八、甲状腺干细胞
干细胞是未分化细胞，能够自我更新和分化成一种或多种功能的细胞。“成体”干细胞，通常称为“祖细胞”，只能分化为它们所在的器官特异性的细胞型。一些器官有成体干细胞的存在，其在疾病或损伤后的修复中起着关键作用。虽然许多年前就假设甲状腺干/祖细胞的存在[36]，但近几年才在成人甲状腺中找到支持的证据。
首先在骨髓中发现一群叫侧群细胞（Side Population，SP）的亚群细胞，随后发现存在于各种非造血组织[37]。这些细胞的特征是可外排活性染料Hoechst33342，与真正的干细胞有许多相同的特征。SP细胞有助于肝实质的再生或骨骼肌管的形成。甲状腺中也发现SP细胞[38]；小鼠中，SP细胞大部分位于滤泡间隙中，少于甲状腺总细胞的1%。SP细胞表达干细胞标志物Oct-4和核干因子（Nucleostemin），而几乎检测不到分化标志物如甲状腺球蛋白（Tg）和甲状腺过氧化物酶（TPO）。此外，只有很少的SP细胞表达C细胞标志物——降钙素。人类结节性甲状腺肿的甲状腺细胞中已分离出SP细胞，并显示与小鼠SP细胞相似的分子特征[39]。通常，培养中的SP细胞会进行组织特异性分化。值得注意的是，从正常小鼠甲状腺分离的SP细胞在培养中保持未分化状态，并且不能排列成卵泡样结构。相反，人类SP细胞能够在体内增殖，具有甲状腺表型，对TSH应答。小鼠和人类SP细胞分别来源于正常和甲状腺肿组织，尚不清楚小鼠和人类SP细胞之间的差异是否取决于培养条件不同或细胞来源不同。
除了SP细胞，实性细胞巢（Solid Cell Nests，SCN）的主要细胞也显示许多干细胞的特征。在这些细胞中，不表达生成甲状腺球蛋白或降钙素的基因特异性，而表达端粒酶[40]和p63[41]，p63是常在多层上皮细胞的基底/干细胞中检测到的转录因子。此外，SCN的主要细胞中BCL2的表达增加[40]，BCL2是在TFCs中持续表达的抗凋亡蛋白[42]。这种分子特征与干细胞的定义相符，提示SCN的主要细胞可能是分化为产生激素细胞的多能干细胞的来源。
人类TFCs更新缓慢，一生约分裂5次[36]。因此，人在出生后甲状腺表现为“休眠器官”。然而在动物模型中已经证明，甲状腺在受到严重干扰后（如严重的实验性甲状腺炎[43]或甲状腺部分切除术[44]）可再生和恢复滤泡结构。甲状腺部分切除术后，表达Sca 1（干细胞抗原1）的细胞在术后的几天内增殖[45]，该细胞位于甲状腺的非滤泡间质区。
以前的数据似乎表明，甲状腺的再生可能是甲状腺干/祖细胞替换被破坏的滤泡细胞池而增殖和分化的结果。然而，我们目前缺乏甲状腺干细胞存在的确凿证据，不知道这些细胞的生理学和病理学作用。
参考文献
[1] Werner S.Historical resumè.In: Ingbar S H, Braverman LE, eds.The thyroid[M].Philadelphia: Lippincott, 1986,3-6.
[2] Netter F.Anatomy of the thyroid and parathyroid glands[M].The CIBA collection of medical illustrations.Summit,NJ:CIBA Pharmaceutical Products, 1965, 41-70.
[3] 刘树伟.局部解剖学[M].8版.北京：人民卫生出版社，2013.
[4] Sawicki B.Evaluation of the role of mammalian thyroid parafollicular cells[J].Acta histochemica,1995, 97:389-399.
[5] Yap A S, Stevenson B R, Armstrong J W, et al.Thyroid epithelial morphogenesis in vitro: a role for bumetanidesensitive Cl- secretion during follicular lumen development[J].Experimental cell research,1994,213:319-326.
[6] Bourke J R, Abel K C, Huxham G J, et al.Sodium channel heterogeneity in the apical membrane of porcine thyroid epithelial cells[J].The Journal of endocrinology, 1996,149:101-108.
[7] Royaux I E, Suzuki K, Mori A,et al.Pendrin, the protein encoded by the Pendred syndrome gene (PDS), is an apical porter of iodide in the thyroid and is regulated by thyroglobulin in FRTL-5 cells[J].Endocrinology,2000,141:839-845.
