Inhibition of nuclear factor (erythroid-derived 2)-like 2 promotes hepatic progenitor cell activation and differentiation.
Inhibition of nuclear factor (erythroid-derived 2)-like 2 promotes hepatic progenitor cell activation and differentiation.
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DOI：
10.1038/s41536-021-00137-z
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发表时间：
2021-05-26
影响因子：
7.2
通讯作者：
Serviddio G
中科院分区：
文献类型：
--
作者：
Bellanti F;di Bello G;Iannelli G;Pannone G;Pedicillo MC;Boulter L;Lu WY;Tamborra R;Villani R;Vendemiale G;Forbes SJ;Serviddio G
干细胞自我更新和引导再生的能力依赖于其微环境中复杂信号的平衡。肝祖细胞(HPC)激活调节因子的识别是肝脏再生的决定性因素，并可能改善终末期肝病的细胞移植治疗。这项研究使用了不同的模型来指出核因子(红系衍生的2)样2(NRF2)是HPC命运的关键调节因子。我们初步证实在体内的胆管上皮细胞(BECs)/HPC激活模型存在肝脏氧化应激，在体外激活原代BECs/HPC。NRF2的下调和沉默与分化细胞特有的形态、表型和功能改变有关。此外，胆道中NRF2的激活抑制了受损肝脏的胆管反应。为了明确评估NRF2在HPC生物学中的重要性，我们应用了一种异种移植模型，通过抑制人源性HepaRG细胞中的NRF2，并将其移植到给予抗Fas抗体的SCID/beige小鼠体内，以诱导肝细胞凋亡；这导致了有效的人类肝细胞再生，减少了肝脏损伤。综上所述，抑制NRF2导致肝脏祖细胞的激活和分化。这种氧化还原依赖的转录因子代表了一个潜在的靶点，以调节未分化的肝脏前体细胞对特定谱系的承诺。
The stem cell ability to self-renew and lead regeneration relies on the balance of complex signals in their microenvironment. The identification of modulators of hepatic progenitor cell (HPC) activation is determinant for liver regeneration and may improve cell transplantation for end-stage liver disease. This investigation used different models to point out the Nuclear factor (erythroid-derived 2)-like 2 (NRF2) as a key regulator of the HPC fate. We initially proved that in vivo models of biliary epithelial cells (BECs)/HPC activation show hepatic oxidative stress, which activates primary BECs/HPCs in vitro. NRF2 downregulation and silencing were associated with morphological, phenotypic, and functional modifications distinctive of differentiated cells. Furthermore, NRF2 activation in the biliary tract repressed the ductular reaction in injured liver. To definitely assess the importance of NRF2 in HPC biology, we applied a xenograft model by inhibiting NRF2 in the human derived HepaRG cell line and transplanting into SCID/beige mice administered with anti-Fas antibody to induce hepatocellular apoptosis; this resulted in effective human hepatocyte repopulation with reduced liver injury. To conclude, NRF2 inhibition leads to the activation and differentiation of liver progenitors. This redox-dependent transcription factor represents a potential target to regulate the commitment of undifferentiated hepatic progenitors into specific lineages.
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DOI：
10.1152/ajpgi.00069.2014
发表时间：
2015-02-15
期刊：
American journal of physiology. Gastrointestinal and liver physiology
影响因子：
--
作者：
Dollé L;Theise ND;Schmelzer E;Boulter L;Gires O;van Grunsven LA
通讯作者：
van Grunsven LA
DOI：
10.1152/ajpgi.00420.2014
发表时间：
2015-04-01
期刊：
American journal of physiology. Gastrointestinal and liver physiology
影响因子：
--
作者：
Dollé L;Boulter L;Leclercq IA;van Grunsven LA
通讯作者：
van Grunsven LA
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
4.3
作者：
Ezzat, Tarek;Dhar, Dipok Kumar;Dannink, Steven W. M. Olde
通讯作者：
Dannink, Steven W. M. Olde
影响因子：
8.8
作者：
Hawkins KE;Joy S;Delhove JM;Kotiadis VN;Fernandez E;Fitzpatrick LM;Whiteford JR;King PJ;Bolanos JP;Duchen MR;Waddington SN;McKay TR
通讯作者：
McKay TR