Our research interest is Cellular Mechanobiology. We are currently focused on the implications & molecular mechanisms underlying mechanical modulation of neural cells and mesenchymal stem/stromal cells (MSCs).

We develop cell-culture platforms with defined biochemical and mechanical features mimicking physiological or pathological properties of the extracellular matrix, being usable for a wide range of cells, conditions and applications.

Mechanobiology of neural cells
It was reported that CNS diseases like Multiple Sclerosis (MS) or Alzheimer’s disease (AD) are accompanied by changes in the mechanical properties of the brain.

We showed that oligodendrocytes are highly mechanosensitive cells (doi:10.3389/fncel.2016.00277, doi: 10.1038/srep21563), being currently elucidating its underlying molecular mechanisms, aiming to understand specific aspects of oligodendrocyte biology and disease (particularly MS) and to exploit mechanobiology-based screening platforms to study novel therapeutic agents.

We are also exploring mechanotransduction in a context of AD, by targeting specific intracellular mechanisms involved in the disease identified as being regulated by mechanosignalling, hence elucidating its fundamental mechanisms and exploiting future therapeutic opportunities.

Mechanomodulation of MSCs
MSCs are adult progenitor cells with extensive self-renewal and differentiation capacity (doi:10.1371/journal.pone.0111059), holding a great potential for cell-based clinical applications. MSCs also provide important trophic and immunomodulatory factors that may contribute to tissue regeneration and regulation of inflammation & immunity.

We are tackling the mechanomodulation of MSCs during reprogramming (doi:10.1038/s41598-019-45352-3) and differentiation towards clinically-relevant lineages. We are also elucidating the molecular mechanisms underlying the response of MSCs to mechanical cues and its influence in the MSC proteome, as well as exploitation of future clinical applications.


Keywords 

Mechanobiology
Cell Biology
Intracellular signaling
Stem Cells
Cell fate decisions
 

Research Lines

1.    Oligodendrocyte mechanobiology and multiple sclerosis

2.    Neuronal mechanotransduction and Alzheimer’s disease

3.    Molecular mechanisms underlying mechanotransduction in mechanosensitive cells

4.    Mechanomodulation of MSC during reprogramming and differentiation

5.    Mechanomodulation of the MSC proteome

Ongoing Research Projects

Projects as PI or Co-PI

2019 – 2021, co-PI (consortium project), ‘MSCellProduction' project, led by STEMLAB S.A., supported by the Portuguese program Portugal 2020/Programa Operacional Competitividade e Internacionalização (project nr. POCI-01-0247-FEDER-038313) and co-funded by the European Regional Development Fund (ERDF).

2018 - 2021, PI, ‘BrEin-MS — Brain Elasticity in Multiple Sclerosis and implications in mechanomodulation of oligodendrocytes: a cellular and clinical approach”, reference POCI-01-0145-FEDER-029516, co-financed by the ERDF under the framework "POCI” (Competitiveness and Internationalization Operational Program) and by national funds through FCT/MCTES through the State Budget.

Ficha do Projeto

Projects as member of team

2018 – 2021, member of team (PI Bruno Manadas, CNC), ‘New approaches on Hypoxic-Ischemic Encephalopathy: translational research to diagnose and monitor stem cell therapy’, reference POCI-01-0145-FEDER-029311, co-financed by the ERDF under the framework "POCI” (Competitiveness and Internationalization Operational Program) and by national funds through FCT/MCTES through the State Budget.

2016 – 2019, member of team (PI Carlos B. Duarte, CNC), ‘Novel cerebrospinal fluid and serum biomarkers for Multiple Sclerosis’, Grant RG-1601-07502, funded by the National Multiple Sclerosis Society (NMSS), USA.

External Collaborations

Artur Paiva, Coimbra University Hospital Center (CHUC), Coimbra, Portugal, https://www.chuc.min-saude.pt/paginas/servicos-do-chuc/patologia-clinica.php

Cláudia Lobato da Silva, Instituto Superior Técnico (IST), Lisbon, Portugal, http://scerg.tecnico.ulisboa.pt/cldasilva.html

Gonçalo Castelo-Branco, Karolinska Institute, Sweden, https://ki.se/en/mbb/goncalo-castelo-branco-group

João B. Relvas, I3S/IBMC, University of Porto, Porto, Portugal, https://www.i3s.up.pt/research-group?x=25#researchTeam

João Carvalho, Centro de Física da Universidade de Coimbra (CFisUC), Department of Physics, University of Coimbra, Coimbra, Portugal, https://cfisuc.fis.uc.pt/people.php?oid=77424

José Lopes da Silva, QOPNA, Chemistry Department, University of Aveiro, Aveiro, Portugal, https://www.ua.pt/qopna/PageText.aspx?id=17760

Livia Sousa, Coimbra University Hospital Center (CHUC), Coimbra, Portugal, http://www.neurohuc.com/corpoclinico.php, https://www.linkedin.com/in/livia-sousa-89021538/

Miguel Castelo-Branco, Coimbra Institute for Biomedical Imaging and Translational Research (CIBIT), University of Coimbra, Portugal, https://www.uc.pt/en/uid/cibit/AboutUs/CIBITpeople, https://orcid.org/0000-0003-4364-6373

Rui Bernardes, Coimbra Institute for Biomedical Imaging and Translational Research (CIBIT), University of Coimbra, Portugal, https://www.uc.pt/en/uid/cibit/AboutUs/CIBITpeople, https://orcid.org/0000-0002-6677-2754

