Bone marrow skeletal stem/progenitor cell defects in dyskeratosis congenita and telomere biology disorders
Bone marrow skeletal stem/progenitor cell defects in dyskeratosis congenita and telomere biology disorders
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DOI：
10.1182/blood-2014-06-566810
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发表时间：
2015-01-29
期刊：
影响因子：
20.3
通讯作者：
Robey, Pamela G.
中科院分区：
文献类型：
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作者：
Balakumaran, Arun;Mishra, Prasun J.;Robey, Pamela G.
先天性角化不良（DC）是一种遗传性多系统疾病，其特征在于口腔白斑、指甲营养不良和异常皮肤色素沉着，以及高发生率的骨髓（BM）衰竭、实体瘤和其他医学问题如骨质减少。DC和端粒生物学病症（在此统称为TBD）由端粒生物学基因中的种系突变引起，导致非常短的端粒和造血干细胞的有限增殖潜力。我们发现骨髓基质细胞群（BMSC，也称为BM衍生的间充质干细胞）中的骨骼干细胞（SSC）可能有助于血液表型。TBD-BMSCs在体外表现出集落形成能力降低，自发分化为脂肪细胞和纤维化细胞，并增加衰老。在体内移植到小鼠中后，TBD-BMSCs不能形成骨或支持造血，不像正常的BMSCs。通过小干扰TERC-RNA（siTERC-RNA）减少正常BMSC中的TERC（TBD相关基因），通过减少增殖和次级集落形成效率以及通过加速体外衰老来概括TBD-BMSC表型。对照组和siTERC-BMSCs的微阵列图谱显示信使RNA水平的造血因子减少，蛋白水平的因子分泌减少。这些发现与TBD中导致BM失败的SSC/BMSC缺陷一致。
Dyskeratosis congenita (DC) is an inherited multisystem disorder, characterized by oral leukoplakia, nail dystrophy, and abnormal skin pigmentation, as well as high rates of bone marrow (BM) failure, solid tumors, and other medical problems such as osteopenia. DC and telomere biology disorders (collectively referred to as TBD here) are caused by germline mutations in telomere biology genes leading to very short telomeres and limited proliferative potential of hematopoietic stem cells. We found that skeletal stem cells (SSCs) within the BM stromal cell population (BMSCs, also known as BM-derived mesenchymal stem cells), may contribute to the hematologic phenotype. TBD-BMSCs exhibited reduced clonogenicity, spontaneous differentiation into adipocytes and fibrotic cells, and increased senescence in vitro. Upon in vivo transplantation into mice, TBD-BMSCs failed to form bone or support hematopoiesis, unlike normal BMSCs. TERC reduction (a TBD-associated gene) in normal BMSCs by small interfering TERC-RNA (siTERC-RNA) recapitulated the TBD-BMSC phenotype by reducing proliferation and secondary colony-forming efficiency, and by accelerating senescence in vitro. Microarray profiles of control and siTERC-BMSCs showed decreased hematopoietic factors at the messenger RNA level and decreased secretion of factors at the protein level. These findings are consistent with defects in SSCs/BMSCs contributing to BM failure in TBD.