Homeostatic and tumourigenic activity of SOX2+ pituitary stem cells is controlled by the LATS/YAP/TAZ cascade
- King's College London, United Kingdom
- Great Ormond Street Hospital for Children, United Kingdom
- The University of Texas, MD Anderson Cancer Center, United States
- University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany
Abstract
SOX2 positive pituitary stem cells (PSCs) are specified embryonically and persist throughout life, giving rise to all pituitary endocrine lineages. We have previously shown the activation of the STK/LATS/YAP/TAZ signalling cascade in the developing and postnatal mammalian pituitary. Here, we investigate the function of this pathway during pituitary development and in the regulation of the SOX2 cell compartment. Through loss- and gain-of-function genetic approaches, we reveal that restricting YAP/TAZ activation during development is essential for normal organ size and specification from SOX2+ PSCs. Postnatal deletion of LATS kinases and subsequent upregulation of YAP/TAZ leads to uncontrolled clonal expansion of the SOX2+ PSCs and disruption of their differentiation, causing the formation of non-secreting, aggressive pituitary tumours. In contrast, sustained expression of YAP alone results in expansion of SOX2+ PSCs capable of differentiation and devoid of tumourigenic potential. Our findings identify the LATS/YAP/TAZ signalling cascade as an essential component of PSC regulation in normal pituitary physiology and tumourigenesis.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Cynthia Lilian Andoniadou
Funding
Medical Research Council (MR/L016729/1)
- Cynthia Lilian Andoniadou
Lister Institute of Preventive Medicine (Prize Fellowship 2016)
- Cynthia Lilian Andoniadou
Deutsche Forschungsgemeinschaft (CRC/Transregio 205/1)
- Stefan R Bornstein
- Cynthia Lilian Andoniadou
Guy's and St Thomas' Charity (Prize PhD Programme)
- Emily J Lodge
Deutsche Forschungsgemeinschaft (GRK 2251)
- Stefan R Bornstein
- Cynthia Lilian Andoniadou
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in accordance to UK Home Office Regulations and experimental procedures were approved by the King's College Ethical Review Process.
Copyright
© 2019, Lodge et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Homeostatic and tumourigenic activity of SOX2+ pituitary stem cells is controlled by the LATS/YAP/TAZ cascade
eLife 8:e43996.
https://doi.org/10.7554/eLife.43996
Further reading
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- Stem Cells and Regenerative Medicine
Background:
In idiopathic pulmonary fibrosis (IPF) patients, alveolar architectures are lost and gas transfer function would decline, which cannot be rescued by conventional anti-fibrotic therapy. P63+ lung basal progenitor cells are reported to have potential to repair damaged lung epithelium in animal models, which need further investigation in clinical trials.
Methods:
We cloned and expanded P63+ progenitor cells from IPF patients to manufacture cell product REGEND001, which were further characterized by morphology and single-cell transcriptomic analysis. Subsequently, an open-label, dose-escalation autologous progenitor cell transplantation clinical trial was conducted. We treated 12 patients with ascending doses of cells: 0.6x, 1x, 2x and 3.3x106 cells/kg bodyweight. The primary outcome was the incidence and severity of cell therapy-related adverse events (AEs); secondary outcome included other safety and efficacy evaluations.
Results:
P63+ basal progenitor cell was safe and tolerated at all doses, with no dose-limiting toxicity or cell therapy-related severe adverse events observed. Patients in three higher dose groups showed significant improvement of lung gas transfer function as well as exercise ability. Resolution of honeycomb lesion was observed in patients of higher dose groups.
Conclusions:
REGEND001 has high safety profile and meanwhile encourages further efficacy exploration in IPF patients.
Funding:
National High Level Hospital Clinical Research Funding (2022-PUMCH-B-108), National Key Research and Development Plan (2024YFA1108900, 2024YFA1108500), Jiangsu Province Science and Technology Special Project Funding (BE2023727), National Biopharmaceutical Technology Research Project Funding (NCTIB2023XB01011), Non-profit Central Research Institute Fund of Chinese Academy of Medical Science (2020-PT320-005), and Regend Therapeutics.
Clinical trial number:
Chinese clinical trial registry: CTR20210349.
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- Neuroscience
- Stem Cells and Regenerative Medicine
Sensory dorsal root ganglion (DRG) neurons have a unique pseudo-unipolar morphology in which a stem axon bifurcates into a peripheral and a central axon, with different regenerative abilities. Whereas peripheral DRG axons regenerate, central axons are unable to regrow. Central axon regeneration can however be elicited by a prior conditioning lesion to the peripheral axon. How DRG axon asymmetry is established remains unknown. Here we developed a rodent in vitro system replicating DRG pseudo-unipolarization and asymmetric axon regeneration. Using this model, we observed that from early development, central DRG axons have a higher density of growing microtubules. This asymmetry was also present in vivo and was abolished by a conditioning lesion that decreased microtubule polymerization of central DRG axons. An axon-specific microtubule-associated protein (MAP) signature, including the severases spastin and katanin and the microtubule regulators CRMP5 and tau, was found and shown to adapt upon conditioning lesion. Supporting its significance, interfering with the DRG MAP signature either in vitro or in vivo readily abolished central-peripheral asymmetries in microtubule dynamics and regenerative ability. In summary, our data unveil that axon-specific microtubule regulation drives asymmetric regeneration of sensory neuron axons.
