Topic of the Month The Plasticity of Stem Cell Plasticity
Perhaps because of the high stakes in human health, rigorous experimental corroboration of these exciting claims was somewhat neglected. But recently, numerous efforts have been undertaken in proving or disproving plasticity of stem cells. The emerging picture is one of technical problems (such as mixed starting populations and potentially cross-reacting antibodies) and in certain instances cell fusion, resulting in cells that masquerade as ‘transdifferentiated’ cells. For those in search of a comprehensive primer on stem cell plasticity and the debated issues, the review by Wagers and Weissman is recommendable. The authors critically discuss the literature, focusing on the hematopoietic stem cell, which is the best characterized adult stem cell and central to the debate on stem cell plasticity.
Plasticity of adult stem cells. ABSTRACT Wagers AJ, Weissman IL (2004). Cell 116:639. Since this review went to press, several additional papers have appeared or were presented at the Keystone stem cell meeting in January of this year. Some of the Keystone presentations are summarized in the Topic of the Month (TOM) of February . In back-to-back papers flouting clinical reports that heart tissue can be regenerated through transdifferentiation, two independent groups demonstrate with rigorous experimentation that hematopoietic stem cells do not transdifferentiate into heart tissue.
By way of explaining discrepancies, experimental artifact has been cited repeatedly. Jackson et al. contribute to this worthwhile endeavor through their description of strong autofluorescence in the green spectral region of skeletal muscle fibers. Skeletal muscle fiber-specific green autofluorescence: potential for stem cell engraftment artifacts. ABSTRACT Cell fusion has also been demonstrated in several contexts of ‘transdifferentiation’, and additional work provides further evidence that cells fuse. In fact, several cell types have the natural ability to fuse, such as myoblasts and macrophages/monocytes, and abundant literature documents fusion in physiological and pathological conditions (see Wagers and Weissman’s review). Not surprisingly then, two groups have tentatively identified the macrophage as the cell fusing with hepatocytes after injection of bone marrow cells ( see TOM February). Then, there are myoblasts, which fuse naturally to each other, and to muscle fibers, to form myotubes. Reinecke et al. show that the myoblast cell line C2C12 fuses with cardiomyocytes. Evidence for Fusion Between Cardiac and Skeletal Muscle Cells. ABSTRACT As a next step, Shi et al. showed that C2C12 myoblasts fuse better with mesenchymal stem cells (MSC) than with hematopoietic stem cells (HSC), in vitro. They concluded that HSC are refractory to myogenoic fusion, whereas MSCs contribute readily to regenerating skeletal muscles in vivo. Myogenic fusion of human bone marrow stromal cells, but not hematopoietic cells. ABSTRACT Additional work suggests that a particular cell type within the ckit +/Sca1 +/linˉ subpopulation may be the hemangioblast, a hypothesized common precursor of HSC and endothelial cells. Bailey et al. show that transplantation of one single cell can lead to hematopoietic reconstitution and incorporation into vessel walls in the liver. It is therefore entirely possible that the ‘transdifferentiated’ cells observed in certain organs after injury and regeneration are in fact hemangioblast-derived endothelial cells lining vessels. Transplanted adult hematopoietic stems cells differentiate into functional endothelial cells. ABSTRACT Ratajczak et al. provide another explanation of transdifferentiation. Using freshly isolated cells to avoid culture artifacts, the group found a small subpopulation of non-adherent cells in the bone marrow that express mRNA for markers of early muscle, neural progenitors and liver. These cells can be mobilized into the peripheral blood by G-CSF treatment. Importantly, these cells can be highly enriched by chemotaxis to an SDF-1 gradient . The group also showed that mRNA for SDF-1 is upregulated in damaged organs including hypoxic myocardium, and liver and kidney exposed to CCl 4. These findings raise the interesting possibility that these cells may have been the very cells reported by others to have ‘transdifferentiated’. Additional work needs to be performed to determine whether this subpopulation of bone marrow can a) regenerate tissue, and b) may play a physiological role.
On the other hand, possible support for the existence of plasticity may come from the long-known but poorly understood phenomenon called fetal-maternal microchimerism. During pregnancy, fetal cells cross the placenta and can be detected in the mother’s blood after 36 weeks of pregnancy and have been detected more than 20 years later. In their review, Khosrotehrani and Bianchi describe this interesting phenomenon in more detail and speculate on the possible contribution of fetal cells to physiological tissue regeneration in the mother, a phenomenon observed years after pregnancy. Fetal cell microchimerism: helpful or harmful to the parous woman? ABSTRACT Which cells exactly are transferred during pregnancy is yet unclear, but based on the analysis of cell surface molecules, fetal-origin cells can be found persisting within the CD34 + population of the mother. Additional experimental corroboration of this theory was presented at the Keystone meeting. For more details go to: http://www.isscr.org/scientists/TOM/Feb2004.htm Is it possible that all this discussion around ‘transdifferentiation’ is only semantics? After all, each cell in the body contains exactly the same genes. During development and differentiation of any single cell, genes are expressed and repressed in an orchestrated fashion. At the end of that journey, the bone cell has effectively silenced genes that are not needed for its phenotype. This epigenetic regulation can however be broken, as already demonstrated by reprogramming of nuclei occurring after SCNT. It is therefore not unreasonable to hypothesize that ‘reprogramming’ could also happen under certain physiological conditions. Particularly in the context of injury, where many cytokines, growth factors, chemokines and other signaling molecules are induced, any one of which can induces or repress numerous genes. There is abundant evidence for changes in stem cell fate in vitro; this is demonstrated again by Watanabe et al.
In their report however, instead of changing culture parameters, the group stably transfected C2C12 myoblasts with a transcription repressor involved in terminal differentiation of neuronal stem cells (NSC) to neurons. By replacing the two repressor domains of the transcription factor with activation domains, they were able to activate neuronal target genes. Under muscle-differentiation culture conditions, transfected C2C12 myoblasts down-regulated myosin heavy chain and adopted a neuronal phenotype, rather than entering the muscle differentiation pathway. The authors then showed that these in vitro-derived neuronal cells can survive when injected into the brain, do not form tumors and continue to express neuronal marker. And so it seems that simple reversion of repression of a few central genes can change cell fate, in vitro. Whether this happens in physiological conditions remains to be determined. In conclusion, all these studies indicate that the days of stem cell plasticity are not over. But while stem cell plasticity is certainly a hot topic, its clinical applicability is questionable. The frequency of the few cells that may have truly transdifferentiated is so low that clinical applications for the near future become doubtful. Moreover, emerging literature demonstrates that adult stem cell quality does not improve with age -- another blow for the ‘cure for all diseases’ with autologous stem cells, as most potential beneficiaries of stem cell therapies are old. Updated: April 21, 2004 |
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