Areas of focus

Currently, the Biomaterials and Stem Cell-Based Therapeutic research group has two main avenues of research: (i) development of bioengineering platforms for efficient differentiation and maturation of stem cells into vascular and cardiomyocyte lineages for drug screening and regenerative medicine applications, (ii) development of nanomedicine platforms to modulate the activity of stem cells and their progenies.

1- Bioengineering platforms to modulate the differentiation and maturation of stem cells. One of the main objectives of the research group is to develop biomaterials and bioengineering platforms for the efficient differentiation, maturation and engraftment of stem cells and their progenies (focus: cardiovascular lineages). We are primarily working with human pluripotent stem cells (induced pluripotent stem cells and human embryonic stem cells) and fetal hematopoietic stem cells (human cord blood). The group is developing scaffolds capable of retaining the cells at the desired location, while serving as a template for cell assembly, survival, differentiation and engraftment. The group is also designing biomaterials that provide several different types of information to stem cells, with the purpose of controlling their differentiation. Finally, we are studying new strategies based on topography and fluid shear stress to modulate the differentiation of mesoderm cells such as vascular cells and cardiomyocytes derived from human pluripotent stem cells.

2- Nanomedicine platforms to modulate the activity of stem cells and their progenies. The development of a wide spectrum of nanotechnologies (referred as Nanomedicine by National Institutes of Health for applications in the biomedical area) during the last years are very promising for the study of stem cell biology and to control exogenous and endogenous stem cells for regenerative medicine. Our group is particularly interested to use these tools to induce in vivo stem cell differentiation and to mobilize stem cells from their niches to treat cardiovascular diseases. For this purpose, we are developing nanomaterials that release efficiently small molecules or non-coding RNA (miRNAs) to manipulate stem cells or their progenies.

Significance
Cardiovascular diseases (CVDs), a group of disorders of the heart and blood vessels, are the number one cause of death globally. More people die annually from CVDs than from any other cause. In 2005, 17.5 million people around the world died from CVDs, representing 30% of all global deaths (data from World Health Organization). Of these deaths, an estimated 7.6 million were due to coronary heart disease and 5.7 million were due to stroke. In Portugal, CVDs are the most common cause of death and morbidity. Stem cells are an important source of cells for regenerative medicine applications. Several clinical trials are underway to investigate their therapeutic effects. Yet, it is of utmost importance to understand the bioactivity of stem cells and eventually to control it. The paracrine effect of stem cells remains to be elucidated as well as new platforms to improve stem cell survival after transplantation. Stem cells are also an important source of cardiac and vascular cells for drug screening and toxicological assessment. They can be an useful in vitro model to study specific diseases and to find new therapeutic targets.
 

Approaches
We use many approaches to answer our research questions, including the design of new biomaterials (nanoparticles, microparticles, gels, coatings, etc…) with relevant biological information, molecular and cell biology, microfluidic systems, high content analysis, and animal experimentation. We have designed nanomaterials that can be monitored by Magnetic Resonance Imaging (MRI) and efficiently deliver miRNAs within cells, nanomaterials that can release efficiently hydrophobic small molecules such as retinoic acid, gels to efficiently transplant stem cells in chronic wounds, etc… We use molecular analysis to identify signaling pathways that are activated when cells are exposed to specific signals or extracellular matrixes. We have high experience in the differentiation of pluripotent stem cells into vascular lineages (endothelial and smooth muscle cells). We are also working with disesase-specific induced pluripotent stem cells (iPSCs) that can provide insights into the mechanisms underlying cardiovascular diseases.

Contributions

Our laboratory has developed methodologies to differentiate efficiently human pluripotent stem cells into vascular cells (smooth muscle cells and endothelial cells), a stem cell based therapy to treat diabetic chronic wounds, 3D scaffolds for stem cell differentiation and transplantation, platforms to modulate exogenous and endogenous stem cell niches, and a nano-formulation that is able to monitor transplanted cells in vivo by non-invasive imaging methods such as MRI and to manipulate simultaneously them by intracellular delivery of miRNAs. Our laboratory has started a biomaterials spin-off (Matera) with headquarters at Biocant (Cantanhede). Furthermore, the group has licensed to companies 5 patents in the last 5 years. The group has been awarded in 2012 with an ERC grant.

Further information: http://biomaterials.biocant.pt/wp/

Lino Ferreira Group Leader Principal Investigator   Tlf. 231419040		Akhilesh Rai   Assistant Researcher		Luis Estronca   Lab Manager		Susana Rosa   Post-Doc
Sónia Pinho   Post-Doc		Vitor Francisco   Post-Doc		Susana Simões   Post-Doc		Arnab Banerjee   Post-Doc
Henrique V. Almeida   Post-Doc		Patricia Pitrez   Post-Doc		Luis Monteiro   PhD Student		Deolinda Santinha   PhD Student
Catarina Rebelo   PhD Student		Emanuel Quartim   PhD Student		Helena Antunes   PhD Student		Andreia Vilaça   PhD Student
Rita Sa Ferreira   PhD Student		Ricardo Abreu   PhD Student		Inês Tomé   MSc Student		Helena Aires   MSc Student
Catia Seabra   MSc Student		Antonio Santinha   MSc Student		Vanessa Pinto   MSc Student		João Freitas   Collaborator
Cristiana Paulo   Collaborator		Miguel Lino   Technician		Josephine Blersch   Technician		Catarina Almeida   Technician

