UM171 induces a homeostatic inflammatory-detoxification response supporting human HSC self-renewal
UM171 induces a homeostatic inflammatory-detoxification response supporting human HSC self-renewal
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DOI：
10.1371/journal.pone.0224900
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发表时间：
2019-11-08
期刊：
影响因子：
3.7
通讯作者：
Sauvageau, Guy
中科院分区：
文献类型：
--
作者：
Chagraoui, Jalila;Lehnertz, Bernhard;Sauvageau, Guy
阐明平衡成体干细胞自我更新和分化所需的分子线索对于推进细胞疗法至关重要。在此，我们报道造血干细胞（HSC）自我更新激动剂UM171触发平衡的促炎/抗炎/解毒网络，该网络分别依赖于NFκB激活和蛋白C受体依赖性ROS解毒。我们证明，在这个网络中，EPCR 作为一个关键的保护成分，因为它的缺失使原始造血细胞对促炎信号和 ROS 积累过度敏感，从而导致干细胞功能受损。相反，通过地塞米松、cAMP 升高剂或 NFkB 抑制剂治疗消除 UM171 的促炎活性，从而消除 EPCR 上调和 HSC 扩增。总之，这些结果表明 UM171 通过在自我更新的关键促炎介质和抗炎介质之间建立关键平衡来刺激离体 HSC 扩增。
Elucidation of the molecular cues required to balance adult stem cell self-renewal and differentiation is critical for advancing cellular therapies. Herein, we report that the hematopoietic stem cell (HSC) self-renewal agonist UM171 triggers a balanced pro- and anti-inflammatory/detoxification network that relies on NFKB activation and protein C receptor-dependent ROS detoxification, respectively. We demonstrate that within this network, EPCR serves as a critical protective component as its deletion hypersensitizes primitive hematopoietic cells to pro-inflammatory signals and ROS accumulation resulting in compromised stem cell function. Conversely, abrogation of the pro-inflammatory activity of UM171 through treatment with dexamethasone, cAMP elevating agents or NFkB inhibitors abolishes EPCR upregulation and HSC expansion. Together, these results show that UM171 stimulates ex vivo HSC expansion by establishing a critical balance between key pro- and anti-inflammatory mediators of self-renewal.