The new stem cell biology: something for everyone

Abstract

The ability of multipotential adult stem cells to cross lineage boundaries (transdifferentiate) is currently causing heated debate in the scientific press. The proponents see adult stem cells as an attractive alternative to the use of embryonic stem cells in regenerative medicine (the treatment of diabetes, Parkinson's disease, etc). However, opponents have questioned the very existence of the process, claiming that cell fusion is responsible for the phenomenon. This review sets out to provide a critical evaluation of the current literature in the adult stem cell field.

Figure 1

A hierarchy of stem cell potential. Stem cell(s) can divide asymmetrically to maintain their number while giving rise to transit amplifying cells (TA), whose functional capacity evolves concomitantly with a reduction in division potential. Eventually, TA cells become terminally differentiated (TD) and are programmed to die in a tissue specific manner.

Figure 2

A mammalian gut crypt is a tube of cells arrayed on a basement membrane (green). Stem cells (red) are located in the basal region along with Paneth cells, but their exact location is variable and both types account for only a fraction of the cells present in the regions shown. A portion of the basement membrane in the stem cell region may be specialised (dark green). Stem cell progeny (yellow) known as transit amplifying (TA) cells move upwards and differentiate. Underlying mesenchymal cells (green) send signals that help regulate stem cell activity. (Reprinted by permission from Nature. Copyright (2001), Macmillan Publishers Ltd.)

Figure 3

Possible pathways of differentiation in adult stem cells. (Reprinted with permission from Science. Copyright (2002), American Association for the Advancement of Science.)

Figure 4

Photomicrograph of a thyroid section of a progressively enlarging adenomatous goitre, showing thyroid follicular nuclei after fluorescent in situ hybridisation analysis for the X (red) chromosome and Y (green) chromosome (original magnification, ×400). Epithelial cells with X chromosomes only can be seen in the left hand corner, whereas in a single row of adjacent epithelial cells the cells have no more than one X and one Y chromosome. See text for further details (from Srivatsa et al, with permission).

Figure 5

Bone marrow derived intestinal subepithelial myofibroblasts in the female mouse colon after male bone marrow transplantation are present as Y chromosome positive cells, immunoreactive for α smooth muscle actin (αSMA), two weeks after transplantation (arrows and high power insets). The Y chromosome is seen as a brown/black punctate density; red cytoplasmic staining indicates immunohistochemical staining for αSMA (from Brittan et al, with permission from the BMJ Publishing Group).

Figure 6

Liver histology of mice deficient in the enzyme fumarylacetoacetate hydrolase (FAH^−/− mice) seven months after bone marrow transplantation. FAH^−/− mice were transplanted with 1 × 10⁶ bone marrow cells from ROSA26 mice. (A) Repopulating nodules are detected in the liver with X-gal histochemistry. (B) FAH staining of the nodule. The dark red areas are FAH positive hepatocytes and are adjacent to an FAH negative area (from Lagasse et al, with permission).

Figure 7

Comparison of self renewal during haemopoietic stem cell development and leukaemic transformation. Because of their high level of self renewal, stem cells are particularly good targets for leukaemic transformation. Unlike normal haemopoiesis, where signalling pathways that have been proposed to regulate self renewal are tightly regulated (top), during transformation of stem cells, the same mechanisms may be dysregulated to allow uncontrolled self renewal (middle). Furthermore, if the transformation event occurs in progenitor cells, it must endow the progenitor cell with the self renewal properties of a stem cell, because these progenitors would otherwise differentiate (bottom). (Reprinted by permission from Nature. Copyright (2001), Macmillan Publishers Ltd.)

Figure 8

Some potential clinical uses of stem cells. Regeneration of two dimensional (skin) and three dimensional (bone) tissues using stem cells. (A) Skin autografts are produced by culturing keratinocytes (which may be sorted for p63, the recently described epidermal stem cell marker) under appropriate conditions not only to generate an epidermal sheet, but also to maintain the stem cell population (holoclones). The epidermal sheet is then placed on top of a dermal substitute comprising devitalised dermis or bioengineered dermal substitutes seeded with dermal fibroblasts. Such two dimensional composites, generated ex vivo, completely regenerate full thickness wounds. (B) Bone regeneration requires ex vivo expansion of bone marrow derived skeletal stem cells and their attachment to three dimensional scaffolds, such as particles of a hydroxyapatite/tricalcium phosphate ceramic. This composite can be transplanted into segmental defects and will subsequently regenerate an appropriate three dimensional structure in vivo. (Reprinted by permission from Nature. Copyright (2001), Macmillan Publishers Ltd.)