TC1(C8orf4) Regulates Hematopoietic Stem/Progenitor Cells and Hematopoiesis

Hematopoiesis is a complex process requiring multiple regulators for hematopoietic stem/progenitor cells (HSPC) and differentiation to multi-lineage blood cells. TC1(C8orf4) is implicated in cancers, hematological malignancies and inflammatory activation. Here, we report that Tc1 regulates hematopoiesis in mice. Myeloid and lymphoid cells are increased markedly in peripheral blood of Tc1–deleted mice compared to wild type controls. Red blood cells are small-sized but increased in number. The bone marrow of Tc1−/− mice is normocellular histologically. However, Lin−Sca-1+c-Kit+ (LSK) cells are expanded in Tc1−/− mice compared to wild type controls. The expanded population mostly consists of CD150−CD48+ cells, suggesting the expansion of lineage-restricted hematopoietic progenitor cells. Colony forming units (CFU) are increased in Tc1−/− mice bone marrow cells compared to controls. In wild type mice bone marrow, Tc1 is expressed in a limited population of HSPC but not in differentiated cells. Major myeloid transcriptional regulators such as Pu.1 and Cebpα are not up-regulated in Tc1−/− mice bone marrow. Our findings indicate that TC1 is a novel hematopoietic regulator. The mechanisms of TC1-dependent HSPC regulation and lineage determination are unknown.

造血过程是一项复杂的生物学进程，需要多种调控因子参与调控造血干/祖细胞（hematopoietic stem/progenitor cells, HSPC）的功能，并促使其分化为多谱系血细胞。TC1(C8orf4)已被证实与癌症、血液系统恶性肿瘤及炎症激活相关。本研究报道，Tc1可调控小鼠体内的造血过程。与野生型对照组相比，Tc1敲除小鼠的外周血中髓系细胞与淋巴系细胞显著增多；红细胞体积偏小但数量增加。Tc1⁻/⁻小鼠的骨髓组织学表现为细胞密度正常。然而，与野生型对照组相比，Tc1⁻/⁻小鼠骨髓中的Lin⁻Sca-1⁺c-Kit⁺（LSK）细胞群体发生扩增，且扩增的细胞群体主要由CD150⁻CD48⁺细胞构成，提示谱系受限的造血祖细胞发生了扩增。与对照组相比，Tc1⁻/⁻小鼠骨髓细胞的集落形成单位（colony forming units, CFU）数量增多。在野生型小鼠骨髓中，Tc1仅在少量造血干/祖细胞群体中表达，而在分化成熟的血细胞中无表达。Tc1⁻/⁻小鼠骨髓中，主要的髓系转录调控因子如Pu.1与Cebpα并未出现上调。本研究结果表明，TC1是一种新型的造血调控因子。目前，TC1依赖的造血干/祖细胞调控及谱系定向的具体机制仍未明确。