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1. A computational model reveals an early transient decrease in fiber cross-linking that unlocks adult regeneration

Author

Anastasia Pacary, Diane Peurichard, Laurence Vaysse, Paul Monsarrat, Clémence Bolut, Adeline Girel, Christophe Guissard, Anne Lorsignol, Valérie Planat-Benard, Jenny Paupert, Marielle Ousset, and Louis Casteilla

Subjects
Medicine
Abstract

Abstract The decline in regeneration efficiency after birth in mammals is a significant roadblock for regenerative medicine in tissue repair. We previously developed a computational agent based-model (ABM) that recapitulates mechanical interactions between cells and the extracellular-matrix (ECM), to investigate key drivers of tissue repair in adults. Time calibration alongside a parameter sensitivity analysis of the model suggested that an early and transient decrease in ECM cross-linking guides tissue repair toward regeneration. Consistent with the computational model, transient inhibition or stimulation of fiber cross-linking for the first six days after subcutaneous adipose tissue (AT) resection in adult mice led to regenerative or scar healing, respectively. Therefore, this work positions the computational model as a predictive tool for tissue regeneration that with further development will behave as a digital twin of our in vivo model. In addition, it opens new therapeutic approaches targeting ECM cross-linking to induce tissue regeneration in adult mammals.

Published
2024
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2. Generation of functionally active resident macrophages from adipose tissue by 3D cultures

Author

Adèle Arlat, Marie-Laure Renoud, Jean Nakhle, Miguel Thomas, Jessica Fontaine, Emmanuelle Arnaud, Cédric Dray, Hélène Authier, Paul Monsarrat, Agnès Coste, Louis Casteilla, Marielle Ousset, and Béatrice Cousin

Subjects
resident macrophage, macrophage subpopulation, adipose tissue, bone marrow, 3D culture, metabolism, Immunologic diseases. Allergy, RC581-607
Abstract

IntroductionWithin adipose tissue (AT), different macrophage subsets have been described, which played pivotal and specific roles in upholding tissue homeostasis under both physiological and pathological conditions. Nonetheless, studying resident macrophages in-vitro poses challenges, as the isolation process and the culture for extended periods can alter their inherent properties.MethodsStroma-vascular cells isolated from murine subcutaneous AT were seeded on ultra-low adherent plates in the presence of macrophage colony-stimulating factor. After 4 days of culture, the cells spontaneously aggregate to form spheroids. A week later, macrophages begin to spread out of the spheroid and adhere to the culture plate.ResultsThis innovative three-dimensional (3D) culture method enables the generation of functional mature macrophages that present distinct genic and phenotypic characteristics compared to bone marrow–derived macrophages. They also show specific metabolic activity and polarization in response to stimulation, but similar phagocytic capacity. Additionally, based on single-cell analysis, AT-macrophages generated in 3D culture mirror the phenotypic and functional traits of in-vivo AT resident macrophages.DiscussionOur study describes a 3D in-vitro system for generating and culturing functional AT-resident macrophages, without the need for cell sorting. This system thus stands as a valuable resource for exploring the differentiation and function of AT-macrophages in vitro in diverse physiological and pathological contexts.

Published
2024
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3. Fibre crosslinking drives the emergence of order in a three-dimensional dynamical network model

Author

Pauline Chassonnery, Jenny Paupert, Anne Lorsignol, Childérick Séverac, Marielle Ousset, Pierre Degond, Louis Casteilla, and Diane Peurichard

Subjects
interaction networks, three-dimensional mathematical modelling, self-organization, extracellular matrix, dynamical crosslinking, architecture emergence, Science
Abstract

