Ilardo Melissa, Dos Santos Maria C Ferreira, Grote Beverborg Niels, Rajan Malini, Said M Abdullah, Verweij Niek, Van Der Harst Pim, Van Der Meer Peter, Leibold Elizabeth A
Maze Therapeutics, San Francisco, CA, United States.
Department of Internal Medicine, Division of Hematology and Hematologic Malignancies, The University of Utah, Salt Lake City, UT, United States.
Front Physiol. 2022 Jan 27;12:760851. doi: 10.3389/fphys.2021.760851. eCollection 2021.
The Bajau Sea Nomads were recently demonstrated to have evolved larger spleens as an adaptation to millennia of a marine foraging lifestyle. The large-spleen phenotype appears to derive from increases in thyroid hormone (TH) production as a result of reduced expression of phosphodiesterase 10A (PDE10A), though the exact mechanism remains unknown. Through pharmacological inhibition of PDE10A using the selective inhibitor MP-10 in mice, we were able to mimic the Bajau adaptation and show that treated mice had significantly larger spleens than control animals. This difference appears connected to an excess of early stage erythrocytes and an apparent increase in red blood cell (RBC) precursor proliferation in response to increased TH. However, we determined that the stimulation of RBC production in the mouse model TH is Erythropoietin (EPO)-independent, unlike in the altitude (chronic hypoxemia) response. We confirmed this using human GWAS data; although the Bajau PDE10A variants are significantly associated with increased TH levels and RBC count, they are not associated with EPO levels, nor are other strongly thyroid-associated SNPs. We therefore suggest that an EPO-independent mechanism of stimulating RBC precursor proliferation TH upregulation underlies the increase in spleen size observed in Sea Nomad populations.
巴夭海游牧民最近被证明已经进化出更大的脾脏，以适应数千年的海洋觅食生活方式。大脾脏表型似乎源于磷酸二酯酶10A（PDE10A）表达降低导致的甲状腺激素（TH）产生增加，尽管确切机制尚不清楚。通过在小鼠中使用选择性抑制剂MP-10对PDE10A进行药理学抑制，我们能够模拟巴夭人的适应性变化，并表明处理过的小鼠脾脏明显大于对照动物。这种差异似乎与早期红细胞过多以及红细胞（RBC）前体增殖明显增加有关，这是对TH增加的反应。然而，我们确定在小鼠模型中TH刺激红细胞生成与促红细胞生成素（EPO）无关，这与高原（慢性低氧血症）反应不同。我们使用人类全基因组关联研究（GWAS）数据证实了这一点；尽管巴夭人的PDE10A变体与TH水平升高和RBC计数显著相关，但它们与EPO水平无关，其他与甲状腺密切相关的单核苷酸多态性（SNP）也无关。因此，我们认为在海洋游牧民群体中观察到的脾脏大小增加的基础是一种不依赖EPO的机制，即TH上调刺激RBC前体增殖。
