES cell lines. We believe, as do others, that these cell lines will be of great importance in the study of genetic disorders.

The challenge of immunoreaction 

One of the potential (and major) problems in using differentiated hES cell lines clinically is immunoreaction. However, when enough well-characterized hES cell lines are available worldwide, this problem may not be much greater than choosing, for instance, the right blood group for a blood transfusion. A suitable cell line might be found somewhere, and could easily be transported in a frozen state. Improved freezing methods support this approach. According to a recent study on the efficacy of cryopreservation, the vitrification technique enabled the recovery of more than 80% of hES cell clumps.8 By comparison, traditional slow freezing yielded a recovery rate of approximately 23%.

Therapeutic cloning, a new technique characterized by tailor-made cells, may address the problem of immunoreaction directly. Therapeutic cloning is also known as somatic cell nuclear transfer, and is the preferred term in the United States because of certain basic technical similarities with reproductive cloning. With this type of cloning, the patient's own DNA is transplanted into an unfertilized, denucleated oocyte. Electricity, specific chemicals, or both are used to mimic the fertilization process, then the embryo is developed and grown to the blastocyst stage. The ICM is then isolated to form a stem cell line. These cells, because of their origin, will not react immunologically when replaced in the recipient.

Future prospects and realities 

There is general agreement among researchers that hES cell lines will not be used clinically on a large scale until at least another five to 10 years. Today, the risks seem too great, including the risks for such events as spontaneous and uncontrolled cellular differentiation or malignant degeneration. Using stem cells to build whole organs remains a remote possibility.

One application that may be developed in the near future is the use of differentiated stem cells to test the teratogenic effects of new drugs. Hepatocytes may be ideal for this purpose. In vitro culturing of such cells would provide an accurate testing environment as well as reduce the amount of experimental testing in animals.

Other exciting applications may come from our growing understanding of stem cell biology. A recently published study from our laboratory showed that stem cells predominantly act not by invading an organ, like the heart or pancreas, but by producing and releasing chemical activators with the capacity to induce differentiation in endogenous stem cells, which for some reason have lost that ability. Proof for such a mechanism was established in experiments involving the iris.9

No one can predict what the future will bring. But it is our belief that despite inevitable delays relating to laws, regulations, and restrictions, hES cell lines will gradually revolutionize regenerative medicine and, we hope, prolong healthy life expectancy within a few decades.