The extracellular-matrix (ECM) is a complex interconnected three-dimensional network that provides structural support for the cells and tissues and defines organ architecture as key for their healthy functioning. However, the intimate mechanisms by which ECM acquire their three-dimensional architecture are still largely unknown. In this paper, we study this question by means of a simple three-dimensional individual based model of interacting fibres able to spontaneously crosslink or unlink to each other and align at the crosslinks. We show that such systems are able to spontaneously generate different types of architectures. We provide a thorough analysis of the emerging structures by an exhaustive parametric analysis and the use of appropriate visualization tools and quantifiers in three dimensions. The most striking result is that the emergence of ordered structures can be fully explained by a single emerging variable: the number of links per fibre in the network. If validated on real tissues, this simple variable could become an important putative target to control and predict the structuring of biological tissues, to suggest possible new therapeutic strategies to restore tissue functions after disruption, and to help in the development of collagen-based scaffolds for tissue engineering. Moreover, the model reveals that the emergence of architecture is a spatially homogeneous process following a unique evolutionary path, and highlights the essential role of dynamical crosslinking in tissue structuring.

Published
2024
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4. Driving regeneration, instead of healing, in adult mammals: the decisive role of resident macrophages through efferocytosis

Author

Lise Rabiller, Virginie Robert, Adèle Arlat, Elodie Labit, Marielle Ousset, Marie Salon, Agnès Coste, Léa Da Costa-Fernandes, Paul Monsarrat, Bruno Ségui, Mireille André, Christophe Guissard, Marie-Laure Renoud, Marine Silva, Gilles Mithieux, Isabelle Raymond-Letron, Luc Pénicaud, Anne Lorsignol, Louis Casteilla, Cécile Dromard Berthézène, and Béatrice Cousin

Subjects
Medicine
Abstract

Abstract Tissue repair after lesion usually leads to scar healing and thus loss of function in adult mammals. In contrast, other adult vertebrates such as amphibians have the ability to regenerate and restore tissue homeostasis after lesion. Understanding the control of the repair outcome is thus a concerning challenge for regenerative medicine. We recently developed a model of induced tissue regeneration in adult mice allowing the comparison of the early steps of regenerative and scar healing processes. By using studies of gain and loss of function, specific cell depletion approaches, and hematopoietic chimeras we demonstrate here that tissue regeneration in adult mammals depends on an early and transient peak of granulocyte producing reactive oxygen species and an efficient efferocytosis specifically by tissue-resident macrophages. These findings highlight key and early cellular pathways able to drive tissue repair towards regeneration in adult mammals.

Published
2021
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5. Clonal Dynamics Reveal Two Distinct Populations of Basal Cells in Slow-Turnover Airway Epithelium

Author

Julie K. Watson, Steffen Rulands, Adam C. Wilkinson, Aline Wuidart, Marielle Ousset, Alexandra Van Keymeulen, Berthold Göttgens, Cédric Blanpain, Benjamin D. Simons, and Emma L. Rawlins

Subjects
Biology (General), QH301-705.5
Abstract

Epithelial lineages have been studied at cellular resolution in multiple organs that turn over rapidly. However, many epithelia, including those of the lung, liver, pancreas, and prostate, turn over slowly and may be regulated differently. We investigated the mouse tracheal epithelial lineage at homeostasis by using long-term clonal analysis and mathematical modeling. This pseudostratified epithelium contains basal cells and secretory and multiciliated luminal cells. Our analysis revealed that basal cells are heterogeneous, comprising approximately equal numbers of multipotent stem cells and committed precursors, which persist in the basal layer for 11 days before differentiating to luminal fate. We confirmed the molecular and functional differences within the basal population by using single-cell qRT-PCR and further lineage labeling. Additionally, we show that self-renewal of short-lived secretory cells is a feature of homeostasis. We have thus revealed early luminal commitment of cells that are morphologically indistinguishable from stem cells.

