Peninsula Medical School, University of Plymouth, Plymouth PL6 8BU, UK.
Department of Biology and Biochemistry, University of Bath, Bath BA2 7AX, UK.
Cells. 2022 Jun 23;11(13):2012. doi: 10.3390/cells11132012.
Hematopoietic stem and progenitor cell (HSPC) maintenance and the differentiation of various lineages is a highly complex but precisely regulated process. Multiple signaling pathways and an array of transcription factors influence HSPC maintenance and the differentiation of individual lineages to constitute a functional hematopoietic system. Nuclear factor of activated T cell (NFAT) family transcription factors have been studied in the context of development and function of multiple mature hematopoietic lineage cells. However, until now their contribution in HSPC physiology and HSPC differentiation to multiple hematopoietic lineages has remained poorly understood. Here, we show that NFAT proteins, specifically NFATc1, play an indispensable role in the maintenance of HSPCs. In the absence of NFATc1, very few HSPCs develop in the bone marrow, which are functionally defective. In addition to HSPC maintenance, NFATc1 also critically regulates differentiation of lymphoid, myeloid, and erythroid lineage cells from HSPCs. Deficiency of NFATc1 strongly impaired, while enhanced NFATc1 activity augmented, the differentiation of these lineages, which further attested to the vital involvement of NFATc1 in regulating hematopoiesis. Hematopoietic defects due to lack of NFATc1 activity can lead to severe pathologies such as lymphopenia, myelopenia, and a drastically reduced lifespan underlining the critical role NFATc1 plays in HSPC maintenance and in the differentaion of various lineages. Our findings suggest that NFATc1 is a critical component of the myriad signaling and transcriptional regulators that are essential to maintain normal hematopoiesis.
造血干细胞和祖细胞（HSPC）的维持以及各种谱系的分化是一个高度复杂但精确调控的过程。多种信号通路和一系列转录因子影响 HSPC 的维持以及各个谱系的分化，从而构成一个功能齐全的造血系统。核因子活化 T 细胞（NFAT）家族转录因子已在多个成熟造血谱系细胞的发育和功能方面得到研究。然而，直到现在，它们在 HSPC 生理学和 HSPC 向多个造血谱系分化中的贡献仍知之甚少。在这里，我们表明 NFAT 蛋白，特别是 NFATc1，在 HSPC 的维持中发挥不可或缺的作用。在缺乏 NFATc1 的情况下，骨髓中很少有 HSPC 发育，而且功能有缺陷。除了 HSPC 的维持外，NFATc1 还严格调控 HSPC 向淋巴样、髓样和红系谱系细胞的分化。NFATc1 的缺失强烈地抑制了这些谱系的分化，而 NFATc1 活性的增强则增强了这些分化，这进一步证明了 NFATc1 在调节造血中的重要作用。由于缺乏 NFATc1 活性而导致的造血缺陷可导致严重的病理，如淋巴细胞减少症、髓细胞减少症和寿命明显缩短，这突显了 NFATc1 在 HSPC 维持和各种谱系分化中的关键作用。我们的研究结果表明，NFATc1 是维持正常造血所必需的众多信号和转录调节剂的关键组成部分。
