The presence of thyroid stem/progenitor cells has not been clearly demonstrated, nor their specific cell surface markers are known. Mice are used as a model animal to study stem/progenitor cells of thyroid, and partial thyroidectomy as a tool to activate their stem/progenitor cells. The latter is based on the hypothesis that a sudden loss of thyroid tissue may activate otherwise dormant stem/progenitor cells to participate in thyroid regeneration. Previously, we demonstrated that verapamil-resistant side population (SP) cells of mouse thyroid constituted 1% of total cells as determined by FACS analysis, which exhibited stem/progenitor cell characteristics. A half of the thyroid SP cells were stem cell antigen 1 (Sca1) positive, suggesting that Sca1 may potentially be used as a marker for thyroid stem/progenitor cells. In another study using partial thyroidectomy, we demonstrated that partial thyroidectomy resulted in an increase of BrdU positive proliferating cells and immature cells with clear or faintly eosinophilic cytoplasm that may have been derived from either follicular cells or C cells in the central proliferative area and the overlapping area close to the cut-edge of the thyroid lobe. The gene expression profiling analysis demonstrated that the genes involved in embryonic development and cancer, among the processes where stem cells are known to play roles, were affected by partial thyroidectomy. These results suggested that the immature cells may participate in the repair and/or regeneration of thyroid. In order to understand whether and/or how Sca1-positive cells participate in thyroid repair after partial thyroidectomy, and whether and/or how Sca1-positive cells are related to partial thyroidectomy-induced immature cells, we carried out time course immunohistochemical analyses of Sca1-positive cells using thyroids harvested at various time points after partial thyroidectomy. This experiment was combined with the use of beta-galactosidase reporter mouse that expresses beta-galactosidase only in differentiated mature thyroid follicular cells, thus allowing tracing the thyroid lineage by examining the expression of beta-galactosidase. Further, BrdU long label-retaining cell analysis was used, in which BrdU positivity was used as a surrogate marker for stem/progenitor cells due to the fact that BrdU positive stem/progenitor cells do not divide frequently or asymmetrically divide, thus BrdU being retained only in stem/progenitor cells. The preliminary results suggested that 1) Sca1-positive cells are different from previously identified immature cells with clear or faintly eosinophilic cytoplasm, 2) Sca1-positive, BrdU-positive, beta-galactosidase-negative cells suggestive of non-thyroid follicular cell origin of dividing cells are first found in mesenchymal area of thyroid by 1 week post-partial thyroidectomy, 3) by 4 weeks post-partial thyroidectomy, these cells become part of follicular cells, where 4) they start losing Sca1 expression while thyroid differentiation marker gene such as NKX2-1 start appearing. We are currently carrying out immunofluorescence study to clearly locate cells positive or negative for Sca1, BrdU, beta-galactosidase, and/or NKX2-1, and their time-dependent relationships to each other and to follicular repair/maturation. Through these studies, we hope to understand the role of Sca1-positive cells during repair of partially thyroidectomized thyroids.

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