Our group addresses the mechanisms that regulate tissue repair and regeneration and the role of the immune system in development and disease. In recent years, the focus has been on investigating epithelial repair in Drosophila and organ regeneration in zebrafish, including the retina, spinal cord, kidney and fin. We expect that studying the molecular and cellular mechanisms of regeneration in animal models will contribute to a better understanding of tissue homeostasis and disease. Concurrently, the main effort to translate our research to humans has been on identifying new biomarkers and developing novel therapeutic approaches to target cancer and improve organ regenerative capacity.
Mechanisms of tissue and organ regeneration
Contacts: raquel.lourenço(at)nms.unl.pt; ana.brandao(at)nms.unl.pt; nidia.sousa(at)nms.unl.pt
Regeneration is an impressive biological process that allows the replacement of lost body parts due to damage. In contrast to mammals, it is well documented that non-mammalian vertebrates, such as zebrafish (Danio rerio), exhibit an enhanced capacity to regenerate whole organs and large sections of the adult body in a very efficient and consistent manner. Thus, our lab focuses on understanding the basic molecular and cellular mechanisms underlying tissue regeneration using zebrafish as a model system. We are particularly interested in addressing how distinct tissues, namely the caudal fin, the retina, the spinal cord and the kidney respond to an injury and activate a cascade of events that culminates in complete recovery of organ architecture and function. This should provide valuable insights about the basic mechanisms by which tissues are restored and also aid in the development of strategies to enhance regenerative capacity in mammalian systems.
Representative images of zebrafish organs and tissues with high regenerative capacity. The retina is used to understand how, in the context of light-induced damage, progenitor cells arise and originate new photoreceptors (labelled in magenta). Injury to the spinal cord allows us to investigate how the lesion microenvironment and senescent cells (labelled in dark blue) modulate the spinal cord healing process. Finally, using the caudal fin we can understand how bone secreting cells (labelled in green and blue) are reprogrammed and differentiate to ensure proper bone regeneration after fin amputation.
Mechanisms of wound detection and epithelial repair
Contacts: lara.carvalho(at)nms.unl.pt and carolina.crespo(at)nms.unl.pt)
Epithelia are fundamental tissues in all multicellular organisms by establishing a physical barrier between the external environment and the different body compartments. 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 wound detection by the immune system and of re-epithelialization in simple epithelia and how they contribute for efficient wound closure. From a translational point of view, our models aim at discovering new therapies for chronic inflammatory diseases, like IBD.
We use two different models to address these questions: the zebrafish Danio rerio, which is an excellent model to visualize dynamics of inflammatory responses to wounds, and the fruit-fly Drosophila melanogaster, which allows us to follow the behavior of epithelial cells during wound closure.
Wound closure in the Drosophila embryonic epithelium. Left panel: video showing mitochondrial dynamics. Right panel: image showing an epithelial wound 1 hour after injury marked for the actin cytoskeleton (magenta) and the occluding junctions (green).
Dynamics of neutrophils (green) and macrophages (magenta) response to zebrafish tailfin wounds.
Inflammation in disease and regeneration
Contacts: guadalupe.cabral(at)nms.unl.pt and anateresa.tavares(at)nms.unl.pt)
Inflammation is the body´s response to detrimental stimuli such as infectious, physiological or chemical agents. The inflammatory molecules and the pathways through which they interact can be turned on/off in numerous ways in reaction to the body’s needs. However, the mechanisms by which inflammation is regulated can fail and the inflammatory process is now a well-recognized factor in the pathophysiology of several diseases.
In our group we are interested in studying inflammation in the context of:
Inflammation and the overall immune system have a dual role in cancer. Understanding the immune signatures in the tumor microenvironment involved in anti-tumor or in pro-tumor activity is important for prognosis and for designing therapeutic strategies. We are focused on finding immune features in the tumor microenvironment of breast cancer (BC), using patients’ samples, which could be translated into putative biomarkers of patient’s response to conventional treatment or into new targeted therapies.
Triple-negative breast cancer (TNBC) is the most aggressive form of BC. Women from African-origin, who have a higher frequency of this BC subtype, have a worse prognosis and a higher mortality rate. To clarify the biology of this BC subtype and this race disparity we are using bioinformatics and patients’ samples to analyse immune and non-immune molecular traits of TNBC that are altered in African patients regarding other races/other BC subtypes.
