PCLAF-DREAM drives alveolar cell plasticity for lung regeneration

被引:4
作者
Kim, Bongjun [1 ]
Huang, Yuanjian [1 ]
Ko, Kyung-Pil [1 ]
Zhang, Shengzhe [1 ]
Zou, Gengyi [1 ]
Zhang, Jie [1 ]
Kim, Moon Jong [1 ]
Little, Danielle [2 ]
Ellis, Lisandra Vila [2 ]
Paschini, Margherita [3 ,4 ,5 ]
Jun, Sohee [1 ]
Park, Kwon-Sik [6 ]
Chen, Jichao [2 ]
Kim, Carla [3 ,4 ,5 ]
Park, Jae-Il [1 ,7 ,8 ]
机构
[1] Univ Texas MD Anderson Canc Ctr, Dept Expt Radiat Oncol, Div Radiat Oncol, Houston, TX 77030 USA
[2] Univ Texas MD Anderson Canc Ctr, Dept Pulm Med, Houston, TX 77030 USA
[3] Boston Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA
[4] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA
[5] Boston Childrens Hosp, Div Pulm Med, Boston, MA 02115 USA
[6] Univ Virginia, Dept Microbiol Immunol & Canc Biol, Charlottesville, VA 22908 USA
[7] Univ Texas MD Anderson Canc Ctr, Grad Sch Biomed Sci, Houston, TX 77030 USA
[8] Univ Texas MD Anderson Canc Ctr, Program Genet & Epigenet, Houston, TX 77030 USA
基金
美国国家卫生研究院;
关键词
TGF-BETA; PULMONARY-FIBROSIS; STEM-CELLS; I CELLS; COMPLEX; PROTEIN; PAF; DIFFERENTIATION; DISTINCT; TRANSCRIPTION;
D O I
10.1038/s41467-024-53330-1
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Cell plasticity, changes in cell fate, is crucial for tissue regeneration. In the lung, failure of regeneration leads to diseases, including fibrosis. However, the mechanisms governing alveolar cell plasticity during lung repair remain elusive. We previously showed that PCLAF remodels the DREAM complex, shifting the balance from cell quiescence towards cell proliferation. Here, we find that PCLAF expression is specific to proliferating lung progenitor cells, along with the DREAM target genes transactivated by lung injury. Genetic ablation of Pclaf impairs AT1 cell repopulation from AT2 cells, leading to lung fibrosis. Mechanistically, the PCLAF-DREAM complex transactivates CLIC4, triggering TGF-beta signaling activation, which promotes AT1 cell generation from AT2 cells. Furthermore, phenelzine that mimics the PCLAF-DREAM transcriptional signature increases AT2 cell plasticity, preventing lung fibrosis in organoids and mice. Our study reveals the unexpected role of the PCLAF-DREAM axis in promoting alveolar cell plasticity, beyond cell proliferation control, proposing a potential therapeutic avenue for lung fibrosis prevention. Cell plasticity, changes in cell fate, is involved in tissue regeneration. Here, Kim et al. show that PCLAF-DREAM-driven alveolar cell plasticity is crucial for lung regeneration and targetable as a preventative strategy for lung fibrosis.
引用
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页数:16
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