Published
2015
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6. Driving regeneration, instead of healing, in adult mammals: the decisive role of resident macrophages through efferocytosis

Author

Anne Lorsignol, Isabelle Raymond-Letron, Léa Da Costa-Fernandes, Lise Rabiller, Béatrice Cousin, Marine Silva, Adèle Arlat, Elodie Labit, Paul Monsarrat, Agnès Coste, Bruno Ségui, Gilles Mithieux, Marie-Laure Renoud, Mireille André, Cécile Dromard Berthézène, Marie Salon, Luc Pénicaud, Virginie Robert, Marielle Ousset, Christophe Guissard, Louis Casteilla, STROMALab, Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Etablissement Français du Sang-Institut National de la Santé et de la Recherche Médicale (INSERM), McGill University = Université McGill [Montréal, Canada], Geroscience and rejuvenation research center (RESTORE), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Calgary, Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Institut de Recherche pour le Développement (IRD), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Nutrition, diabète et cerveau, Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Cell biology, Physiology, [SDV]Life Sciences [q-bio], Immunology, Biomedical Engineering, Medicine (miscellaneous), Granulocyte, Biology, Regenerative medicine, Article, Lesion, 03 medical and health sciences, 0302 clinical medicine, medicine, Efferocytosis, Tissue homeostasis, Loss function, 030304 developmental biology, 0303 health sciences, Regeneration (biology), 3. Good health, Haematopoiesis, medicine.anatomical_structure, Medicine, medicine.symptom, 030217 neurology & neurosurgery, Developmental Biology
Abstract

Tissue repair after lesion usually leads to scar healing and thus loss of function in adult mammals. In contrast, other adult vertebrates such as amphibians have the ability to regenerate and restore tissue homeostasis after lesion. Understanding the control of the repair outcome is thus a concerning challenge for regenerative medicine. We recently developed a model of induced tissue regeneration in adult mice allowing the comparison of the early steps of regenerative and scar healing processes. By using studies of gain and loss of function, specific cell depletion approaches, and hematopoietic chimeras we demonstrate here that tissue regeneration in adult mammals depends on an early and transient peak of granulocyte producing reactive oxygen species and an efficient efferocytosis specifically by tissue-resident macrophages. These findings highlight key and early cellular pathways able to drive tissue repair towards regeneration in adult mammals.

Published
2021
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7. Extra-cellular matrix rigidity may dictate the fate of injury outcome

Author

Marielle Ousset, Louis Casteilla, Pierre Degond, Benjamin Aymard, Jenny Paupert, Diane Peurichard, Anne Lorsignol, Modelling and Analysis for Medical and Biological Applications (MAMBA), Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Jacques-Louis Lions (LJLL (UMR_7598)), Université Paris Diderot - Paris 7 (UPD7)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), STROMALab, Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Etablissement Français du Sang-Institut National de la Santé et de la Recherche Médicale (INSERM), Mathématiques pour les Neurosciences (MATHNEURO), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Department of Mathematics [Imperial College London], Imperial College London, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS), The Royal Society, Engineering & Physical Science Research Council (EPSRC), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), and Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS)

Subjects
Life Sciences & Biomedicine - Other Topics, 0301 basic medicine, q-bio.TO, Individual-based model, Cellular differentiation, [SDV]Life Sciences [q-bio], Adipose tissue, Matrix (biology), Extracellular matrix, 0302 clinical medicine, Tissues and Organs (q-bio.TO), biology, Applied Mathematics, General Medicine, Planaria, Biomechanical Phenomena, Extracellular Matrix, Cell biology, Fiber insemination, ADIPOSE-TISSUE, Adipose Tissue, Modeling and Simulation, Lernaean Hydra, General Agricultural and Biological Sciences, Life Sciences & Biomedicine, Statistics and Probability, Morphogenesis, Models, Biological, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Tissue remodeling, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Animals, Humans, Regeneration, Computer Simulation, Biology, 01 Mathematical Sciences, Probability, Wound Healing, Evolutionary Biology, Science & Technology, General Immunology and Microbiology, Regeneration (biology), [SDV.BDD.MOR]Life Sciences [q-bio]/Development Biology/Morphogenesis, Quantitative Biology - Tissues and Organs, 06 Biological Sciences, biology.organism_classification, 030104 developmental biology, FOS: Biological sciences, Mathematical & Computational Biology, 08 Information and Computing Sciences, 030217 neurology & neurosurgery, Constrained minimization
Abstract