[8] De Deken X, Wang D, Many M C, et al.Cloning of two human thyroid cDNAs encoding new members of the NADPH oxidase family[J].The Journal of biological chemistry,2000, 275:23227-23233.
[9] Paire A, Bernier-Valentin F, Selmi-Ruby S, et al.Characterization of the rat thyroid iodide transporter using anti-peptide antibodies.Relationship between its expression and activity[J].The Journal of biological chemistry,1997,272:18245-18249.
[10] Gerard C, Gabrion J, Verrier B,et al.Localization of the Na+/K+-ATPase and of an amiloride sensitive Na+ uptake on thyroid epithelial cells[J].European journal of cell biology,1985, 38:134-141.
[11] Costagliola S, Rodien P, Many M C, et al.Genetic immunization against the human thyrotropin receptor causes thyroiditis and allows production of monoclonal antibodies recognizing the native receptor[J].Journal of immunology, 1998, 160:1458-1465.
[12] Denker B M, Nigam SK.Molecular structure and assembly of the tight junction[J].The American journal of physiology,1998, 274:F1-9.
[13] Yap A S, Stevenson B R, Abel K C, et al.Microtubule integrity is necessary for the epithelial barrier function of cultured thyroid cell monolayers[J].Experimental cell research,1995, 218:540-550.
[14] Munari-Silem Y, Rousset B.Gap junction-mediated cellto-cell communication in endocrine glands-molecular and functional aspects: a review[J].European journal of endocrinology / European Federation of Endocrine Societies, 1996, 135:251-264.
[15] Yap A S, Manley S W.Contact inhibition of cell spreading:a mechanism for the maintenance of thyroid cell aggregation in vitro[J].Experimental cell research, 1993, 208:121-127.
[16] Yap A S, Stevenson B R, Keast J R, et al.Cadherinmediated adhesion and apical membrane assembly define distinct steps during thyroid epithelial polarization and lumen formation[J].Endocrinology, 1995, 136:4672-4680.
[17] Yap A S, Manley S W.Thyrotropin inhibits the intrinsic locomotility of thyroid cells organized as follicles in primary culture[J].Experimental cell research, 1994,214:408-417.
[18] Yap A S.Initiation of cell locomotility is a morphogenetic checkpoint in thyroid epithelial cells regulated by ERK and PI3-kinase signals[J].Cell motility and the cytoskeleton, 2001, 49:93-103.
[19] Yap A S, Abel K C, Bourke JR, et al.Differential regulation of thyroid cell-cell and cell-substrate adhesion by thyrotropin[J].Experimental cell research, 1992,202:366-369.
[20] Pellerin S, Croizet K, Rabilloud R, et al.Regulation of the three-dimensional organization of thyroid epithelial cells into follicle structures by the matricellular protein,thrombospondin-1[J].Endocrinology, 1999, 140:1094-1103.(https://www.daowen.com)
[21] Gartner R, Schopohl D, Schaefer S,et al.Regulation of transforming growth factor beta 1 messenger ribonucleic acid expression in porcine thyroid follicles in vitro by growth factors, iodine, or delta-iodolactone[J].Thyroid:official journal of the American Thyroid Association,1997, 7:633-640.
[22] Toda S, Matsumura S, Fujitani N, et al.Transforming growth factor-beta1 induces a mesenchyme-like cell shape without epithelial polarization in thyrocytes and inhibits thyroid folliculogenesis in collagen gel culture[J].Endocrinology, 1997, 138:5561-5575.
[23] Paire A, Bernier-Valentin F, Rabilloud R, et al.Expression of alpha- and beta-subunits and activity of Na+/K+ ATPase in pig thyroid cells in primary culture:modulation by thyrotropin and thyroid hormones[J].Molecular and cellular endocrinology, 1998, 146:93-101.
[24] Tacchetti C, Zurzolo C, Monticelli A, et al.Functional properties of normal and inverted rat thyroid follicles in suspension culture[J].Journal of cellular physiology,1986, 126:93-98.
[25] Gerard A C, Denef J F, Many M C, et al.Relationships between cell division, expression of growth factors and microcirculation in the thyroids of Tg-A2aR transgenic mice and patients with Graves’disease[J].The Journal of endocrinology, 2003, 177:269-277.
[26] Colin I M, Denef J F, Lengele B, et al.Recent insights into the cell biology of thyroid angiofollicular units[J].Endocrine reviews, 2013, 34:209-238.