Tissue and organ regeneration
Inflammation also plays a dual role in tissue/organ regeneration. Regeneration seems to depend on a critically balanced interaction between pro and anti-inflammatory cells/molecules. We are interested in clarifying the immune events involved in human renal regeneration after an episode of acute kidney injury (AKI), and in identifying potential urinary immune biomarkers (immune cells and immune secreted soluble factors) of this regenerative process.
Ontogeny of the hematopoietic system
Macrophages play critical roles in tissue integrity and host defense. Vertebrates have two major macrophage lineages with different developmental origins: the bone marrow-derived population and the tissue-resident population (including microglia), which develops from yolk-sac progenitors. In contrast to our current knowledge on bone marrow-derived macrophages, little is known about the biology of tissue-resident macrophages, including how their origin impacts on their specific functions in tissue homeostasis and inflammation. Using lineage-specific genetic tools in different vertebrate models (zebrafish, chick and mouse), we are investigating the ontogeny of tissue-resident macrophages and microglial cells, and the pathological consequences of their malformation during development.
Two-day-old chicken embryo with stained hematopoietic progenitors.
Two-day-old zebrafish larva with stained blood vessels and blood cells
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The Discoveries Center mission is to perform world-leading research in regenerative and precision medicine, by anchoring research activities of the best research groups in Portugal, promoting excellence, advanced training, increasing performance, translational research outputs and commercialization strategies that can, in the long-run generate an important economic impact, besides impacting the quality of life of an ageing European population affected by neurodegenerative, cardiovascular and musculoskeletal diseases.
Occluding Junctions as novel regulators of epithelial mechanics during development and repair.
Targeting early stages of gut inflammation.
2018: Consortium: HLA-DR+ T cell subsets as biomarkers of breast cancer aggressiveness and patient response to neoadjuvant chemotherapy.
Projectos de Investigação em Medicina 2018/Tagus Tank
Therapeutic Targets for Triple Negative Breast Cancer: Development of mono and bispecific antibodies against Notch1 ligands.
Fundação para a Ciência e Tecnologia (FCT)
Cell plasticity and reprogramming during tissue regeneration
Fundação para a Ciência e Tecnologia (FCT)
Tissue growth regulation during zebrafish regeneration.
Fundação para a Ciência e Tecnologia (FCT)
European Research Council
Genetics of Nonsyndromic Cleft Lip and Palate (NSCLP).
Fundação para a Ciência e Tecnologia (FCT)
The role of reinnervation in tissue regeneration.
Fundação para a Ciência e Tecnologia (FCT)
Microarray analysis of transcription during nerve-dependent fin regeneration in zebrafish.
Gabinete de Apoio à Investigação Científica e Tecnológica
- 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. Expression of HLA-DR in Cytotoxic T Lymphocytes: A Validated Predictive Biomarker and a Potential Therapeutic Strategy in Breast Cancer. Cancers (Basel). 2021 Jul 30;13(15):3841. doi: 10.3390/cancers13153841. PMID: 34359741; PMCID: PMC8345089.
- Silva NV, Carregosa D, Gonçalves C, Vieira OV, Santos CN, Jacinto A, Crespo CL. Dietary Cholesterol-Based Intestinal Inflammation Assay for Improving Drug-Discovery on Inflammatory Bowel Diseases. Front. Cell Dev. Biol., 03 June 2021. doi: 10.3389/fcell.2021.674749
- Ana S. Brandão, Anabela Bensimon-Brito, Raquel Lourenço, Jorge Borbinha, Ana Rosa Soares, António Jacinto. Yap induces osteoblast differentiation by modulating Bmp signalling during zebrafish caudal fin regeneration. Journal of Cell Science 2019 : jcs.231993 doi: 10.1242/jcs.231993
- Lozza L, Moura-Alves P, Domaszewska T, Lage Crespo C5 Streata I, Kreuchwig A, Puyskens A, Bechtle M, Klemm M, Zedler U, Silviu Ungureanu B, Guhlich-Bornhof U, Koehler AB, Stäber M, Mollenkopf HJ, Hurwitz R, Furkert J, Krause G, Weiner J, Jacinto A, Mihai I, Leite-de-Moraes M, Siebenhaar F, Maurer M, Kaufmann SHE. The Henna pigment Lawsone activates the Aryl Hydrocarbon Receptor and impacts skin homeostasis. Sci Rep. 2019 Jul 26;9(1):10878. doi: 10.1038/s41598-019-47350-x.
