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Institute for Bioengineering and Biosciences
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Engineering Organoids for Modeling PKU

Engineering Organoids for Modeling PKU | iBB | Scoop.it

Phenylketonuria (PKU) is a recessive genetic disorder of amino-acid metabolism, where impaired phenylalanine hydroxylase function in the liver of patients leads to the accumulation of neurotoxic phenylalanine levels in the brain. Despite the current knowledge, the chronic effect of PKU in the brain is still poorly understood. In a recent publication in Frontiers in Molecular Neurosciences, DBE faculty and SCERG-iBB researcher Tiago Fernandes, discusses the need for better predictive models, able to recapitulate specific mechanisms of this disease. New exciting in vitro platforms to model specific PKU-derived neuronal impairment are presented in a attempt to understand the impact of phenylalanine in the brain of patients, and ultimately contribute to the understanding of this disease.

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Transcriptomic Profiling of Human Pluripotent Stem Cell-Derived Cerebellar Organoids

Transcriptomic Profiling of Human Pluripotent Stem Cell-Derived Cerebellar Organoids | iBB | Scoop.it

 

Endogenous human brain tissue is not easily available for studying neurodevelopment and neurodegenerative diseases. However, human pluripotent stem cells (PSCs) have been used to generate a variety of glial and neuronal cells of the central nervous system. Still, reproducible protocols for generating in vitro models of the human cerebellum are scarce. In this context, Silva et al. describe the scalable production of human PSC-derived cerebellar organoids using single-use vertical-wheel bioreactors. The transcriptomic profile of cerebellar organoids derived under dynamic conditions demonstrates a faster cerebellar differentiation combined with significant enrichment of extracellular matrix and upregulation of transcripts involved in angiogenesis when compared with the static protocol. The authors anticipate that large-scale production of cerebellar organoids may help developing models for drug screening, toxicological tests and studying pathological pathways involved in cerebellar degeneration.

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Affinity-based Physical Hydrogels for Stem Cell Encapsulation and Differentiation

Affinity-based Physical Hydrogels for Stem Cell Encapsulation and Differentiation | iBB | Scoop.it

Affinity-triggered hydrogels were created using one of the most selective and high-affinity pairs found in Nature, avidin-biotin. The multimerization of biotin was studied by conjugation into different multi-arm polyethylene glycol molecules. Depending on the multimerization, assemblies with tunable affinity constant were obtained leading to hydrogels with different mechanical properties and controllable erosion time and profiles. The results showed that mimicking natural multivalency gave rise to robust biocompatible hydrogel with applications in tissue engineering and stem cell research. The study results from ongoing collaboration between Cecília Roque (FCT-NOVA) and Tiago Fernandes (DBE-Técnico) and was recently published in the ACS journal Biomacromolecules.

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Special Research Topic on “Stem Cell Systems Bioengineering”

Special Research Topic on “Stem Cell Systems Bioengineering” | iBB | Scoop.it

Tiago G. Fernandes from SCERG-iBB is guest-editing a special topic for the open-access journal "Frontiers in Bioengineering and Biotechnology" entitled "Stem Cell Systems Bioengineering". Advances in the bioengineering field have allowed the manipulation of singular aspects of the cellular microenvironment, and this Research Topic aims to focus on outstanding examples of bioengineering approaches used to promote the self-organization of human cells and the production of tissue-like structure formation.

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Teresa Silva Defends PhD Thesis in Bioengineering (Cell Therapies and Regenerative Medicine)

Teresa Silva Defends PhD Thesis in Bioengineering (Cell Therapies and Regenerative Medicine) | iBB | Scoop.it

Teresa Silva will be defending his PhD thesis in Bioengineering (MIT Portugal) at Instituto Superior Técnico, wednesday the 26th October 2018 (15:00 H, room PA3). During the last years, and under the supervision of Carmo Fonseca from IMM and Tiago Fernandes and Evguenia Bekman from SCERG-iBB, Teresa worked on the development of new models to study neurodegenerative diseases such as ataxias that are caused by dysfunction of the cerebellum. The title of her thesis is "Novel bioengineering strategies for modeling cerebellar ataxias”.

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Neural Induction of Human Induced Pluripotent Stem Cells for Neurodevelopmental Toxicity Studies

Neural Induction of Human Induced Pluripotent Stem Cells for Neurodevelopmental Toxicity Studies | iBB | Scoop.it

The ability to differentiate neural progenitors (NP) from human induced pluripotent stem cells (hiPSCs) provides an opportunity to develop new applications for cellular therapy, disease modelling and drug screening. SCERG-iBB researchers developed a platform that can be applied towards the study of the effect of neurotoxic molecules that impair normal embryonic development, such as the antiepileptic drug valproic acid (VPA). It was verified that exposure to VPA led to a prevalence of NP structures over neuronal differentiation, confirmed by analysis of the expression of neural cell adhesion molecule, and neural rosette number and morphology. This methodology can potentially complement current toxicity tests for the detection of teratogenic compounds that can interfere with normal embryonic development. The work was published in Toxicology Letters.

