Stem Cells: Biology, Ethics and Potential for Medicine

Résumé

The remarkable ability to generate an embryo from a single fertilized oocyte, to periodically replace dying cells within tissues and to repair tissues damaged during injury, is a direct consequence of stem cells, nature’s gift to multicellular organisms. The gold standard of stem cells is the fertilized egg, which produces an organism replete with ~ 220 specialized cell types, including reproductive germ stem cells. As the embryo first develops, an outer protective shell of support cells, referred to as the trophectoderm, encases an undifferentiated mass (the inner cell mass) of pluripotent embryonic stem (ES) cells that will make the animal. As tissues and organs develop, stem cells become more restricted in their options (Fuchs et al. 2004; Fuchs 2007).

Although cell type specification is largely complete at or shortly after birth, organs must possess a mechanism to replenish those cells within the tissue that die or become damaged with age. This process of cell replacement by natural wear and tear is referred to as homeostasis, and is fueled by adult stem cells which typically reside within a tissue. Some tissues, like the skin epidermis or intestinal epithelium, undergo constant turnover and rejeuvenation involving the entire tissue. For other tissues/organs, e.g. the brain, it has only been recently that scientists have appreciated the existence of stem cells that have the ability to replenish specialized neurons, glial cells and oligodendrocytes over time, even if this capacity is much reduced in comparison to the hematopoietic system or epithelial tissues. Increasing evidence is pointing to the view that most tissues of the body have adult stem cells.

Like ES cells, adult stem cells undergo self-renewal, the ability to divide to generate self, and the ability to generate cells that will differentiate to produce tissues. Adult stem cells, however, typically give rise to only a few different types of tissues, a feature often referred to as multipotent. Some stem cells, e.g. germ stem cells, are thought to give rise to only one lineage, in this case, either oocyte (female germ stem cells) or sperm (male germ stem cells). Given the fountain of youth ability of adult stem cells to generate tissues during normal homeostasis and wound-repair, these stem cells are typically set aside in protected reservoirs within the developing tissue. They are often used sparingly, and hence undergo fewer divisions than their activated progeny. The protective niches are composed not only of stem cells but also a complex “microenvironment” of neighboring differentiated cell types which secrete and organize a diverse range of extracellular matrix and other factors that allow stem cells to manifest their unique intrinsic properties (Fuchs et al. 2004; Moore and Lemischka 2006; Morrison and Kimble 2006).

Harnessing adult stem cells for regenerative medicine has long been a major focus of scientists and clinicians alike. Examples of the successful use of stem cells for regenerative medicine include bone marrow transplants to replace cells of the hematopoietic system and cultured epidermal sheets for the replacement of epidermis lost in badly burned skin (Weissman 2000; De Luca et al. 2006). ES cells have received more attention because of their broader potential and hence greater promise for generating cell types to treat injuries and degenerative conditions for which we presently have no cures. With the promise are also ethical considerations dealing with the use of fertilized eggs for research necessary to harness this potential. Scientists have countered with technology referred to as nuclear transfer, often mistakenly referred to as human cloning. This technology involves making a hybrid somatic cell from an unfertilized oocyte whose nucleus was removed and replaced by an adult somatic cell (Hochedlinger and Jaenisch 2006). In collaboration with the laboratory of Peter Mombaerts at the Rockefeller University, my laboratory has used this technology to demonstrate that ES cells and in fact healthy viable mice could be generated from hybrid diploid totipotent cells, each composed of an unfertilized enucleated mouse oocyte and an adult hair follicle stem cell, normally able to differentiate into only epidermis, hair follicles and sebaceous glands (Blanpain and Fuchs 2006; Li et al. 2007). Although nuclear transfer technology has not yet been successful for generation of human ES cells, scientists recently succeeded in generating primate ES cells through nuclear transfer (Byrne et al. 2007).

Can adult skin cells be utilized to generate ES cells directly, without the use of an unfertilized oocyte? Breakthroughs over the past year have led scientists to predict that this may be possible in the future. In a pioneering study published in summer, 2007, Yamanaka and coworkers reported the generation of germline competent “induced pluripotent stem cells” (iPS cells) generated by retroviral infection of mouse skin fibroblasts to force the expression of four transcription factors normally expressed by ES cells but not by adult somatic cells (Meissner et al. 2007; Okita et al. 2007). Unfortunately, one of the transcription factors was a potent cell cycle stimulator and the mice generated developed tumors with time. Since this time, however, researchers have now succeeded in eliminating this gene from the mix, and now only three transcription factors appear to be sufficient (Nakagawa et al. 2008; Park et al. 2008). Moreover, in animal mouse models of human disease, iPS cells have already shown promise for treatments (Hanna et al. 2007), and in the past several months, two groups have independently succeeded in generating human iPS cells from adult skin cells (Takahashi et al. 2007; Yu et al. 2007).

This explosion of research bodes well for the future of human regenerative medicine. The challenge now will be how to avoid the genetic manipulation (in some cases, > 50 integrated retroviral DNAs) that occurs in generating iPS cells and/or overcoming the present hurdles in generating human ES cells by nuclear transfer. While nuclear transfer is preferable in using epigenetic reprogramming rather than genetic manipulation, it still uses unfertilized oocytes. That said, the excitement and promise of stem cells for regenerative medicine continues to grow and 2007 has been a very successful year in overcoming technological barriers that less than a decade ago were thought to be insurmountable.