Scientists successfully demonstrate that fine-tuning of cholesterol homeostasis emerges as a key mechanism for regulating erythropoiesis, according to a Shandong University study published in Advanced Science.

Mammalian erythropoiesis starts with the commitment of hematopoietic stem cells to erythroid progenitors. This is followed by terminal differentiation to give rise to mature red blood cells. Abnormal erythrocyte development leads to many diseases, including thalassemia, sickle cell anemia, Diamond-Blackfan anemia and polycythemia, according to the corresponding author Zhao Baobing, professor from the School of Pharmaceutical Sciences. PhD candidates Lu Zhiyuan and Huang Lixia are the first authors.

Throughout terminal erythropoiesis, erythroblasts undergo fast cell divisions, cell size decrease, nuclei breakdown and histones releasing, and these events lead to cell cycle exit and nuclear polarization, all required for the final expulsion of the pyknotic nucleus. Although multiple molecular and signaling pathways have been revealed to be involved in these processes, the mechanisms that drive successful maturation and enucleation remain largely undefined, Prof. Zhao said.

Cholesterol, an essential lipid that localizes predominantly to cell membranes, plays an important role in a diverse array of physiological functions, not only as an important structural component of cell membranes but also as a precursor of steroid hormones and bile acids. "Given that quick cell proliferation of erythroblasts requires cholesterol as building block to support their growth, it’s not unreasonable to expect that cholesterol metabolism would play an important role in terminal erythropoiesis". Prof. Zhao and his collaborator Prof. Li Jian said, both of them are the Qilu Young Scholars of Shandong University. "Multiple lines of evidence support this hypothesis. However, the mechanism by which cholesterol regulates terminal erythropoiesis still remains largely unknown." Prof. Zhao said, who is also the leader of the Multidisciplinary Research and Innovation Team of Young Scholars of Shandong University.

These findings uncovered a critical role for cholesterol homeostasis in terminal erythropoiesis. "Our study may provide clues for the pathogenesis of erythroid related diseases of unknown etiology", Prof. Zhao said. "This is especially relevant in patients with high-erythropoietic activity anemia and myelodysplastic syndromes in which a failure of cell cycle exit is one of the key features of dyserythropoiesis".Prof. Zhao and his collaborators monitored the dynamics of the intracellular cholesterol levels during terminal erythropoiesis. They found that the master transcriptional factor GATA1 binds to Sterol-regulatory element binding protein 2 (SREBP2) to downregulate cholesterol biosynthesis, leading to a gradual reduction in intracellular cholesterol levels. The reduced cholesterol functions to block erythroid proliferation via the cholesterol/mTORC1/ribosome biogenesis axis, which coordinates cell cycle exit in the late stages of erythroid differentiation. "The interaction of GATA1 and SREBP2 also provides a feedback loop for regulating globin expression through the transcriptional control of NFE2 by SREBP2", Prof. Zhao said."Importantly, we show that disrupting intracellular cholesterol hemostasis resulted in a defect of terminal erythroid differentiation in vivo."

This work was supported by grants from the National Natural Science Foundation of China (81874294), Young Taishan Scholars Program (TSQN201812015), Shandong Natural Science Fund (21510005202107), Qilu Young Scholars Program (B.Z. and J.L.), Multidisciplinary Research and Innovation Team of Young Scholars (2020QNQT007), Rongxiang Regenerative Medicine Foundation (2019SDRX-04) of Shandong University. This work was also supported by the program for Innovative Research Team in University of Ministry of Education of China (IRT_17R68).

Prof. Zhao's lab is interested in the discovery of leading compounds and drug targets. The lab studies the molecular mechanism of normal hematopoiesis and pathogenesis of blood disorders, including red blood cell development and hematopoietic stem cell self-renewal towards exploring potential drug targets. Recently, some of these works have been published in J Clin Invest, Dev Cell, Blood, Leukemia and Haematologica etc.

More information: Zhiyuan Lu et al. Fine-tuning of cholesterol homeostasis controls erythroid differentiation, Advanced Science(2021).https://onlinelibrary.wiley.com/doi/epdf/10.1002/advs.202102669