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Featured Photo: hiPSC-Derived Cardiomyocytes

Featured Photo: hiPSC-Derived Cardiomyocytes | iBB | Scoop.it
Description: Culture of hiPSC-derived cardiomyocytes expressing Cardiac Troponin T (green) and N-Cadherin (red) featured photo by Tiago Dias, Copyright SCERG-iBB 2016. 

Context: SCERG researchers led by Joaquim Cabral, Margarida Diogo and Tiago Fernandes are establishing new methodologies for cardiac differentiation of human induced pluripotent stem cells (hiPSC). The work is being performed in the context of iBB’s Strategic Area 1: Stem Cell Engineering.
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Tiago Fernandes selected for 2016 Regenerative Medicine Workshop Young Investigator Postdoctoral Award

Tiago Fernandes selected for 2016 Regenerative Medicine Workshop Young Investigator Postdoctoral Award | iBB | Scoop.it

The work entitled, “Factorial Analysis of Signaling Pathways Involved in Pluripotency and Lineage Specification Reveals a Dominant Effect of Wnt Signaling in Mesendoderm Differentiation of Human Pluripotent Stem Cells,” by Tiago Fernandes from BERG-iBB and coworkers has been selected for the inaugural 2016 Regenerative Medicine Workshop Young Investigator Postdoctoral Award, which will take place at the Harbour Town Clubhouse & Conference Center, SC, USA. As the awardee, Tiago Fernandes will be given a featured presentation at the workshop, on Saturday, March 19, 2016 at 10:00 a.m.

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3D Microarray Platform for Toxicology Assays in Neural Development

3D Microarray Platform for Toxicology Assays in Neural Development | iBB | Scoop.it

In collaboration with Rensselaer Polytechnic Institute (RPI/USA), BERG researchers at the Stem Cell Bioengineering and Regenerative Medicine Laboratory (SCBL) have recently developed a 3D microarray platform to perform high-throughput studies of human Neural Stem Cell (hNSC) Differentiation and Toxicology. By using this platform it is possible to screen for the differential toxicity of small molecules to hNSCs which may help to predict, in vitro, which compounds pose an increased threat to neural development and should therefore be prioritized for further screening and evaluation. The work was published in “Stem Cell Research” journal. Click on title to learn more,

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Modeling Rett Syndrome with Human Pluripotent Stem Cells: Mechanistic Outcomes and Future Clinical Perspectives

Modeling Rett Syndrome with Human Pluripotent Stem Cells: Mechanistic Outcomes and Future Clinical Perspectives | iBB | Scoop.it

Rett syndrome (RTT) is a rare neurodevelopmental disorder caused by mutations in the gene encoding for the MeCP2 protein. Among different roles, MeCP2 has a high phenotypic impact during the different stages of brain development. Thus, it is essential to investigate the function of MeCP2 and its regulated targets. In a review paper published in the International Journal of Molecular Sciences, a team of researchers at SCERG-iBB provides a brief summary of the main neurological features of RTT and of the impact of MeCP2 mutations in the neuropathophysiology of the disease. A thorough revision of recent advances and future prospects of RTT modeling using human neural cells derived from pluripotent stem cells and its contribution for the current and future clinical trials for RTT is also provided.

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Modeling Rett Syndrome With Human Patient-Specific Forebrain Organoids

Modeling Rett Syndrome With Human Patient-Specific Forebrain Organoids | iBB | Scoop.it

Engineering brain organoids from human induced pluripotent stem cells (hiPSCs) is a powerful tool for modeling brain development and neurological disorders. Rett syndrome (RTT), a rare neurodevelopmental disorder, can greatly benefit from this technology, since it affects multiple neuronal subtypes in forebrain sub-regions. SCERG-iBB researchers have recently established dorsal and ventral forebrain organoids from control and RTT patient-specific hiPSCs recapitulating the 3D organization and functional network complexity of this brain region. The data obtained revealed a premature development of the deep-cortical layer, associated to the formation of TBR1 and CTIP2 neurons, and a lower expression of neural progenitor/proliferative cells in RTT dorsal organoids. Moreover, calcium imaging and electrophysiology analysis demonstrated functional defects of RTT neurons. Additionally, assembly of RTT dorsal and ventral organoids revealed impairments of interneuron’s migration. Overall, these models provide a better understanding of RTT during early stages of neural development, demonstrating a great potential for personalized diagnosis and drug screening. The paper was published in Frontiers in Cell Development Biology.