- Ponte S, Jacinto A, Carvalho L. The occluding junction protein Neurexin-IV is required for tissue integrity in the Drosophila wing disc epithelium. Matters. Apr 5, 2019. DOI 10.19185/matters.201903000014
- Cristo, I., Carvalho, L., Ponte, S., Jacinto, A. (2018). New role for Grainy head in the regulation of adherens junctions turnover is essential to maintain epithelial features in wound healing. J Cell Sci 131(17).
- Carvalho L, Patrício P, Ponte S, Heisenberg C-P, Almeida L, Nunes AS, et al. Occluding junctions as novel regulators of tissue mechanics during wound repair. J Cell Biol 2018;217:4267–83. DOI: 10.1083/jcb.201804048
- Saraiva DP, Guadalupe Cabral M, Jacinto A, Braga S. How many diseases is triple negative breast cancer: the protagonism of the immune microenvironment. ESMO Open 2017;2:e000208. doi: 10.1136/esmoopen-2017-000208
- Saraiva DP, Jacinto A, Borralho P, Braga S, Cabral MG (2018) HLA-DR in Cytotoxic T Lymphocytes Predicts Breast Cancer Patients' Response to Neoadjuvant Chemotherapy Front. Immunol. 9:2605. doi: 10.3389/fimmu.2018.02605
- Tavares AT, Jacinto A and Belo JA (2018) Identification of chick Lefty2 asymmetric enhancer. Matters Select (Zur) doi: 10.19185/matters.201807000006
- Serrado Marques J, Teixeira V, Jacinto A, Tavares AT. Identification of Novel Hemangioblast Genes in the Early Chick Embryo. Cells. 2018 Jan 31;7(2). pii: E9. doi: 10.3390/cells7020009.
- Galliot B, Crescenzi M, Jacinto A, Tajbakhsh S. (2017) Trends in tissue repair and regeneration. Development. 2017 Feb 1;144(3):357-364. doi: 10.1242/dev.144279.
- Portela R, Patrício P, Almeida PL, Sobral RG, Franco JM, Leal CR. (2016) Rotational tumbling of Escherichia coli aggregates under shear. Phys Rev E. 2016 Dec;94(6-1):062402. doi: 10.1103/PhysRevE.94.062402. Epub 2016 Dec 8.
- Coelho S. (2016) What is the Role of HbA1c in Diabetic Hemodialysis Patients? Semin Dial. 2016 Jan-Feb;29(1):19-23. doi: 10.1111/sdi.12408. Epub 2015 Jul 2.
- Yoo SK, Pascoe HG, Pereira T, Kondo S, Jacinto A, Zhang X, Hariharan IK. (2016) Plexins function in epithelial repair in both Drosophila and zebrafish. Nat Commun. 2016 Jul 25;7:12282. doi: 10.1038/ncomms12282.
- Domingues N, Estronca LM, Silva J, Encarnação MR, Mateus R, Silva D, Santarino IB, Saraiva M, Soares MI, Pinho E Melo TM, Jacinto A, Vaz WL, Vieira OV. (2016) Cholesteryl hemiesters alter lysosome structure and function and induce proinflammatory cytokine production in macrophages. Biochim Biophys Acta. 2016 Oct 26. pii: S1388-1981(16)30283-9. doi: 10.1016/j.bbalip.2016.10.009. [Epub ahead of print]
- Ravasio A, Cheddadi I, Chen T, Pereira T, Ong HT, Bertocchi C, Brugues A, Jacinto 3, Kabla AJ, Toyama Y, Trepat X, Gov N, Neves de Almeida L, Ladoux B. Gap geometry dictates epithelial closure efficiency. Nat Commun. 2015. 6:7683. doi: 10.1038/ncomms8683.
- Ravasio A, Cheddadi I, Chen T, Pereira T, Ong HT, Bertocchi Mateus R, Lourenço R, Fang Y, Brito G, Farinho A, Valério F and Jacinto A. Control of tissue growth by Yap relies on cell density and F-actin in zebrafish fin regeneration (2015). Development 146 (16): 2752-2763. doi: 10.1242/dev.119701.
