The role of Occluding Junctions during development and repair
Team Members: Lara Carvalho, António Jacinto
Epithelia are fundamental tissues in all multicellular organisms by establishing a protective barrier between the external environment and the organisms as well as between its different organs. Failure in the repair of these tissues upon injury is implicated not only in the pathology of chronic wounds, but also in other chronic diseases such as inflammatory bowel diseases (IBD) and cancer. Simple epithelia, such as the ones found in embryos and in the adult intestinal lining, have the remarkable capacity to resolve wounds in a rapid, efficient and scarless manner, representing excellent models to study wound healing. Our goal is to study the cellular and molecular mechanisms of re-epithelialization in simple epithelia and how they contribute for efficient wound closure. In this project, we investigate the role of Occluding Junctions, a type of intercellular junction present in all epithelial cells. For this we use the fruit-fly Drosophila melanogaster as a model system, which allows us to follow the cellular and molecular dynamics of wound closure in the context of the whole organism, in real-time and with high resolution. From a translational point of view, our aim is to contribute to the discovery of new and better therapies for chronic inflammatory diseases, like IBD and cancer.
- Ponte S, Carvalho L, Gagliardi M, Campos I, Oliveira PJ, Jacinto A (2020) Drp1-mediated mitochondrial fission regulates calcium and F-actin dynamics during wound healing. Biology Open bio.048629. http://dx.doi.org/10.1242/bio.048629
- Ponte S, Jacinto A, Carvalho L (2019) The occluding junction protein Neurexin-IV is required for tissue integrity in the Drosophila wing disc epithelium. Matters. http://dx.doi.org/10.19185/matters.201903000014
- Carvalho L, Patrício P, Ponte S, Heisenberg CP, Almeida L, Jacinto A (2018) Occluding junctions as novel regulators of tissue mechanics during wound repair. J Cell Biol. jcb.201804048. http://dx.doi.org/10.1083/jcb.201804048
Pedro Patrício, Genilson Carvalho, Nuno Araújo, CFTC, FCUL, Universidade de Lisboa
FCT - MechanOJunctions (PTDC/BIA-BID/29709/2017)
Mechanisms of reinnervation during skin repair: novel roles for intercellular communication
Team Members: Lara Carvalho, António Jacinto, Telmo Pereira, Maria Catarina Tordo Dias, Mariana Correia, Rita Teodoro, Benedita Vasconcelos
Besides being a protective barrier, the skin is also a highly sensitive organ. The skin is densely innervated by different types of sensory neurons that can recognize distinct external stimuli, allowing the sense of touch, pain, and temperature. When subject to severe injury, the skin is not able to recover its original structure and sensory function. Chronic wounds are also associated with diseases that involve nerve damage, such as diabetes, spinal cord injury or autoimmune diseases. Whether deficient skin repair is caused by defective reinnervation is still a mystery. The mechanisms that regulate reinnervation after a wound are also mostly unknown. These are all important questions we hope to answer with this project. We study this in the context of an organism and in real-time by using the skin of the fruit-fly Drosophila melanogaster, high-resolution microscopy, and sophisticated genetic manipulations. This approach allows to dissect the specific contribution of epidermal and nerve cells and how they interact with each other during repair, and to identify novel molecules required for this process, which can hopefully be translatable to humans. This work will also advance our knowledge about the general mechanisms of intercellular interactions and nerve repair in other disease contexts, such as diabetes and neurodegenerative diseases.
FCT - ReInnervate (EXPL/BIA-CEL/1484/2021)
Metabolic-driven regenerative mechanisms in the retina
Team Members: Rita Gorgulho, Raquel Lourenço, António Jacinto
Retina degeneration leads to visual impairment/blindness, affecting millions of people worldwide. While mammals lack the ability to regenerate their retina, zebrafish are able to regenerate lost/damaged retinal tissue, relying on the activity of Müller Glia (MG) cells, which re-enter the cell cycle and produce progenitor cells to restore the damaged retina.
With cell metabolism being an important factor guiding alternate cell fates, we are currently interested in addressing the impact of metabolic reprogramming on the onset of MG cell fate transitions, during zebrafish retina regeneration.
Our findings suggest a potential role of glucose metabolism in prompting early events of retina regeneration, with Hexosamine Biosynthesis Pathway being one of the main mediators of MG cell-cycle re-entry and proliferation after injury. This research will offer new insights on how alterations in the energy metabolism can regulate the early events necessary for MG response to damage, and how they influence the zebrafish retina regenerative response.