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Maturation of Human Pluripotent Stem Cell-Derived Cerebellar Neurons in the Absence of Co-Culture

Maturation of Human Pluripotent Stem Cell-Derived Cerebellar Neurons in the Absence of Co-Culture | iBB | Scoop.it

In a new paper published in Frontiers in Bioengineering and Biotechnology, SCERG-iBB researchers in collaboration with colleagues from the Institute of Molecular Medicine (iMM) describe a novel differentiation strategy that uses defined medium to generate Purkinje cells, granule cells, interneurons, and deep cerebellar nuclei projection neurons, that self-formed and matured into electrically active cells. This research is expected to result in better models for the study of cerebellar dysfunctions and represent an important advancement towards the development of autologous replacement strategies for treating cerebellar degenerative diseases.

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Design Principles for Pluripotent Stem Cell-Derived Organoid Engineering

Design Principles for Pluripotent Stem Cell-Derived Organoid Engineering | iBB | Scoop.it

Human morphogenesis is a complex process involving distinct microenvironmental and physical signals that are manipulated in space and time to give rise to complex tissues and organs. The development of organoids represents a novel way to modeling such complexity. Advances in the bioengineering field have allowed the manipulation of different components, including cellular and noncellular factors, to better mimic the natural microenvironment and generate better organoid models of human morphogenesis. In a paper published in Stem Cells International, a team of researchers from the Stem Cell Engineering Research Group (SCERG) at iBB in collaboration with the Institute of Molecular Medicine reviewed the bioengineering strategies used to control the initial state and spatiotemporal positioning of cells within organoids and, lastly, the growth and remodeling of multicellular aggregates to achieve mini organ-like structures.

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Expansion of Human Induced Pluripotent Stem Cells in Vertical-Wheel Bioreactors

Expansion of Human Induced Pluripotent Stem Cells in Vertical-Wheel Bioreactors | iBB | Scoop.it

The successful use of Human induced Pluripotent Stem Cells (hiPSC) for disease modelling, drug discovery and, ultimately, for regenerative therapies depends on the development of robust bioprocesses capable of generating large numbers of hiPSC and derivatives. SCERG-iBB researchers developed a bioprocess for the scalable generation of hiPSC in a microcarrier-based system using, for the first time, single-use Vertical-Wheel bioreactors. hiPSC culture was performed in working volumes up to 300 mL, maintaining the pluripotency and genomic integrity of the cells, providing an important tool for the successful manufacturing of hiPSC-based products.  The work was published in the Journal of Chemical Technology and Biotechnology.

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Structural Maturation of Human Cardiomyocytes Derived from Pluripotent Stem Cells

Structural Maturation of Human Cardiomyocytes Derived from Pluripotent Stem Cells | iBB | Scoop.it

Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) have an enormous potential for in vitro modeling of cardiac diseases and for testing the effect and toxicity of new drugs. However, when compared to adult CMs, hiPSC-CMs are very immature, exhibiting low structural development and functionality. SCERG-iBB researchers developed a novel methodological framework to quantify structural aspects of hiPSC-CMs during long-term culture. hiPSC-CMs showed significant progression in several structural characteristics namely cardiomyocyte fiber density and length. Importantly, this methodology contributes to set new metrics to develop applications for drug screening and disease modeling for hiPSC-CMs. The research has been published on Biochemical and Biophysical Research Communications.

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Stem Cell Biosystems Engineering

Stem Cell Biosystems Engineering | iBB | Scoop.it
Tiago Fernandes, will be giving a talk entitled “Stem Cell Biosystems Engineering”, Monday the 10th April, at 12h30m, in room QA1.3, South Tower, IST (Alameda). The seminar will highlight progress made on integrated platforms that brings together engineering and biology in order to accelerate progress towards designing the stem cell fate and its microenvironment. Tiago Fernandes is currently an Assistant Professor ate DBE, IST and a Research Associate at SCERG-iBB. His research has focused on the development of predictive models of signaling networks from raw data, study the dynamic regulation of pluripotency circuit components, and gain new insights into the regulatory mechanisms underlying multilineage cell specification, ultimately enabling novel tools for Regenerative and Precision Medicine, including stem cell-based therapies, and thus positively impacting health and welfare. The talk is included in the 2nd Edition of iBB seminars.
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Neural Commitment of Human Pluripotent Stem Cells Under Defined Conditions Recapitulates Neural Development and Generates Patient-specific Neural Cells

Neural Commitment of Human Pluripotent Stem Cells Under Defined Conditions Recapitulates Neural Development and Generates Patient-specific Neural Cells | iBB | Scoop.it

In a recent publication in Biotechnology Journal researchers from the Stem Cell Bioengineering and Regenerative Medicine Laboratory (SCBL) at BERG-iBB describe a novel methodology capable of providing patient-specific neural cells under defined conditions using vitronectin and dual SMAD inhibition. The authors show how pluripotent stem cells can be used to generate patient-specific neural cells that could be used to gain a better understanding of disease mechanisms. This ability to recapitulate the development of the human nervous system in vitro could provide important insights on the mechanisms involved in the maturation of specific neural cell types, making this approach transversal to other related areas in neurodevelopmental research.

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