International audience; After injury, while regeneration can be observed in hydra, planaria and some vertebrates,regeneration is rare in mammals and particularly in humans. In this paper, we investigatethe mechanisms by which biological tissues recover after injury. We explore this question onadipose tissue, using the mathematical framework recently developed in Peurichard et al.,J. Theoret. Biol. 429 (2017), pp. 61-81. Our assumption is that simple mechanical cuesbetween the Extra-Cellular Matrix (ECM) and differentiated cells can explain adipose tissuemorphogenesis and that regeneration requires after injury the same mechanisms. We validatethis hypothesis by means of a two-dimensional Individual Based Model (IBM) of interactingadipocytes and ECM fiber elements. The model successfully generates regeneration or scarformation as functions of few key parameters, and seems to indicate that the fate of injuryoutcome could be mainly due to ECM rigidity.

Published
2018
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8. Reactivation of multipotency by oncogenic PIK3CA induces breast tumour heterogeneity

Author

Gaëlle Bouvencourt, Rajshekhar R. Giraddi, May Yin Lee, Sandrine Rorive, Marielle Ousset, Christine Dubois, Christos Sotiriou, Aline Wuidart, Wayne A. Phillips, Sylvain Brohée, Cédric Blanpain, Isabelle Salmon, Alexandra Van Keymeulen, Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles (ULB), Brussels 1070, Belgium., Université libre de Bruxelles (ULB), Institut Jules Bordet [Bruxelles], Faculté de Médecine [Bruxelles] (ULB), and Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)

Subjects
Cellular differentiation, Cell of origin, [SDV]Life Sciences [q-bio], Mice, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, Genes, p53 -- genetics, Mutation -- genetics, Receptors, Progesterone -- metabolism, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Multidisciplinary, Cell Differentiation, Sciences bio-médicales et agricoles, Phenotype, 3. Good health, Cell Transformation, Neoplastic, Receptors, Estrogen, 030220 oncology & carcinogenesis, Receptors, Estrogen -- metabolism, Female, Receptors, Progesterone, Reprogramming, Cell Division, Breast Neoplasms -- genetics -- metabolism -- pathology, Tumour heterogeneity, Class I Phosphatidylinositol 3-Kinases, Breast Neoplasms, Mammary Neoplasms, Animal, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Cell fate determination, Biology, 03 medical and health sciences, Progesterone receptor, Animals, Humans, Cell Lineage, Neoplasm Invasiveness, Progenitor cell, neoplasms, 030304 developmental biology, Cell Differentiation -- genetics, Phosphatidylinositol 3-Kinases -- genetics -- metabolism, Genes, p53, Mammary Neoplasms, Animal -- genetics -- metabolism -- pathology, Neoplasm Invasiveness -- genetics, Immunology, Mutation, Cancer research
Abstract

Breast cancer is the most frequent cancer in women and consists of heterogeneous types of tumours that are classified into different histological and molecular subtypes. PIK3CA and P53 (also known as TP53) are the two most frequently mutated genes and are associated with different types of human breast cancers. The cellular origin and the mechanisms leading to PIK3CA-induced tumour heterogeneity remain unknown. Here we used a genetic approach in mice to define the cellular origin of Pik3ca-derived tumours and the impact of mutations in this gene on tumour heterogeneity. Surprisingly, oncogenic Pik3ca(H1047R) mutant expression at physiological levels in basal cells using keratin (K)5-CreER(T2) mice induced the formation of luminal oestrogen receptor (ER)-positive/progesterone receptor (PR)-positive tumours, while its expression in luminal cells using K8-CReER(T2) mice gave rise to luminal ER(+)PR(+) tumours or basal-like ER(-)PR(-) tumours. Concomitant deletion of p53 and expression of Pik3ca(H1047R) accelerated tumour development and induced more aggressive mammary tumours. Interestingly, expression of Pik3ca(H1047R) in unipotent basal cells gave rise to luminal-like cells, while its expression in unipotent luminal cells gave rise to basal-like cells before progressing into invasive tumours. Transcriptional profiling of cells that underwent cell fate transition upon Pik3ca(H1047R) expression in unipotent progenitors demonstrated a profound oncogene-induced reprogramming of these newly formed cells and identified gene signatures characteristic of the different cell fate switches that occur upon Pik3ca(H1047R) expression in basal and luminal cells, which correlated with the cell of origin, tumour type and different clinical outcomes. Altogether our study identifies the cellular origin of Pik3ca-induced tumours and reveals that oncogenic Pik3ca(H1047R) activates a multipotent genetic program in normally lineage-restricted populations at the early stage of tumour initiation, setting the stage for future intratumoural heterogeneity. These results have important implications for our understanding of the mechanisms controlling tumour heterogeneity and the development of new strategies to block PIK3CA breast cancer initiation., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2015
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9. A DNA-dependent stress response involving DNA-PK occurs in hypoxic cells and contributes to cellular adaptation to hypoxia