- Carvalho, L., Jacinto, A., Matova, N. (2014) The Toll/NF-kappaB signaling pathway is required for epidermal wound repair in Drosophila. Proc Natl Acad Sci U S A. 111(50):E5373-82
- Simões MG, Bensimon-Brito A, Fonseca M, Farinho A, Valério F, Sousa S, Afonso N, Kumar A, Jacinto A. Denervation impairs regeneration of amputated zebrafish fins. BMC Dev Biol. 2014 Dec 31; 14:49. doi: 10.1186/s12861-014-0049-2.
- Monteiro J, Aires R, Becker JD, Jacinto A, Certal AC, Rodríguez-León J.V-ATPase proton pumping activity is required for adult zebrafish appendage regeneration. PLoS One. 2014 Mar 26;9(3):e92594. doi:10.1371/journal.pone.0092594.
- Regan JC, Brandão AS, Leitão AB, Mantas Dias AR, Sucena E, Jacinto A, Zaidman-Rémy A. Steroid hormone signaling is essential to regulate innate immune cells and fight bacterial infection in Drosophila. PLoS Pathog. 2013 Oct;9(10):e1003720. doi: 10.1371/journal.ppat.1003720.
- Moreira CG, Jacinto A, Prag S. Drosophila integrin adhesion complexes are essential for hemocyte migration in vivo. Biol Open. 2013 Jun 6;2(8):795-801.
- Antunes M, Pereira T, Cordeiro JV, Almeida L, Jacinto A. Coordinated waves of actomyosin flow and apical cell constriction immediately after wounding. J Cell Biol. 2013 Jul 22;202(2):365-79.
- Teixeira N, Varahan S, Gorman MJ, Palmer KL, Zaidman-Remy A, Yokohata R, Nakayama J, Hancock LE, Jacinto A, Gilmore MS, de Fátima Silva Lopes M. Drosophila host model reveals new enterococcus faecalis quorum-sensing associated virulence factors. PLoS One. 2013 May 29;8(5):e64740.
- Cordeiro JV, Jacinto A. The role of transcription-independent damage signals in the initiation of epithelial wound healing. Nat Rev Mol Cell Biol. 2013 Apr;14(4):249-62. Review.
- Henriques CM, Carneiro MC, Tenente IM, Jacinto A, Ferreira MG. Telomerase is required for zebrafish lifespan. PLoS Genet. 2013;9(1):e1003214.
- Azevedo AS, Sousa S, Jacinto A, Saúde L. An amputation resets positional information to a proximal identity in the regenerating zebrafish caudal fin. BMC Dev Biol. 2012 Aug 25;12:24. doi: 10.1186/1471-213X-12-24.
- Mateus R, Pereira T, Sousa S, de Lima JE, Pascoal S, Saúde L, Jacinto A. In vivo cell and tissue dynamics underlying zebrafish fin fold regeneration. PLoS One. 2012;7(12):e51766. doi: 10.1371/journal.pone.0051766.
- Sousa S, Valerio F, Jacinto A. A new zebrafish bone crush injury model. Biol Open. 2012 Sep 15;1(9):915-21. doi:10.1242/bio.2012877.
- Moreira CG, Regan JC, Zaidman-Rémy A, Jacinto A, Prag S. Drosophila hemocyte migration: an in vivo assay for directional cell migration. Methods Mol Biol. 2011; 769:249-60.
- Azevedo D, Antunes M, Prag S, Ma X, Hacker U, Brodland GW, Hutson MS, Solon J, Jacinto A. DRhoGEF2 regulates cellular tension and cell pulsations in the Amnioserosa during Drosophila dorsal closure. PLoS One. 2011;6(9):e23964. Epub 2011 Sep 16.
- Zaidman-Rémy A, Regan JC, Brandão AS, Jacinto A. The Drosophila larva as a tool to study gutassociated macrophages: PI3K regulates a discrete hemocyte population at the proventriculus. Dev Comp Immunol. Nov 4, 2011.
- Geiger JA, Carvalho L, Campos I, Santos AC, Jacinto A. Hole-in-One Mutant Phenotypes Link EGFR/ERK Signaling to Epithelial Tissue Repair in Drosophila. PLoS One. 2011;6(11):e28349. Epub 2011 Nov 29.
