Yap/Taz regulate alveolar regeneration and resolution of lung inflammation

LaCanna, Ryan; Liccardo, Daniela; Zhang, Peggy; Tragesser, Lauren; Wang, Yan; Cao, T.; Chapman, Harold A.; Morrisey, Edward E.; Shen, Hao; Koch, Walter J.; Kośmider, Beata; Wolfson, Marla R.; Tian, Ying

doi:10.1172/jci125014

Cited by 218 publications

(256 citation statements)

References 59 publications

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“…Our results predict distinct transcriptional regulators as key switch points in terminal AT1 differentiation, including TAZ (Wwtr1), Sox4 and beta-catenin (Ctnnb1). The mechanistic importance of Wwtr1 (YAP/TAZ -Hippo pathway) in AT2 to AT1 transdifferentiation has recently been demonstrated by using small molecule inhibition and conditional knock-out in mouse lung organoids and in vivo injury experiments 17,64 , thus validating our prediction that this factor commits Krt8+ progenitors for AT1 cell fate. Moreover, an important role of beta-catenin and the canonical Wnt signaling pathways has been suggested based on in vitro differentiation of isolated AT2 cells 61 .…”

Section: Discussionsupporting

confidence: 77%

“…6g). We also observed pre-AT1 specific expression of the transcriptional coactivator TAZ (Wwtr1), which acts as a downstream regulatory target in the Hippo signaling pathway and was recently reported to be critical for AT2 cell differentiation during alveolar regeneration 17 . Also, the expression of the key downstream component of the canonical Wnt signaling pathway beta-catenin (Ctnnb1) transiently peaked in the pre-AT1 stage.…”

Section: Krt8+ Cells Are Alveolar Progenitors That Reconstitute the Amentioning

confidence: 68%

“…Recent evidence points towards the critical importance of inflammation-induced NFkappaB activation to drive AT2 cells into the cell cycle for alveolar regeneration 16 . However, the negative regulation of the NFkappaB pathway mediated by Yap/Taz in AT2 cells was also shown to be key for successful alveolar regeneration 17 . Moreover, the TGF-beta pathway has been proposed to mediate cell cycle arrest in AT2 cells followed by transdifferentiation into AT1 cells 18 .…”

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confidence: 99%

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Longitudinal single cell transcriptomics reveals Krt8+ alveolar epithelial progenitors in lung regeneration

Strunz

Ansari

et al. 2019

Preprint

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Lung disease is a major health burden accounting for one in six deaths globally 1 . The lung's large surface area is exposed to a great variety of environmental and microbial insults causing injuries to its epithelium that require a regenerative response mediated by tissue-resident stem and progenitor Lung injury activates quiescent stem and progenitor cells to regenerate alveolar structures. The sequence and coordination of transcriptional programs during this process has largely remained elusive. Using single cell RNA-seq, we first generated a whole-organ bird's-eye view on cellular dynamics and cell-cell communication networks during mouse lung regeneration from ~30,000 cells at six timepoints. We discovered an injury-specific progenitor cell state characterized by Krt8 in flat epithelial cells covering alveolar surfaces. The number of these cells peaked during fibrogenesis in independent mouse models, as well as in human acute lung injury and fibrosis. Krt8+ progenitors featured a highly distinct connectome of receptor-ligand pairs with endothelial cells, fibroblasts, and macrophages. To 'sky dive' into epithelial differentiation dynamics, we sequenced >30,000 sorted epithelial cells at 18 timepoints and computationally derived cell state trajectories that were validated by lineage tracing genetic reporter mice. Airway stem cells within the club cell lineage and alveolar type-2 cells underwent transcriptional convergence onto the same Krt8+ progenitor cell state, which later resolved by terminal differentiation into alveolar type-1 cells. We derived distinct transcriptional regulators as key switch points in this process and show that induction of TNF-alpha/NFkappaB, p53, and hypoxia driven gene expression programs precede a Sox4, Ctnnb1, and Wwtr1 driven switch towards alveolar type-1 cell fate. We show that epithelial cell plasticity can induce non-gradual transdifferentiation, involving intermediate progenitor cell states that may persist and promote disease if checkpoint signals for terminal differentiation are perturbed.

