Stem Cells Cultures are Confronted to Heterogeneity
7 Jun, 2007 04:11 pm
Identification, isolation and large scale culture of stem cells for potential medical applications is a major challenge in cell biology. However, the culture of stem cells, but also of any other cell types is confronted to a difficulty. Cell type heterogeneity emerges spontaneously even in clonal cell populations making difficult to expand a homogenous subpopulations of cells with given properties, or "phenotype". The clonal origin of the cells and the global uniformity of the environment make it difficult to explain the induction of new cellular phenotypes by genetic or external causes. The heterogeneity is generated by the cellular system itself presumably by interactions between its own elements, the cells.
The results of the computer simulations were compared with the observations made on a muscle cell line and primary human muscles. It appears, that the "intrinsic" and "extrinsic" mechanisms are likely to correspond to two idealized solutions that act together. Indeed, the hybrid model that combined the "intrinsic" and "extrinsic" hypotheses provided predictions that were close to the observed reality. The "extrinsic" component in the model refers to the cell's capacity to react to fluctuations in the environment. This reaction involves changes in the gene expression pattern and conditioned by the local concentration gradients of factors and metabolites secreted by the cells, nutrients, oxygen etc. However, the phenotypic change is not a graded transition that follows even the small variation of the local environment; rather it is like switch of a multistable system from one stable state to another. The cellular phenotype is robust and can resist small spontaneous fluctuation of the environment which can only induce fluctuations around the stable phenotypic state. Large fluctuations, however, destabilize the cell and generate changes. In this sense, the "intrinsic" probability in the hybrid model refers to the phenotypic robustness based on epigenetic mechanisms and transcription regulation networks rather than to a spontaneous propensity for differentiation.
These observations reported in the PlosONE paper has to be interpreted in the perspective of the currently emerging view that differentiation is context-dependent rather than a pre-programmed attribute of the cells. Cell type heterogeneity is a natural and unavoidable feature of the cell populations even in culture. This can be seen as an obstacle for the large scale culture of cells with a desired type, but also as an opportunity to set up cultures where the heterogeneity is canalised by the operator in the desired direction.
Although this work does not provide a ready-to-use protocol for the culture of stem cells, it can help to formulate new research strategies that aim to increase the efficiency of stem cell-related culture methods and, perhaps, even to develop stem cells from already differentiated cells instead of using embryos.
Stockholm D., et al, The Origin of Phenotypic Heterogeneity in a Clonal Cell Population In Vitro, PlosONE, 25 April 2007.