[27] Gerard A C, Poncin S, Caetano B, et al.Iodine deficiency induces a thyroid stimulating hormone-independent early phase of microvascular reshaping in the thyroid[J].The American journal of pathology, 2008, 172:748-760.
[28] Le Douarin N, Fontaine J, Le Lievre C.New studies on the neural crest origin of the avian ultimobranchial glandular cells—interspecific combinations and cytochemical characterization of C cells based on the uptake of biogenic amine precursors[J].Histochemistry,1974, 38:297-305.
[29] Martin-Lacave I, Conde E, Montero C, et al.Quantitative changes in the frequency and distribution of the C-cell population in the rat thyroid gland with age[J].Cell and tissue research, 1992, 270:73-77.
[30] Suzuki K, Kobayashi Y, Katoh R, et al.Identification of thyroid transcription factor-1 in C cells and parathyroid cells[J].Endocrinology, 1998, 139:3014-3017.
[31] Kusakabe T, Hoshi N, Kimura S.Origin of the ultimobranchial body cyst: T/ebp/NKX2-1 expression is required for development and fusion of the ultimobranchial body to the thyroid[J].Developmental dynamics : an official publication of the American Association of Anatomists,2006, 235:1300-1309.
[32] Meunier D, Aubin J, Jeannotte L.Perturbed thyroid morphology and transient hypothyroidism symptoms in Hoxa5 mutant mice[J].Developmental dynamics :an official publication of the American Association of Anatomists, 2003, 227:367-378.
[33] Martin-Lacave I, Rojas F, Bernabe R, et al.Comparative immunohistochemical study of normal, hyperplastic and neoplastic C cells of the rat thyroid gland[J].Cell and tissue research, 2002, 309:361-368.
[34] Kameda Y, Oyama H, Endoh M, et al.Somatostatin immunoreactive C cells in thyroid glands from various mammalian species[J].The Anatomical record, 1982,204:161-170.
[35] Blaker M, de Weerth A, Tometten M, et al.Expression of the cholecystokinin 2-receptor in normal human thyroid gland and medullary thyroid carcinoma[J].European journal of endocrinology / European Federation of Endocrine Societies, 2002, 146:89-96.
[36] Dumont J E, Lamy F, Roger P, et al.Physiological and pathological regulation of thyroid cell proliferation and differentiation by thyrotropin and other factors[J].Physiological reviews, 1992, 72:667-697.
[37] Hussain S Z, Strom S C, Kirby M R, et al.Side population cells derived from adult human liver generate hepatocytelike cells in vitro[J].Digestive diseases and sciences,2005, 50:1755-1763.
[38] Hoshi N, Kusakabe T, Taylor B J, et al.Side population cells in the mouse thyroid exhibit stem/progenitor celllike characteristics[J].Endocrinology, 2007, 148:4251-4258.
[39] Lan L, Cui D, Nowka K, et al.Stem cells derived from goiters in adults form spheres in response to intense growth stimulation and require thyrotropin for differentiation into thyrocytes[J].The Journal of clinical endocrinology and metabolism, 2007, 92:3681-3688.
[40] Preto A, Cameselle-Teijeiro J, Moldes-Boullosa J, et al.Telomerase expression and proliferative activity suggest a stem cell role for thyroid solid cell nests[J].Modern pathology : an official journal of the United States and Canadian Academy of Pathology, 2004, 17:819-826.
[41] Reis-Filho J S, Preto A, Soares P, et al.p63 expression in solid cell nests of the thyroid: further evidence for a stem cell origin[J].Modern pathology : an official journal of the United States and Canadian Academy of Pathology, 2003,16:43-48.
[42] Koga M, Hiromatsu Y, Jimi A, et al.Immunohistochemical analysis of Bcl-2, Bax, and Bak expression in thyroid glands from patients with subacute thyroiditis[J].The Journal of clinical endocrinology and metabolism, 1999,84:2221-2225.
[43] Chen C Y, Kimura H, Landek-Salgado MA, et al.Regenerative potentials of the murine thyroid in experimental autoimmune thyroiditis: role of CD24[J].Endocrinology, 2009,150:492-499.
[44] Ozaki T, Matsubara T, Seo D, et al.Thyroid regeneration:characterization of clear cells after partial thyroidectomy[J].Endocrinology, 2012, 153:2514-2525.
[45] Okamoto M, Hayase S, Miyakoshi M, et al.Stem cell antigen 1-positive mesenchymal cells are the origin of follicular cells during thyroid regeneration[J].PloS one,2013, 8:e80801.