Stem Cell Antigen 1-Positive Mesenchymal Cells Are the Origin of Follicular Cells during Thyroid Regeneration

Many tissues are thought to contain adult stem/progenitor cells that are responsible for repair of the tissue where they reside upon damage and/or carcinogenesis, conditions when cellular homeostasis becomes uncontrolled. While the presence of stem/progenitor cells of the thyroid has been suggested, how these cells contribute to thyroid regeneration remains unclear. Here we show the origin of thyroid follicular cells and the process of their maturation to become follicular cells during regeneration. By using β-galactosidase (β-gal) reporter mice in conjunction with partial thyroidectomy as a model for thyroid regeneration, and bromodeoxyuridine (BrdU) long label-retaining cell analysis, we demonstrated that stem cell antigen 1 (Sca1) and BrdU-positive, but β-gal and NKX2-1 negative cells were found in the non-follicular mesenchymal area 7 days after partial thyroidectomy. They temporarily co-expressed cytokeratin 14, and were observed in part of follicles by day 35 post-partial thyroidectomy. Sca1, BrdU, β-gal, and NKX2-1-positive cells were found 120 days post-partial thyroidectomy. These results suggested that Sca1 and BrdU positive cells may participate in the formation of new thyroid follicles after partial thyroidectomy. The process of thyroid follicular cell regeneration was recapitulated in ex vivo thyroid slice collagen gel culture studies. These studies will facilitate research on thyroid stem/progenitor cells and their roles in thyroid diseases, particularly thyroid carcinomas.

诸多组织被认为含有成体干细胞/祖细胞，此类细胞可在组织受损或发生癌变（此时细胞稳态失去调控）时，对所在组织进行修复。尽管已有研究提示甲状腺中存在干细胞/祖细胞，但此类细胞参与甲状腺再生的具体机制仍未明确。本研究阐明了甲状腺滤泡细胞的起源，及其在再生过程中向滤泡细胞成熟的完整历程。本研究利用β-半乳糖苷酶（β-galactosidase, β-gal）报告基因小鼠，结合部分甲状腺切除术构建甲状腺再生模型，并辅以溴脱氧尿苷（bromodeoxyuridine, BrdU）长时程标记滞留细胞分析技术，结果显示：在部分甲状腺切除术后7天，非滤泡间质区域可检测到干细胞抗原1（stem cell antigen 1, Sca1）与BrdU双阳性，但β-gal和NKX2-1双阴性的细胞。此类细胞会暂时性共表达细胞角蛋白14，并在部分甲状腺切除术后35天时出现在部分滤泡中。在部分甲状腺切除术后120天，可观测到Sca1、BrdU、β-gal及NKX2-1均阳性的细胞。上述结果表明，Sca1与BrdU双阳性细胞可能参与了部分甲状腺切除术后新生甲状腺滤泡的形成过程。甲状腺滤泡细胞再生的过程在离体甲状腺切片胶原凝胶培养实验中得到了复现。本研究成果将为甲状腺干细胞/祖细胞及其在甲状腺疾病（尤其是甲状腺癌）中的作用相关研究提供助力。