The Heterogeneity of Cell Populations

All cases of mosaicism can be divided into two large groups if the classification of Russell (1964) is slightly modified (1) structural-genetical mosaicism where the 

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The heterogeneity of cell populations led to the realization of differential gene activity on the tissue level. The differences between cellular and tissue levels of differentiation can be illustrated when biochemical markers are used (Fig. 70). Suppose there are two electrophoretic variants of protein A (Aj-fast and A2-SI0W) which are controlled by a pair of alleles. Codominant expression will explain the presence of both electrophoretic variants in heterozygous individuals. This occurs at the cellular level. There is, however, a second possibility. There are cells which can synthesize only the Aj variant and cells which synthesize only the A2 variant. The proliferation of these cells will lead to clones. Therefore, these traits are also codominant at the tissue level. However, in each separate cell there is only one allele. 

CE-based chemical cytometry can be used to evaluate many cell constituents simultaneously and is thus, as shown in Fig. 1, categorized as a high information content technique. This comes at a cost, however, as the cell injection schemes and use of a single capillary make the technique extremely low throughput. Ideally, the contents of hundreds of cells could be individually analyzed for statistical evaluation of the heterogeneity of a population in practice, however, the arduous and time-consuming nature of chemical cytometry typically limits it to a few cells (i.e., <10) per analysis. 

The recent development and application of methodologies sensitive at the single cell wall level has shown that traditional bulk analytical techniques average out important intrinsic heterogeneity in sampled populations. By exploring the diversity of cell walls using novel cryopreservation techniques for electron microscopy and non-invasive... 

Fig. 1. Microenvironmental factors and the invasive process. The primary tumor is a heterogeneous mix of cell populations, further diversified by gradients of blood-borne nutrients, oxygen, and drugs. Hypoxia contributes to treatment resistance, upregulates pro-angiogenic and pro-invasive molecules, and helps to maintain cancer stem-like cell populations. Tumor cells may undergo epithelial-to-mesenchymal transition (EMT), enter blood vessels, and disseminate to distant sites where they extravasate, invade, and colonize the tissues. Once established, the cells may undergo the reverse program (mesen-chymal-to-epithelial transition, MET) and proliferate to form metastases, the major reason for treatment failure.

The most prevalent question facing investigators is the choice of cell type. At present, no strong scientific rationale exists for this selection. Yet, developing such a rationale is critical if the therapy is to be optimized. Patients suffering from heart disease are a heterogeneous population, who present at... 

Flow cytometry [141, 142] is a technique that allows the measurement of multiple parameters on individual cells. Cells are introduced in a fluid stream to the measuring point in the apparatus. Here, the cell stream intersects a beam of light (usually from a laser). Light scattered from the beam and/or cell-associated fluorescence are collected for each cell that is analysed. Unlike the majority of spectroscopic or bulk biochemical methods it thus allows quantification of the heterogeneity of the cell sample being studied. This approach offers tremendous advantages for the study of cells in industrial processes, since it not only enables the visualisation of the distribution of a property within the population, but also can be used to determine the relationship between properties. As an example, flow cytometry has been used to determine the size, DNA content, and number of bud scars of individual cells in batch and continuous cultures of yeast [143,144]. This approach can thus provide information on the effect of the cell cycle on observed differences between cells that cannot be readily obtained by any other technique. 

The aggregation of cells in suspension culture leads to a heterogeneous population that confound the analysis and operations of the reactor types mentioned above in many cases. For non-growth associated products, immobilization of cells provides a... 

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