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Section: Discussionsupporting

confidence: 77%

Section: Krt8+ Cells Are Alveolar Progenitors That Reconstitute the Amentioning

confidence: 68%

mentioning

confidence: 99%

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Longitudinal single cell transcriptomics reveals Krt8+ alveolar epithelial progenitors in lung regeneration

Strunz

Ansari

et al. 2019

Preprint

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“…Similarly, Yap/Taz are induced and nuclear localized following skin wounding and skin‐specific K5‐CreERt induced double knockouts (dKO) of yap flox/flox and taz flox/flox had minor effects on normal adult skin proliferation, while strongly impairing cell proliferation during skin wound healing [ 31 ] ( Figure 4 ). Tissue‐specific yap flox/flox taz flox/flox dKO with a variety of different Cre‐driver lines also reveals key regenerative functions in mouse heart, [ 32,33 ] liver, [ 34 ] kidney, [ 35 ] and lung [ 36 ] as well as in angiogenesis. [ 37–39 ] These physiological functions in wound healing and regeneration may explain the widespread activation of YAP/TAZ in human tumors, in accordance with Virchow's tissue damage and inflammation theory of cancer.…”

Section: Introductionmentioning

confidence: 99%

“…Lung ADC is thought to arise primarily from type II alveolar epithelial cells, [ 52–54 ] where YAP/TAZ has roles in pulmonary regeneration. [ 36,55 ] In mice, AdenoCre‐mediated conditional yap flox/flox homozygous knockout reduced primary tumor growth driven by Cre‐inducible LSL K‐Ras G12D and LKB1 flox/flox . [ 56 ] Silencing of yap by lentiviral shRNA knockdown in primary mouse lung ADC cells isolated from K‐Ras G12D , LKB ‐/‐ mice was sufficient to impair tumor cell proliferation in vitro by half and also reduce tumor growth by around half following xenografting into mice.…”

Section: Introductionmentioning

confidence: 99%

YAP/TAZ: Drivers of Tumor Growth, Metastasis, and Resistance to Therapy

2020

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The transcriptional co-activators YAP (or YAP1) and TAZ (or WWTR1) are frequently activated during the growth and progression of many solid tumors, including lung, colorectal, breast, pancreatic, and liver carcinomas as well as melanoma and glioma. YAP/TAZ bind to TEAD-family co-activators to drive cancer cell survival, proliferation, invasive migration, and metastasis. YAP/TAZ activation may also confer resistance to chemotherapy, radiotherapy, or immunotherapy. YAP-TEAD cooperates with the RAS-induced AP-1 (FOS/JUN) transcription factor to drive tumor growth and cooperates with MRTF-SRF to promote activation of cancer-associated fibroblasts, matrix stiffening, and metastasis. The key upstream repressor of YAP/TAZ activation is the Hippo (MST1/2-LATS1/2) pathway and the key upstream activators are mechanically induced Integrin-SRC and E-cadherin-AJUBA/TRIP6/LIMD1, growth factor induced PI3K-AKT, and inflammation-induced G-protein coupled receptor (GPCR) signals, all of which antagonize the Hippo pathway. In this review, strategies to target YAP/TAZ activity in cancer are discussed along with the prospects for synergy with established pillars of cancer therapy.

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Blood flow‐induced angiocrine signals promote organ growth and regeneration

Follert,

Große‐Segerath,

Lammert

2024

BioEssays

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Recently, we identified myeloid‐derived growth factor (MYDGF) as a blood flow‐induced angiocrine signal that promotes human and mouse hepatocyte proliferation and survival. Here, we review literature reporting changes in blood flow after partial organ resection in the liver, lung, and kidney, and we describe the angiocrine signals released by endothelial cells (ECs) upon blood flow alterations in these organs. While hepatocyte growth factor (HGF) and MYDGF are important angiocrine signals for liver regeneration, by now, angiocrine signals have also been reported to stimulate hyperplasia and/or hypertrophy during the regeneration of lungs and kidneys. In addition, angiocrine signals play a critical role in tumor growth. Understanding the mechano‐elastic properties and flow‐mediated alterations in the organ‐specific microvasculature is crucial for therapeutic approaches to maintain organ health and initiate organ renewal.

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Yap/Taz regulate alveolar regeneration and resolution of lung inflammation

Cited by 218 publications

References 59 publications

Longitudinal single cell transcriptomics reveals Krt8+ alveolar epithelial progenitors in lung regeneration

Longitudinal single cell transcriptomics reveals Krt8+ alveolar epithelial progenitors in lung regeneration

YAP/TAZ: Drivers of Tumor Growth, Metastasis, and Resistance to Therapy

Blood flow‐induced angiocrine signals promote organ growth and regeneration

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