Stem cells (embryonic stem cells, somatic stem cells such as neural stem cells, and cardiac stem cells) and cancer cells are known to aggregate and form spheroid structures. This behavior is common in undifferentiated cells and may be necessary for adapting to certain conditions such as low-oxygen levels or to maintain undifferentiated status in microenvironments including stem cell niches. In order to decipher the meaning of this spheroid structure, we established a cardiosphere clone (CSC-21E) derived from the rat heart which can switch its morphology between spheroid and nonspheroid. Two forms, floating cardiospheres and dish-attached flat cells, could be switched reversibly by changing the cell culture condition. We performed differential proteome analysis studies and obtained protein profiles distinct between spherical forms and flat cells. From protein profiling analysis, we found upregulation of glycolytic enzymes in spheroids with some stress proteins switched in expression levels between these two forms. Evidence has been accumulating that certain chaperone/stress proteins are upregulated in concert with cellular changes including proliferation and differentiation. We would like to discuss the possible mechanism of how these aggregates affect cell differentiation and/or other cellular functions. 1. Introduction Two epoch accomplishments in the first decade of 21st century are changing the scope of biomedical research. The first was the completion of the human genome project [1], which enabled the onset of “Omics” or the integrative approach (System Biology) [2]. The second was the discovery of adult stem cells in human [3] followed by induction of pluripotency by Yamanaka factors (Oct3/4, Sox, Klf4, and c-Myc) in both mouse and human somatic cells [4, 5]. Adult stem cells are undifferentiated cells found throughout the body after development. They have the ability to self-renew indefinitely and have the developmental potential to generate many other cell types due to cell fate switching induced by extracellular environmental signals [3]. Plasticity of stem cells as well as the induction and reprogramming of somatic cells ignited the hope of discovering cellular therapy for the regeneration of damaged body parts. The revelation of the involvement of extracellular factors in switching cell types resulted in paradigm shift from “genetic determinism”, the paradigm that all biological processes follow the one-way instruction stored in genomes to an “environment-genome interaction” understanding. Studies on the regulatory molecular mechanisms
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