Development of an improved inhibitor of Lats kinases to promote regeneration of mammalian organs DOI Creative Commons
Nathaniel R. Kastan,

Sanyukta Oak,

Rui Liang

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2022, Volume and Issue: 119(28)

Published: July 8, 2022

The Hippo signaling pathway acts as a brake on regeneration in many tissues. This cascade of kinases culminates the phosphorylation transcriptional cofactors Yap and Taz, whose concentration nucleus consequently remains low. Various types cellular signals can reduce phosphorylation, however, resulting accumulation Taz subsequently mitosis. We earlier identified small molecule, TRULI, that blocks final pathway, Lats1 Lats2, thus elicits proliferation several cell are ordinarily postmitotic aids mammals. In present study, we results chemical modification original compound demonstrate derivative, TDI-011536, is an effective blocker Lats vitro at nanomolar concentrations. fosters extensive retinal organoids derived from human induced pluripotent stem cells. Intraperitoneal administration substance to mice suppresses for hours induces activation target genes heart, liver, skin. Moreover, initiates cardiomyocytes adult following cardiac cryolesions. After further refinement, related compounds might prove useful protective regenerative therapies.

Language: Английский

The Hippo signalling pathway and its implications in human health and diseases DOI Creative Commons

Minyang Fu,

Yuan Hu,

Tianxia Lan

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Nov. 8, 2022

Abstract As an evolutionarily conserved signalling network, the Hippo pathway plays a crucial role in regulation of numerous biological processes. Thus, substantial efforts have been made to understand upstream signals that influence activity pathway, as well its physiological functions, such cell proliferation and differentiation, organ growth, embryogenesis, tissue regeneration/wound healing. However, dysregulation can cause variety diseases, including cancer, eye cardiac pulmonary renal hepatic immune dysfunction. Therefore, therapeutic strategies target dysregulated components might be promising approaches for treatment wide spectrum diseases. Here, we review key critical functions controlled by pathway. Additionally, diseases associated with alterations potential therapies targeting will discussed.

Language: Английский

Citations

335
Mechanical regulation of chromatin and transcription DOI
Sirio Dupont, Sara A. Wickström

Nature Reviews Genetics, Journal Year: 2022, Volume and Issue: 23(10), P. 624 - 643

Published: May 23, 2022

Language: Английский

Citations

147
Multiscale light-sheet organoid imaging framework DOI Creative Commons
Gustavo de Medeiros, Raphaël Ortiz, Petr Strnad

et al.

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Aug. 18, 2022

Organoids provide an accessible in vitro system to mimic the dynamics of tissue regeneration and development. However, long-term live-imaging organoids remains challenging. Here we present experimental image-processing framework capable turning light-sheet imaging intestinal into digital organoids. The combines specific optimization combined with data processing via deep learning techniques segment single organoids, their lumen, cells nuclei 3D over long periods time. By linking lineage trees corresponding segmentation meshes for each organoid, extracted information is visualized using a web-based "Digital Organoid Viewer" tool allowing understanding multivariate multiscale data. We also show backtracking interest, providing detailed about history within entire organoid contexts. Furthermore, cytokinesis failure regenerative that these never reside crypt, hinting at scale control on cellular fidelity.

Language: Английский

Citations

76
Control of stem cell renewal and fate by YAP and TAZ DOI
Jordan H. Driskill, Duojia Pan

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 24(12), P. 895 - 911

Published: Aug. 25, 2023

Language: Английский

Citations

72
The Hippo signaling pathway in development and regeneration DOI Creative Commons
Zhenxing Zhong, Zhihan Jiao, Fa‐Xing Yu

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(3), P. 113926 - 113926

Published: March 1, 2024

The Hippo signaling pathway is a central growth control mechanism in multicellular organisms. By integrating diverse mechanical, biochemical, and stress cues, the orchestrates proliferation, survival, differentiation, mechanics of cells, which turn regulate organ development, homeostasis, regeneration. A deep understanding regulation function therefore holds great promise for developing novel therapeutics regenerative medicine. Here, we provide updates on molecular organization mammalian network, review regulatory signals functional outputs pathway, discuss roles development

Language: Английский

Citations

54
Large-scale production of human blastoids amenable to modeling blastocyst development and maternal-fetal cross talk DOI Creative Commons

Leqian Yu,

Deirdre M. Logsdon,

Carlos A. Pinzón-Arteaga

et al.

