On experimental design and discourse in plasticity research.

Communication in the stem cell field requires a common understanding of terminology and that "plasticity" phenomena are model- and, perhaps, species-dependent. Plasticity has generally been applied to unexpected differentiative events; will the term cease being useful when these unexpected pathways become recognized as normative? Four pathways of cell plasticity have now been recognized: (1) facultative, intraorgan self-renewing stem cells; (2) reversion of differentiated cells to blastema-like appearances, common in amphibians, perhaps restricted to neoplasia in mammals; (3) cells of one lineage directly changing to differentiation of another lineage cued by microenvironemental signals; (4) cell-cell fusion leading to changes in differentiation of the "incoming" cell in response to cytoplasmic and perhaps nuclear cues. In all of these, "differentiation" must be understood as a reflection of gene expression that is a highly intricate system of parallel, i.e., nonlinear molecular interactions. Present controversies regarding the plasticity of adult stem cells may be explained both by differences in experimental variables and techniques as well as by differing nonscientific, political, and/or polemical needs of investigators and commentators. Some of the variables in transplantation experiments, which are likely to be important in experimental outcome, but rarely addressed in interpretation of data, are the age of the cell donor and of the strain of mice or species used, the isolation technique used to obtain the putative stem cells, and the inherent effects of transgenic markers used to identify the donor or host cells. Also of great importance, but rarely controlled for in experimental design and interpretation, are the reproducibility and sensitivity of methods used to detect the markers of donor origin, the capacity of differentiated tissue to silence transgenes or alter marker expression, and--finally and most importantly--the different signals that influence plasticity phenomena in very different types of injury and regeneration. In different models of injury there are likely to be significant differences in promoting cell localization, proliferation, and predominance of "plasticity pathway," if any are involved, in determining outcome.