D'Souza Leonard Clinton, Kuriakose Nithin, Raghu Shamprasad Varija, Kabekkodu Shama Prasada, Sharma Anurag
Nitte (Deemed to be University), Nitte University Centre for Science Education and Research (NUCSER), Division of Environmental Health and Toxicology, Kotekar-Beeri Road, Deralakatte, Mangaluru, 575018, India.
Nitte (Deemed to be University), Nitte University Centre for Science Education and Research (NUCSER), Division of Environmental Health and Toxicology, Kotekar-Beeri Road, Deralakatte, Mangaluru, 575018, India; Nitte (Deemed to be University), Nitte University Centre for Science Education and Research (NUCSER), Division of Proteomics and Cancer Biology, Kotekar-Beeri Road, Deralakatte, Mangaluru, 575018, India.
Free Radic Biol Med. 2022 Nov 20;193(Pt 1):190-201. doi: 10.1016/j.freeradbiomed.2022.10.002. Epub 2022 Oct 7.
Hematopoietic stem cells/progenitor cells (HSC/HPCs) orchestrate the hematopoietic process, effectively regulated by the hematopoietic niche under normal and stressed conditions. The hematopoietic niche provides various soluble factors which influence the differentiation and self-renewal of HSC/HSPs. Unceasing differentiation/proliferation/high metabolic activity of HSC/HPCs makes them susceptible to damage by environmental toxicants like benzene. Oxidative stress, epigenetic modifications, and DNA damage in the HSC/HPCs are the key factors of benzene-induced hematopoietic injury. However, the role of the hematopoietic niche in benzene-induced hematopoietic injury/response is still void. Therefore, the current study aims to unravel the role of the hematopoietic niche in benzene-induced hematotoxicity using a genetically tractable model, Drosophila melanogaster. The lymph gland is a dedicated hematopoietic organ in Drosophila larvae. A group of 30-45 cells called the posterior signaling center (PSC) in the lymph gland acts as a niche that regulates Drosophila HSC/HPCs maintenance. Benzene exposure to Drosophila larvae (48 h) resulted in aberrant hemocyte production, especially hyper-differentiation of lamellocytes followed by premature lymph gland dispersal and reduced adult emergence upon developmental exposure. Subsequent genetic experiments revealed that benzene-induced lamellocyte production and premature lymph gland dispersal were PSC mediated. The genetic experiments further showed that benzene generates Dual oxidase (Duox)-dependent Reactive Oxygen Species (ROS) in the PSC, activating Toll/NF-κB signaling, which is essential for the aberrant hemocyte production, lymph gland dispersal, and larval survival. Together, the study establishes a functional perspective of the hematopoietic niche in a benzene-induced hematopoietic emergency in a genetic model, Drosophila, which might be relevant to higher organisms.
造血干细胞/祖细胞（HSC/HPCs）协调造血过程，在正常和应激条件下受造血微环境有效调控。造血微环境提供多种可溶性因子，影响HSC/HSPs的分化和自我更新。HSC/HPCs持续的分化/增殖/高代谢活性使其易受苯等环境毒物的损伤。HSC/HPCs中的氧化应激、表观遗传修饰和DNA损伤是苯诱导造血损伤的关键因素。然而，造血微环境在苯诱导的造血损伤/反应中的作用仍不明确。因此，本研究旨在利用一种易于遗传操作的模型——黑腹果蝇，揭示造血微环境在苯诱导的血液毒性中的作用。淋巴腺是果蝇幼虫中专门的造血器官。淋巴腺中一组30 - 45个细胞组成的后信号中心（PSC）作为调节果蝇HSC/HPCs维持的微环境。将果蝇幼虫暴露于苯（48小时）会导致血细胞生成异常，尤其是片状细胞过度分化，随后淋巴腺过早分散，发育暴露后成虫羽化率降低。随后的遗传实验表明，苯诱导的片状细胞生成和淋巴腺过早分散是由PSC介导的。遗传实验进一步表明，苯在PSC中产生双氧化酶（Duox）依赖性活性氧（ROS），激活Toll/NF-κB信号通路，这对于异常血细胞生成、淋巴腺分散和幼虫存活至关重要。总之，该研究在遗传模型果蝇中建立了造血微环境在苯诱导的造血紧急情况中的功能观点，这可能与高等生物相关。
