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Manipulating niche composition limits damage to haematopoietic stem cells during Plasmodium infection
Nature Cell Biology ( IF 21.3 ) Pub Date : 2020-11-23 , DOI: 10.1038/s41556-020-00601-w
Myriam L R Haltalli 1, 2, 3, 4 , Samuel Watcham 3, 4 , Nicola K Wilson 3, 4 , Kira Eilers 1 , Alexander Lipien 1 , Heather Ang 1 , Flora Birch 1, 2 , Sara Gonzalez Anton 1, 2 , Chiara Pirillo 1, 2 , Nicola Ruivo 1 , Maria L Vainieri 1, 5 , Constandina Pospori 1, 2 , Robert E Sinden 1 , Tiago C Luis 1 , Jean Langhorne 2 , Ken R Duffy 6 , Berthold Göttgens 3, 4 , Andrew M Blagborough 7 , Cristina Lo Celso 1, 2
Affiliation  

Severe infections are a major stress on haematopoiesis, where the consequences for haematopoietic stem cells (HSCs) have only recently started to emerge. HSC function critically depends on the integrity of complex bone marrow (BM) niches; however, what role the BM microenvironment plays in mediating the effects of infection on HSCs remains an open question. Here, using a murine model of malaria and combining single-cell RNA sequencing, mathematical modelling, transplantation assays and intravital microscopy, we show that haematopoiesis is reprogrammed upon infection, whereby the HSC compartment turns over substantially faster than at steady-state and HSC function is drastically affected. Interferon is found to affect both haematopoietic and mesenchymal BM cells and we specifically identify a dramatic loss of osteoblasts and alterations in endothelial cell function. Osteo-active parathyroid hormone treatment abolishes infection-triggered HSC proliferation and—coupled with reactive oxygen species quenching—enables partial rescuing of HSC function.



中文翻译:

操纵生态位组成可限制疟原虫感染期间对造血干细胞的损害

严重感染是造血功能的主要压力,造血干细胞 (HSC) 的后果最近才开始出现。HSC 功能严重依赖于复杂骨髓 (BM) 壁龛的完整性;然而,BM 微环境在介导感染对 HSC 的影响中起什么作用仍然是一个悬而未决的问题。在这里,使用疟疾的鼠模型并结合单细胞 RNA 测序、数学建模、移植测定和活体显微镜,我们表明造血功能在感染后被重新编程,由此 HSC 隔室的周转速度明显快于稳态和 HSC 功能受到严重影响。发现干扰素影响造血和间充质 BM 细胞,我们特别确定了成骨细胞的显着丧失和内皮细胞功能的改变。骨活性甲状旁腺激素治疗消除了感染引发的 HSC 增殖,并且与活性氧物质淬灭相结合,能够部分挽救 HSC 功能。

更新日期:2020-11-23
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