Stem Cell Reviews and Reports ( IF 4.8 ) Pub Date : 2020-07-20 , DOI: 10.1007/s12015-020-10010-z Mariusz Z Ratajczak 1, 2 , Kamila Bujko 1 , Andrzej Ciechanowicz 2 , Kasia Sielatycka 3, 4 , Monika Cymer 2 , Wojciech Marlicz 4 , Magda Kucia 1, 2
Angiotensin-converting enzyme 2 (ACE2) plays an important role as a member of the renin–angiotensin–aldosterone system (RAAS) in regulating the conversion of angiotensin II (Ang II) into angiotensin (1–7) (Ang [1–7]). But at the same time, while expressed on the surface of human cells, ACE2 is the entry receptor for SARS-CoV-2. Expression of this receptor has been described in several types of cells, including hematopoietic stem cells (HSCs) and endothelial progenitor cells (EPCs), which raises a concern that the virus may infect and damage the stem cell compartment. We demonstrate for the first time that ACE2 and the entry-facilitating transmembrane protease TMPRSS2 are expressed on very small CD133+CD34+Lin−CD45− cells in human umbilical cord blood (UCB), which can be specified into functional HSCs and EPCs. The existence of these cells known as very small embryonic-like stem cells (VSELs) has been confirmed by several laboratories, and some of them may correspond to putative postnatal hemangioblasts. Moreover, we demonstrate for the first time that, in human VSELs and HSCs, the interaction of the ACE2 receptor with the SARS-CoV-2 spike protein activates the Nlrp3 inflammasome, which if hyperactivated may lead to cell death by pyroptosis. Based on this finding, there is a possibility that human VSELs residing in adult tissues could be damaged by SARS-CoV-2, with remote effects on tissue/organ regeneration. We also report that ACE2 is expressed on the surface of murine bone marrow-derived VSELs and HSCs, although it is known that murine cells are not infected by SARS-CoV-2. Finally, human and murine VSELs express several RAAS genes, which sheds new light on the role of these genes in the specification of early-development stem cells.
中文翻译:
SARS-CoV-2 进入受体 ACE2 在非常小的 CD45-造血细胞和内皮细胞前体上表达,并响应病毒尖峰蛋白激活 Nlrp3 炎症小体。
血管紧张素转换酶 2 (ACE2) 作为肾素-血管紧张素-醛固酮系统 (RAAS) 的成员,在调节血管紧张素 II (Ang II) 向血管紧张素 (1-7) (Ang [1-7 ])。但与此同时,ACE2 在人体细胞表面表达时,是 SARS-CoV-2 的进入受体。这种受体的表达已在几种类型的细胞中得到描述,包括造血干细胞 (HSC) 和内皮祖细胞 (EPC),这引起了人们对病毒可能感染和破坏干细胞区室的担忧。我们首次证明 ACE2 和促进进入的跨膜蛋白酶 TMPRSS2 在非常小的 CD133 + CD34 + Lin − CD45 − 上表达人脐带血 (UCB) 中的细胞,可指定为功能性 HSC 和 EPC。这些被称为非常小的胚胎样干细胞 (VSEL) 的细胞的存在已被多个实验室证实,其中一些可能对应于推定的出生后成血管细胞。此外,我们首次证明,在人类 VSEL 和 HSC 中,ACE2 受体与 SARS-CoV-2 刺突蛋白的相互作用会激活 Nlrp3 炎性体,如果过度激活,可能会导致细胞焦亡。基于这一发现,存在于成人组织中的人类 VSEL 有可能被 SARS-CoV-2 损坏,并对组织/器官再生产生远程影响。我们还报告说 ACE2 在鼠骨髓来源的 VSEL 和 HSC 的表面表达,尽管已知鼠细胞不会被 SARS-CoV-2 感染。最后,人和鼠的 VSEL 表达了几个 RAAS 基因,这为这些基因在早期发育干细胞规范中的作用提供了新的线索。