Iacono Giulia, Abay Asena, Murillo Joan S Gallego, Aglialoro Francesca, Yagci Nurcan, Varga Eszter, Bijlsma Tieme, Sohler Justine, Fu Kerly, Reisz Julie A, Argabright Amy, D'Alessandro Angelo, Svendsen Arthur F, von Lindern Marieke, van den Akker Emile
Department of Hematopoiesis Sanquin Research Amsterdam and Landsteiner Laboratory, Amsterdam University Medical Center University of Amsterdam, Plesmanlaan 125, 1066CX, Amsterdam, The Netherlands.
Department of Biotechnology Faculty of Applied Sciences, Delft University of Technology, Delft, The Netherlands.
Sci Rep. 2024 Dec 4;14(1):30157. doi: 10.1038/s41598-024-81746-8.
Understanding how mechanical stress affects erythropoiesis is crucial to produce transfusable erythrocytes in fluid-turbulent bioreactors. We investigated the effects of shear-stress on differentiating CD49dCD235a primary human erythroblasts (EBL) at molecular, cellular, and functional level. Shear-stress, at differentiation onset, enhanced EBL maturation and induced upregulation of genes regulating cholesterol/lipids biosynthesis, causing changes in cell lipid composition. Of note, the osmotic resistance, and the expression of 3-Hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the rate-limiting enzyme of the cholesterol biosynthesis pathway, were higher in dynamic cultures. Inhibition of the S1P-induced proteolytic cleavage, activating SREBPs, led to abrogation of HMCGR expression, and loss of EBL in dynamic cultures, similar to lovastatin administration. This data reveals a role for the S1P-SREBP-HMGCR-axis in the regulation of shear-stress induced adaptation during erythropoiesis, shedding light into mechanisms that will assist the upscaling of erythroid differentiation into bioreactors. Moreover, as shear-stress on hematopoietic cells occurs within the bone-marrow, these results introduce a novel signalling axis in the transduction pathways controlling erythropoiesis.
了解机械应力如何影响红细胞生成对于在流体湍流生物反应器中生产可用于输血的红细胞至关重要。我们在分子、细胞和功能水平上研究了剪切应力对分化中的CD49dCD235a原代人红细胞生成素（EBL）的影响。在分化开始时施加剪切应力可增强EBL成熟，并诱导调节胆固醇/脂质生物合成的基因上调，从而导致细胞脂质组成发生变化。值得注意的是，动态培养中的渗透压耐受性以及胆固醇生物合成途径的限速酶3-羟基-3-甲基戊二酰辅酶A还原酶（HMGCR）的表达更高。抑制鞘氨醇-1-磷酸（S1P）诱导的蛋白水解切割（激活固醇调节元件结合蛋白（SREBPs））会导致动态培养中HMCGR表达的消除和EBL的丧失，这与给予洛伐他汀的情况相似。这些数据揭示了S1P-SREBP-HMGCR轴在红细胞生成过程中调节剪切应力诱导的适应性方面的作用，为有助于将红细胞分化扩大到生物反应器中的机制提供了线索。此外，由于造血细胞上的剪切应力发生在骨髓内，这些结果在控制红细胞生成的转导途径中引入了一个新的信号轴。