Alumini

Funding

Designação do projeto: LIghtBRARY .: Uma biblioteca de nanoparticulas activáveis por acção da luz para a libertação de terapias baseadas em RNA
 

Código do projeto: POCI-01-0145-FEDER-029414  

Objetivo Principal:
Complicações médicas associadas a um deficit na cicatrização da pele constituem um dos grandes problemas na área da saúde. Terapias  baseadas em RNA têm emergido recentemente como uma das terapêuticas mais promissoras para regeneração da pele (2, 3). As terapias baseadas em RNA possuem vantagens relativamente a terapias convencionais baseadas em pequenas moléculas ou outras biomoléculas, tais como especificidade, potencia, numero de alvos acessíveis, produção, etc... (4) Contudo, vários obstáculos precisam de ser ultrapassados antes da translação clínica de terapêuticas baseadas em RNA, em particular, o desenvolvimento de formulações que libertem o RNA em células especificas da pele diminuindo efeitos colaterais e que simultaneamente aumentem a eficácia intracelular do RNA libertado. A hipótese do presente projecto é que nanoparticulas (NPs) activáveis por acção da luz com controlo preciso na libertação de moléculas de RNA em termos de tempo e espaço podem acelerar a translação destas terapias.



Os nossos resultados preliminares mostram que nós conseguimos produzir NPs activáveis pela luz que se dissociam a diferentes velocidades após exposição a radiação UV ou azul. Nós realizamos screenings em grande escala com células repórter para identificar formulações mais facilmente internalizadas por células e que libertassem mais eficientemente siRNA (mais eficientemente que agentes de transfecção comerciais tais como lipofectamina RNAiMAX). Nós identificamos alguns candidatos que foram caracterizados em ensaios secundários no que diz respeito à sua especificidade para células da pele e escape endolisosomal. Neste projecto, nós gostaríamos de expandir a biblioteca de NPs activáveis por acção da luz de forma a ter uma resposta mais rápida quando expostas à luz e demonstrar in vivo o efeito terapêutico dos melhores hits num modelo de cicatrização animal.



Os seguintes objectivos específicos serão prosseguidos: 1- produzir e caracterizar uma biblioteca de NPs activáveis por acção da luz obtida a partir de polímeros com composição química variável e incorporando entidades fotoclivaveis na sua composição; 2- identificar formulações de NPs possuindo uma maior actividade de knockdown que agentes de transfecção comercial, avaliar o mecanismo subjacente e demonstrar a utilidade da formulação em modelos in vitro de cicatrização da pele; 3- avaliar in vivo o efeito terapêutico das melhores formulações de NPs contendo siRNAs relativamente a metodologias convencionais de libertação.



O projecto integra síntese de NPs, analises em grande escala, testes de actividade biológica in vitro e in vivo e integra uma equipa multi-disciplinar formada por académicos Portugueses e por uma grande empresa farmacêutica (AstraZeneca). O projecto contribuirá para o avanço do nosso conhecimento na libertação de terapias baseadas em RNA, formulações avançadas de NPs e cicatrização de pele.

Programa Operacional: Programa Operacional Competitividade e Internacionalização
Data de início: 2018-07-06
Data de conclusão: 2021-07-05

Custo total elegível: 238.697,07€
Apoio financeiro da União Europeia: FEDER

Financiamento foi aprovado pela Comissão Diretiva do Programa Operacional Competitividade e Internacionalização em 2018-04-24, na sua componente FEDER, pela Fundação para a Ciência e Tecnologia, I.P. e homologada pela Tutela, na sua componente nacional.

Publicizing Sheet

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Collaborations Facilities and Equipment

http://biomaterials.biocant.pt/wp/

Collaborations

International collaborations:

Robert Langer
Massachusetts Institute of Technology- MIT, USA)

Jeffrey Karp
Harvard University, USA

Ali Khademhosseini
Harvard University, USA

Tariq Enver
Collaborations Facilities and EquipmentUniversity College of London, UK

Constanza Emanueli
University of Bristol, UK

Xavier Nissam/Marc Peschanski
I-Stem, France

Isidro Sanchez
University of Salamanca, Spain

Hugo Fernandes/ Clemens Blitterswijk
University of Twente, Netherlands

Romeo Cechelli
University of Lille, France

Veronique Préat
University of Louvain, Belgique

Ihor Lemischka/ Filipe Pereira
Mount Sinai, NY, USA

National collaborations:

Joaquim Cabral/ Claudia Lobato
IST, Lisboa

João Malva
Faculdade de Medicina, Universidade de Coimbra

Liliana Bernardino
Universidade da Beira Interior, Covilhã

Eugénia Carvalho
CNC, Coimbra

Rui Carvalho
CNC, Coimbra

Artur Paiva
Hospitais da Universidade de Coimbra (HUCs)

