Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, 720 Westview Dr, Atlanta, GA, 30310, USA.
Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Drive, Atlanta, GA, 30332, USA.
Sci Rep. 2019 Dec 16;9(1):19162. doi: 10.1038/s41598-019-55631-8.
Human cerebral malaria (HCM), a severe encephalopathy associated with Plasmodium falciparum infection, has a 20-30% mortality rate and predominantly affects African children. The mechanisms mediating HCM-associated brain injury are difficult to study in human subjects, highlighting the urgent need for non-invasive ex vivo human models. HCM elevates the systemic levels of free heme, which damages the blood-brain barrier and neurons in distinct regions of the brain. We determined the effects of heme on induced pluripotent stem cells (iPSCs) and a three-dimensional cortical organoid system and assessed apoptosis and differentiation. We evaluated biomarkers associated with heme-induced brain injury, including a pro-inflammatory chemokine, CXCL-10, and its receptor, CXCR3, brain-derived neurotrophic factor (BDNF) and a receptor tyrosine-protein kinase, ERBB4, in the organoids. We then tested the neuroprotective effect of neuregulin-1 (NRG-1) against heme treatment in organoids. Neural stem and mature cells differentially expressed CXCL-10, CXCR3, BDNF and ERBB4 in the developing organoids and in response to heme-induced neuronal injury. The organoids underwent apoptosis and structural changes that were attenuated by NRG-1. Thus, cortical organoids can be used to model heme-induced cortical brain injury associated with HCM pathogenesis as well as for testing agents that reduce brain injury and neurological sequelae.
人类脑疟疾（HCM）是一种与恶性疟原虫感染相关的严重脑病，死亡率为 20-30%，主要影响非洲儿童。由于难以在人类受试者中研究介导 HCM 相关脑损伤的机制，因此迫切需要非侵入性的离体人类模型。HCM 会升高游离血红素的系统水平，从而损害血脑屏障和大脑中不同区域的神经元。我们确定了血红素对诱导多能干细胞（iPSC）和三维皮质类器官系统的影响，并评估了细胞凋亡和分化。我们评估了与血红素诱导的脑损伤相关的生物标志物，包括趋化因子 CXCL-10 及其受体 CXCR3、脑源性神经营养因子（BDNF）和受体酪氨酸蛋白激酶 ERBB4，在类器官中。然后，我们测试了神经调节蛋白 1（NRG-1）对类器官中血红素处理的神经保护作用。神经干细胞和成熟细胞在发育中的类器官中以及对血红素诱导的神经元损伤的反应中差异表达 CXCL-10、CXCR3、BDNF 和 ERBB4。类器官发生细胞凋亡和结构变化，NRG-1 可减轻这些变化。因此，皮质类器官可用于模拟与 HCM 发病机制相关的血红素诱导的皮质脑损伤，以及测试可减少脑损伤和神经后遗症的药物。
