van Gucht Anja L M, Meima Marcel E, Moran Carla, Agostini Maura, Tylki-Szymanska Anna, Krajewska Malgorzata-Walasek, Chrzanowska Krystyna, Efthymiadou Alexandra, Chrysis Dionisios, Demir Korcan, Visser W Edward, Visser Theo J, Chatterjee Krishna, van Dijk Thamar B, Peeters Robin P
Department of Internal Medicine, Erasmus University Medical Center, 3000 Rotterdam, The Netherlands.
Wellcome-Medical Research Council Institute of Metabolic Science, University of Cambridge, CB2 0QQ Cambridge, United Kingdom.
J Clin Endocrinol Metab. 2017 Sep 1;102(9):3517-3525. doi: 10.1210/jc.2017-00840.
Patients with resistance to thyroid hormone (TH) α (RTHα) are characterized by growth retardation, macrocephaly, constipation, and abnormal thyroid function tests. In addition, almost all RTHα patients have mild anemia, the pathogenesis of which is unknown. Animal studies suggest an important role for TH and TH receptor (TR)α in erythropoiesis.
To investigate whether a defect in TRα affects the maturation of red blood cells in RTHα patients.
DESIGN, SETTING, AND PATIENTS: Cultures of primary human erythroid progenitor cells (HEPs), from peripheral blood of RTHα patients (n = 11) harboring different inactivating mutations in TRα (P398R, F397fs406X, C392X, R384H, A382fs388X, A263V, A263S), were compared with healthy controls (n = 11). During differentiation, erythroid cells become smaller, accumulate hemoglobin, and express different cell surface markers. We assessed cell number and cell size, and used cell staining and fluorescence-activated cell sorter analysis to monitor maturation at different time points.
After ∼14 days of ex vivo expansion, both control and patient-derived progenitors differentiated spontaneously. However, RTHα-derived cells differentiated more slowly. During spontaneous differentiation, RTHα-derived HEPs were larger, more positive for c-Kit (a proliferation marker), and less positive for glycophorin A (a differentiation marker). The degree of abnormal spontaneous maturation of RTHα-derived progenitors did not correlate with severity of underlying TRα defect. Both control and RTHα-derived progenitors responded similarly when differentiation was induced. T3 exposure accelerated differentiation of both control- and RTHα patient-derived HEPs.
Inactivating mutations in human TRα affect the balance between proliferation and differentiation of progenitor cells during erythropoiesis, which may contribute to the mild anemia seen in most RTHα patients.
甲状腺激素（TH）α抵抗（RTHα）患者的特征为生长发育迟缓、巨头畸形、便秘以及甲状腺功能检查异常。此外，几乎所有RTHα患者都有轻度贫血，其发病机制尚不清楚。动物研究表明TH和TH受体（TR）α在红细胞生成中起重要作用。
研究TRα缺陷是否会影响RTHα患者红细胞的成熟。
设计、地点和患者：将来自RTHα患者（n = 11）外周血的原代人红系祖细胞（HEP）培养物与健康对照（n = 11）进行比较，这些RTHα患者的TRα存在不同的失活突变（P398R、F397fs406X、C392X、R384H、A382fs388X、A263V、A263S）。在分化过程中，红系细胞会变小、积累血红蛋白并表达不同的细胞表面标志物。我们评估了细胞数量和细胞大小，并使用细胞染色和荧光激活细胞分选分析来监测不同时间点的成熟情况。
体外扩增约14天后，对照和患者来源的祖细胞均自发分化。然而，RTHα来源的细胞分化较慢。在自发分化过程中，RTHα来源的HEP更大，c-Kit（一种增殖标志物）阳性更多，而血型糖蛋白A（一种分化标志物）阳性更少。RTHα来源的祖细胞异常自发成熟的程度与潜在TRα缺陷的严重程度无关。当诱导分化时，对照和RTHα来源的祖细胞反应相似。T3暴露加速了对照和RTHα患者来源的HEP的分化。
人TRα的失活突变影响红细胞生成过程中祖细胞增殖和分化之间的平衡，这可能导致大多数RTHα患者出现轻度贫血。
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