Cell stem cell, Journal Year: 2023, Volume and Issue: 30(9), P. 1246 - 1261.e9

Published: Sept. 1, 2023

Recent advances in human blastoids have opened new avenues for modeling early development and implantation. One limitation of our first protocol blastoid generation was relatively low efficiency. We now report an optimized the efficient large quantities high-fidelity from naive pluripotent stem cells. This enabled proteomics analysis that identified phosphosite-specific signatures potentially involved derivation and/or maintenance signaling states blastoids. Additionally, we uncovered endometrial stromal effects promoting trophoblast cell survival, proliferation, syncytialization during co-culture with blastocysts. Side-by-side single-cell RNA sequencing revealed similarities differences transcriptome profiles between pre-implantation blastocysts, as well post-implantation cultures, a population resembling migratory trophoblasts Our will facilitate broader use accessible, perturbable, scalable, tractable model

Language: Английский

Citations

52
Generation of human alveolar epithelial type I cells from pluripotent stem cells DOI Creative Commons
Claire L. Burgess, Jessie Huang, Pushpinder Bawa

et al.

Cell stem cell, Journal Year: 2024, Volume and Issue: 31(5), P. 657 - 675.e8

Published: April 19, 2024

Alveolar epithelial type I cells (AT1s) line the gas exchange barrier of distal lung and have been historically challenging to isolate or maintain in cell culture. Here, we engineer a human vitro AT1 model system via directed differentiation induced pluripotent stem (iPSCs). We use primary adult global transcriptomes suggest benchmarks pathways, such as Hippo-LATS-YAP/TAZ signaling, enriched these cells. Next, generate iPSC-derived alveolar II (AT2s) find that nuclear YAP signaling is sufficient promote broad transcriptomic shift from AT2 gene programs. The resulting express molecular, morphologic, functional phenotype reminiscent cells, including capacity form flat producing characteristic extracellular matrix molecules secreted ligands. Our results provide an potential source AT1s.

Language: Английский

Citations

30
Systems-based identification of the Hippo pathway for promoting fibrotic mesenchymal differentiation in systemic sclerosis DOI Creative Commons
Feiyang Ma, Pei‐Suen Tsou, Mehrnaz Gharaee‐Kermani

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 3, 2024

Abstract Systemic sclerosis (SSc) is a devastating autoimmune disease characterized by excessive production and accumulation of extracellular matrix, leading to fibrosis skin other internal organs. However, the main cellular participants in SSc remain incompletely understood. Here using differentiation trajectories at single cell level, we demonstrate dual source matrix deposition from both myofibroblasts endothelial-to-mesenchymal-transitioning cells (EndoMT). We further define central role Hippo pathway effectors homeostasis myofibroblast EndoMT, respectively, show that EndoMTs function as communication hubs drive key pro-fibrotic signaling pathways SSc. Together, our data help characterize EndoMT phenotypes skin, hint modulation may contribute reversing EndoMTs.

Language: Английский

Citations

22
The Hippo Pathway Effectors YAP/TAZ-TEAD Oncoproteins as Emerging Therapeutic Targets in the Tumor Microenvironment DOI Open Access

Reza Bayat Mokhtari,

Neda Ashayeri,

Leili Baghaie

et al.

Cancers, Journal Year: 2023, Volume and Issue: 15(13), P. 3468 - 3468

Published: July 2, 2023

Various cancer cell-associated intrinsic and extrinsic inputs act on YAP/TAZ proteins to mediate the hyperactivation of TEAD transcription factor-based transcriptome. This YAP/TAZ-TEAD activity can override growth-limiting Hippo tumor-suppressor pathway that maintains normal tissue homeostasis. Herein, we provide an integrated summary contrasting roles during homeostasis versus tumor initiation progression. In addition upstream factors regulate in TME, critical insights emerging functions immune suppression abnormal vasculature development tumorigenesis are illustrated. Lastly, discuss current methods intervene with oncogenic signaling applications combination therapies, gut microbiota, epigenetic plasticity could potentiate efficacy chemo/immunotherapy as improved therapeutic strategies.

Language: Английский

Citations

34
A conserved role of the Hippo signalling pathway in initiation of the first lineage specification event across mammals DOI Open Access
Claudia Gerri,

Afshan McCarthy,

Gwen Mei Scott

et al.

Development, Journal Year: 2023, Volume and Issue: 150(8)

Published: March 27, 2023

Our understanding of the molecular events driving cell specification in early mammalian development relies mainly on mouse studies, and it remains unclear whether these mechanisms are conserved across mammals, including humans. We have shown that establishment polarity via aPKC is a event initiation trophectoderm (TE) placental programme mouse, cow human embryos. However, transducing into fate embryos unknown. Here, we examined evolutionary conservation Hippo signalling, which thought to function downstream activity, four different species: rat, human. In all species, inhibition pathway by targeting LATS kinases sufficient drive ectopic TE downregulation SOX2. timing localisation markers differ with rat more closely recapitulating developmental dynamics, compared mouse. comparative embryology approach uncovered intriguing differences as well similarities fundamental process among reinforcing importance cross-species investigations.

Language: Английский

Citations

29