- Campos, I., Geiger, J.A., Santos, A.C., Carlos, V., Jacinto, A. (2009) Genetic Screen in Drosophila melanogaster Uncovers a Novel Set of Genes Required for Embryonic Epithelial Repair. Genetics. 2009 Nov 2.
- Garcia-Fernandez B, Campos I, Geiger J, Santos AC, Jacinto A. (2009). Epithelial resealing. Int J Dev Biol. 53(8-10):1549-56.
- Garcia-Fernandez, B., Martinez-Arias, A., and Jacinto, A. (2007). Dpp signalling orchestrates dorsal closure by regulating cell shape changes both in the amnioserosa and in the epidermis. Mech Dev, 124, 884-897.
- Wood W, Jacinto A (2007). Drosophila melanogaster embryonic haemocytes: masters of multitasking. Nat Rev Mol Cell Biol 8: 542-551.
- Simoes, S., Denholm, B., Azevedo, D., Sotillos, S., Martin, P., Skaer, H., Castelli-Gair Hombria, J. and Jacinto, A. (2006). Compartmentalization of Rho regulators directs cell invagination during tissue morphogenesis. Development 133, 4257-4267.
- Lovegrove, B., Simoes, S., Rivas, M. L., Sotillos, S., Johnson, K., Knust, E., Jacinto, A. and Castelli-Gair Hombria J. (2006). Co-ordinated control of cell adhesion, cell polarity and cytoskeleton underlies Hox induced organogenesis in Drosophila. Curr Biol 16, 2206-2216.
- Köppen, M., García-Fernández, B., Carvalho, L., Jacinto, A. and Heisenberg, C-P. (2006). Coordinated cell shape changes control epithelial movement in zebrafish and Drosophila. Development 133, 2671-2681.
- Wood, W., Faria, C. and Jacinto A. (2006) Distinct mechanisms regulate hemocyte chemotaxis during development and wound healing in Drosophila. J. Cell Biol 174, 405-416.
- Woolner, S., Jacinto, A. and Paul Martin, P. (2005) The small GTPase Rac plays multiple roles in epithelial sheet fusion—Dynamic studies of Drosophila dorsal closure. Dev Biol 282, 163-173.
- Moita, C., Simoes, S., Moita, L.F., Jacinto, A. and Fernandes, P. (2005). The cadherin superfamily in Anopheles gambiae: a comparative study with Drosophila Melanogaster. Comparative and Functional Genomics 6, 204-216.
- Stramer, B., Wood, W., Galko, M.J., Redd, M., Jacinto, A., Parkhurst, S.M., and Martin, P. (2005). Live imaging of wound inflammation in Drosophila embryos reveals key roles for small GTPases during in vivo cell migration. J. Cell Biol 168, 567-573.
- Jacinto, A. and Baum, B. (2003). Actin in Development. Mech Dev 120, 1337-1349.
. Otília Vieira, Lysosomes in Chronic Human Pathologies & Infection, CEDOC/NMS
. Patrícia Brito, Faculdade de Ciência e Tecnologia, Universidade Nova de Lisboa
. Pedro Patrício, Instituto Superior de Engenharia de Lisboa (Instituto Politécnico de Lisboa), Centro de Física Teórica e Computacional (Universidade de Lisboa)
. Nuno Araújo, Centro de Física Teórica e Computacional (Universidade de Lisboa)
. Joachim Wittbrodt, Department of Developmental Biology, Centre for Organismal Studies (COS), University of Heidelberg, Heidelberg, Germany
. Ravindra Peravali, Head of Screening Center group, Karlsrhue Institute of Technology, Karlsrhue, Germany
. Eurico Morais-de-Sá, i3S Porto, Portugal
. Richard Hampson, Thelial Technologies SA, Lisbon, Portugal
. Ana Barbas, IBET, Lisbon, Portugal
. Hospital de Vila Franca de Xira, Portugal
. Hospital Prof. Doutor Fernando Fonseca, Amadora-Sintra, Portugal
. Hospital CUF Descobertas – Instituto CUF Oncologia, Lisbon, Portugal
. Hospital de Santa Maria, Lisbon, Portugal