Author

Denis Biard, Frédérique Fallone, Philippe Frit, Bernard Salles, Catherine Muller, Marielle Ousset, Stéphanie Dauvillier, Fanny Bouquet, Forêt et agroforesterie (UR FACF), Centre national du machinisme agricole, du génie rural, des eaux et forêts (CEMAGREF), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Cytosquelette et Intégration des Signaux du Micro-Environnement Tumoral - UMR 6032 (CISMET), Centre National de la Recherche Scientifique (CNRS)-Université de Provence - Aix-Marseille 1-Université de la Méditerranée - Aix-Marseille 2, ‘Ligue Nationale Contre le Cancer’ (Equipe Labélisée, B.S.), the Cancéropole GSO (B.S.), the Association contre le Cancer, ARC (2008-1102, C.M.) and the Radioprotection Committee of EDF (C.M.), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), and Université de la Méditerranée - Aix-Marseille 2-Université de Provence - Aix-Marseille 1-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV]Life Sciences [q-bio], DNA-Activated Protein Kinase, Hydroxamic Acids, Histones, 0302 clinical medicine, Phosphorylation, 0303 health sciences, Glucose Transporter Type 1, biology, Histone deacetylase inhibitor, Autophosphorylation, Acetylation, Antigens, Nuclear, Adaptation, Physiological, Cell Hypoxia, Chromatin, DNA-Binding Proteins, Histone, 030220 oncology & carcinogenesis, medicine.drug, Signal Transduction, medicine.drug_class, DNA damage, Morpholines, DNA repair, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Line, DNA-PK, 03 medical and health sciences, Stress, Physiological, medicine, Humans, Transcription factor, Ku Autoantigen, 030304 developmental biology, hypoxia, Cell Biology, stress response, Hypoxia-Inducible Factor 1, alpha Subunit, Molecular biology, Enzyme Activation, Trichostatin A, Aminoglycosides, Chromones, biology.protein, Enediynes, Protein Processing, Post-Translational, DNA Damage
Abstract

DNA-dependent protein kinase (DNA-PK) is involved in DNA double-strand break (DSB) signalling and repair. We report that DNA-PK is activated by mild hypoxia conditions (0.1–1% O2) as shown by (1) its autophosphorylation on Ser2056, and (2) its mobilisation from a soluble nucleoplasmic compartment to a less extractable nuclear fraction. The recruitment of DNA-PK was not followed by activation and recruitment of the XRCC4–DNA-ligase-IV complex, suggesting that DSBs are not responsible for activation of DNA-PK. To unravel the mechanism of DNA-PK activation, we show that exposure of cells to trichostatin A, a histone deacetylase inhibitor, leads to DNA-PK autophosphorylation and relocalisation to DNA. Histone acetylation (mainly H3K14) is increased in hypoxic cells and treatment with anacardic acid, an inhibitor of histone acetyl transferase, prevented both histone modifications and DNA-PK activation in hypoxic conditions. Importantly, in using either silenced DNA-PK cells or cells exposed to a specific DNA-PK inhibitor (NU7026), we demonstrated that hypoxic DNA-PK activation positively regulates the key transcription factor HIF-1 and one subsequent target gene, GLUT1. Our results show that hypoxia initiates chromatin modification and consequently DNA-PK activation, which positively regulate cellular oxygen-sensing and oxygen-signalling pathways.

Published
2011
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