Helena Gil
Departamento de Engenharia Química, Universidade de Coimbra

Lino Gonçalves
Hospitais da Universidade de Coimbra (HUCs)

Miguel Castelo-Branco
Faculdade de Medicina, Universidade de Coimbra

Selected Publications (out of 90)

Carlos Boto, Emanuel Quartin, Yijun Cai, Alberto Martin-Lorenzo, Maria Begona Garcia Cenador, Sandra Pinto, Rajeev Gupta, Tariq Enver, Isidro Sanchez-Garcia, Deng Li, Ricardo Neves, Lino Ferreira. “Prolonged intracellular accumulation of light-inducible nanoparticles in leukemia cells allows their remote activation”. Nature Communications 2017, 8:15204, DOI: 10.1038/ncomms15204.
 
Vazão H*, Rosa S*, Barata T, Costa R, Pereira P, Honório I, Papatsenko D, Benedito R, Saris D, Khademhosseini A, Pereira CF, Mercader N, Fernandes H, Ferreira L. PNAS 2017, 114(15), E3022-E3031. *Authors contributed equally.
 
Sezin Aday, Marie Besnier, Janet Zoldan, Laura Carreto, Jaimy Saif, Rui Fernandes,Tiago Santos, Liliana Bernardino, Robert Langer, Costanza Emanueli, Lino Ferreira. “Synthetic microparticles conjugated with VEGF165 improve the survival and function of endothelial progenitor cells via microRNA-17 inhibition”. Nature Communications 2017 (in press).

Aday, S., Cecchelli, R., Vanhuxeem, D., Dehouck, MP., Ferreira, L. ”Stem cell-based human blood brain barrier models for drug discovery and delivery”. Trends in Biotechnology 2016 (in press). IF: 12.0.

N. Lang*, M.J. Pereira*, I. Friehs, N. Vasilyev, E. N. Feins, K. Ablasser, E. O’Cearbhaill, C. Xu, A. Fabozzo, Y. Lee, R. Padera, S. Wasserman, F. Freudenthal, L.S. Ferreira, R. Langer, J.M. Karp, P. J. del Nido. “A biocompatible light-activated adhesive for minimally invasive repair of cardiovascular defects”. Science Translational Medicine 2014, 6(218), 218ra6. *Authors contributed equally. IF: 15.8

“Nanoparticles for simultaneous cell tracking and pro-survival/angiogenic miRNA delivery in an ischemic animal model”. Gomes, RSM, Neves, R, Cochlin, L, Lima, AF, Carvalho, R, Korpisalo, P, Dragneva, G, Turunen, M, Liimatainen, T, Clarke, K, Yla-Herttuala, S, Carr, CA, Ferreira, L. ACS Nano 2013, 7(4), 3362-3372. IF: 11.4

“A highly tunable elastomer for local and controlled release of macromolecular therapeutics”. Pereira, MJ, Oyuang, B, Sarkar, D, Lang, N, Sunbdback, C, Fiehs, I, Mureli, S, Pometantseva, I, McFaden, J, Sehn, JD, Mwizerwa, O, del Nido, P, Masiakos, P, Langer, R, Ferreira, LS*, Karp, JM*. Advanced Materials 2013, 25(8), 1209-1215. *Authors contributed equally. IF: 13.9

“Polymeric nanoparticles to control the differentiation of neural stem cells in the subventricular zone of the brain”. Santos, T, Ferreira, R, Maia, J, Agasse, F, Xapelli, S, Cortes, L, Bragança, J, Malva, JO, Ferreira, L*, Bernardino, L*. ACS Nano 2012, 6(12), 10463-10474. *Authors contributed equally. IF: 11.4

Kraehenbuehl, TP, Langer, R*, Ferreira, LS*. “Biomaterials for the self-renewal and differentiation of human pluripotent stem cells”. Nature Methods 2011, 8(9), 731-736. *Corresponding authors. IF: 19.3

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Curriculum Vitae

2012-Present: Coordinator Investigator (equiv. Full Professor)

2012-2015: Principal Investigator (equiv. Associate Professor)

2007-2012: Assistant Researcher (equiv. Assistant Professor)

2010: Invited professor at University of Artois (Lille, France)

2009: Founder of Matera, a Biomaterials spin off of Biocant

2008 (January): Launched the laboratory of “Biomaterials and Stem Cell-Based Therapeutics” at CNC.

2004-2007: Postdoctoral Fellow (Massachusetts Institute of Technology -MIT)

2003-2004: Postdoctoral Fellow (Institute of Biomedical Engineering, Porto, Portugal)

1999-2003: Ph.D. in Chemical Engineering and Biotechnology (University of Coimbra, Portugal). Sandwich research program between Rensselaer Polytechnic Institute (USA) and University of Coimbra.

1995-1998: M.Sc. in Biochemistry (University of Coimbra, Portugal)

1989-1994: B.Sc. in Biochemistry (University of Coimbra, Portugal)

Prizes:
2012- ERC Starting grant.
2008- Crioestaminal Prize