Rui D. M. Travasso, Centro de Física da Universidade de Coimbra (CFisUC), Department of Physics, University of Coimbra, Coimbra, Portugal, https://cfisuc.fis.uc.pt/people.php?oid=144244

Funding Agencies 

• Fundação para a Ciência e a Tecnologia — FCT
• European Regional Development Fund (ERDF)
• Portugal 2020/POCI
• National Multiple Sclerosis Foundation

Selected Publications

Floriddia EM, Lourenco T, Zhang S, van Bruggen D, Hilscher MM, Kukanja P, Goncalves Dos Santos JP, Altinkok M, Yokota C, Llorens-Bobadilla E, Mulinyawe SB, Graos M, Sun LO, Frisen J, Nilsson M, Castelo-Branco G (2020) Distinct oligodendrocyte populations have spatial preference and different responses to spinal cord injury. Nat Commun 11 (1):5860. doi:10.1038/s41467-020-19453-x

Catarina Domingues , A. Margarida Geraldo, Sandra Isabel Anjo , André Matos, Cláudio Almeida, Inês Caramelo, José A. Lopes da Silva , Artur Augusto Paiva , João Carvalho, Ricardo Pires das Neves, Bruno Manadas and Mário Grãos. (2020) Cofilin-1 is a mechanosensitive regulator of transcription., Frontiers in Cell and Developmental Biology (8:678); doi: 10.3389/fcell.2020.00678

Sandra I. Anjo; Patrícia Valério dos Santos; Luiza Rosado; Graça Baltazar; Inês Baldeiras; Diana Pires; Andreia Gomes; Cristina Januário; Miguel Castelo-Branco; Mário Grãos; Bruno Manadas. (2020) A different vision of translational research in biomarker discovery - a pilot study on circulatory mitochondrial proteins as Parkinson's Disease potential biomarkers., Translational Neurodegeneration; doi: 10.1186/s40035-020-00188-0

Gerardo, H., Lima, A., Carvalho, J., Ramos, J. R. D., Couceiro, S., Travasso, R. D. M., . . . Grãos, M. (2019). Soft culture substrates favor stem-like cellular phenotype and facilitate reprogramming of human mesenchymal stem/stromal cells (hMSCs) through mechanotransduction. Sci Rep, 9(1), 9086. doi:10.1038/s41598-019-45352-3

Anjo, S. I., Melo, M. N., Loureiro, L. R., Sabala, L., Castanheira, P., Grãos, M., & Manadas, B. (2019). oxSWATH: An integrative method for a comprehensive redox-centered analysis combined with a generic differential proteomics screening. Redox Biol, 22, 101130. doi:10.1016/j.redox.2019.101130

Lourenço, T., & Grãos, M. (2016). Modulation of oligodendrocyte differentiation by mechanotransduction. Frontiers in Cellular Neuroscience, 10(277). doi:10.3389/fncel.2016.00277

Lourenco, T., Paes de Faria, J., Bippes, C. A., Maia, J., Lopes-da-Silva, J. A., Relvas, J. B., & Grãos, M. (2016). Modulation of oligodendrocyte differentiation and maturation by combined biochemical and mechanical cues. Sci Rep, 6, 21563. doi:10.1038/srep21563

Leite, C., Silva, N. T., Mendes, S., Ribeiro, A., de Faria, J. P., Lourenco, T., . . . Grãos, M. (2014). Differentiation of human umbilical cord matrix mesenchymal stem cells into neural-like progenitor cells and maturation into an oligodendroglial-like lineage. PLoS One, 9(10), e111059. doi:10.1371/journal.pone.0111059

Maia, J., Vazao, H., Pedroso, D. C., Jesus, C. S., Brito, R. M., Grãos, M., . . . Ferreira, L. (2012). VEGF-functionalized dextran has longer intracellular bioactivity than VEGF in endothelial cells. Biomacromolecules, 13(9), 2906-2916. doi:10.1021/bm3009268

Gomes, J. R., Costa, J. T., Melo, C. V., Felizzi, F., Monteiro, P., Pinto, M. J., . . ., Grãos, M., Duarte, C. B. (2012). Excitotoxicity downregulates TrkB.FL signaling and upregulates the neuroprotective truncated TrkB receptors in cultured hippocampal and striatal neurons. J Neurosci, 32(13), 4610-4622. doi:10.1523/JNEUROSCI.0374-12.2012

Goncalves, J. P.*, Graos, M.*, & Valente, A. X. (2009). POLAR MAPPER: a computational tool for integrated visualization of protein interaction networks and mRNA expression data. J R Soc Interface, 6(39), 881-896. doi:10.1098/rsif.2008.0407

Grãos, M., Almeida, A. D., & Chatterjee, S. (2005). Growth-factor-dependent phosphorylation of Bim in mitosis. Biochem J, 388(Pt 1), 185-194. doi:10.1042/BJ20041385

Almeida, R. D., Manadas, B. J., Melo, C. V., Gomes, J. R., Mendes, C. S., Grãos, M., . . . Duarte, C. B. (2005). Neuroprotection by BDNF against glutamate-induced apoptotic cell death is mediated by ERK and PI3-kinase pathways. Cell Death Differ, 12(10), 1329-1343. doi:10.1038/sj.cdd.4401662

​*These authors contributed equally to this work and are considered co-first author.