- Yi Feng, The University of Edinburgh, UK
- Stefan Kempa, MDC Berlin-Mitte, Berlin
FCT (SFRH/BPD/93453/2013; PTDC/BIM-MED/0659/2014)
Ontogeny of tissue-resident macrophages during embryonic development
Team Members: Tomás Madureira, Ana Teresa Tavares, António Jacinto
Vertebrates have two major macrophage lineages with different developmental origins: the bone marrow-derived population, which develops from hematopoietic stem cells, and the tissue-resident population, which develops from embryonic hematopoietic progenitors. In contrast to our current knowledge on bone marrow-derived macrophages, little is known about the development and biology of tissue-resident macrophages, including how their particular embryonic origin may influence their specific functions in tissue homeostasis and inflammation. In pathological conditions, defects in the development and function of tissue-resident macrophages can contribute to immune disorders such as primary immunodeficiencies. In addition, the dysfunction of microglia, the resident macrophages of the central nervous system, has been associated with neurodevelopmental disorders such as autism spectrum disorders. Using lineage-specific genetic tools and loss-of-function approaches in different vertebrate models (zebrafish, chick, hiPSC), we are investigating the ontogeny of hematopoietic cells and the pathological consequences of their malformation during embryonic and fetal development. In particular, we are studying the function of novel genetic regulators of hematopoietic development that have been implicated in the pathogenesis of primary immunodeficiencies and autism. Additionally, we are exploring whether hemogenic endothelial cells exist in postnatal life as extramedullary sources of hematopoietic progenitors. This knowledge is particularly important for improving blood disorder therapies that rely on the isolation and/or in vitro generation of hematopoietic cells.
- Gabriel Martins, Instituto Gulbenkian de Ciência, Oeiras, Portugal
- Tânia Matos and Joana Monteiro, Champalimaud Foundation, Lisbon, Portugal
- Ana Catarina Certal, Champalimaud Foundation, Lisbon, Portugal
- Tânia Carvalho, Champalimaud Foundation, Lisbon, Portugal
- Adrien Jouary e Michael Orger, Fundação Champalimaud, Lisboa, Portugal
- João Farela Neves, Unidade de Imunodeficiências Primárias, Hospital Dona Estefânia, (Centro Hospitalar de Lisboa Central) e NOVA Medical School, Lisboa, Portugal
- Margarida Coucelo, Laboratório de Hemato-Oncologia Molecular, Serviço de Hematologia Clínica (Centro Hospitalar e Universitário de Coimbra), Coimbra, Portugal
FCT (POCI/PPCDT/SAU-MMO/59725/2004; SFRH/BPD/102261/2014; 2022.02611.PTDC), iNOVA4Health (UIDB/04462/2020; UIDP/04462/2020) , BED Master Programme (FCUL), NBR Master Programme (NMS)
Immune-based approaches to improve cancer management
Team Members: Rute Salvador, Bruna Correia, Inês Gomes, Daniela Grosa, Sofia Braga, António Jacinto, Maria Guadalupe Cabral
Despite the vast ongoing research efforts, cancer remains a challenging disease to treat. Increasing evidence has been highlighting the role of immune players and metabolism in cancer progression and response to conventional treatments. Therefore, it is believed that a deeper understanding of the immunobiology and metabolic reprograming of cancer is needed for the implementation of more efficient and tailored treatments for this disease. Using patients’ clinical samples and 3D culture systems our research has been focused on finding particular immune traces in the tumor microenvironment of breast cancer, that could be translated into accurate predictive/prognostic biomarkers or into new target therapies, ultimately aiming to ameliorate breast cancer patients’ care.
- Saraiva DP, Correia BF, Salvador R, De Sousa N, Jacinto A, Braga S, Cabral MG (2021) Circulating Low Density Neutrophils of Breast Cancer Patients are Associated with their Worse Prognosis due to the Impairment of T cell Responses. Oncotarget. 12(24):2388-2403. http://dx.doi.org/10.18632/oncotarget.28135
- Saraiva DP, Azeredo-Lopes S, Antunes A, Salvador R, Borralho P, Assis B, Pereira, IL, Seabra Z, Negreiros I, Jacinto A, Braga S, Cabral MG (2021) Expression of HLA-DR in Cytotoxic T Lymphocytes: A Validated Predictive Biomarker and a Potential Therapeutic Strategy in Breast Cancer. Cancers 13(15):3841. http://dx.doi.org/10.3390/cancers1315384
- Saraiva DP, Matias AT, Braga S, Jacinto A, Cabral MG (2020) Establishment of a 3D Coculture With MDA-MB-231 Breast Cancer Cell Line and Patient-Derived Immune Cells for Application in the Development of Immunotherapies. Frontiers in Oncology 10:1543. http://dx.doi.org/10.3389/fonc.2020.01543
- Saraiva DP, Jacinto A, Borralho P, Braga S, Cabral MG (2018) HLA-DR expression in cytotoxic T Lymphocytes predicts Breast Cancer patients’ response to neoadjuvant chemotherapy. Frontiers in Immunology, 13:9:2605. http://dx.doi.org/10.3390/cancers13153841
Liga Portuguesa Contra o Cancro (Terry Fox Research Grant 2019); Tagus Tank Consortium (Research Prize in Medicine 2018); Pfizer/Sociedade das Ciências Médicas (Clinical Research Prize 2019); iNOVA4Health (UID/Multi/04462/2013-Lisboa-01-0145FEDER-007)