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Article: Induced pluripotent stem cell-based organ-on-a-chip as personalized drug screening tools: A focus on neurodegenerative disorders.

Fanizza, Francesca / Campanile, Marzia / Forloni, Gianluigi / Giordano, Carmen / Albani, Diego

2022 Volume 13, Page(s) 20417314221095339

Abstract: The Organ-on-a-Chip (OoC) technology shows great potential to revolutionize the drugs development pipeline by mimicking the physiological environment and functions of human organs. The translational value of OoC is further enhanced when combined with ... ...

Abstract	The Organ-on-a-Chip (OoC) technology shows great potential to revolutionize the drugs development pipeline by mimicking the physiological environment and functions of human organs. The translational value of OoC is further enhanced when combined with patient-specific induced pluripotent stem cells (iPSCs) to develop more realistic disease models, paving the way for the development of a new generation of patient-on-a-chip devices. iPSCs differentiation capacity leads to invaluable improvements in personalized medicine. Moreover, the connection of single-OoC into multi-OoC or body-on-a-chip allows to investigate drug pharmacodynamic and pharmacokinetics through the study of multi-organs cross-talks. The need of a breakthrough thanks to this technology is particularly relevant within the field of neurodegenerative diseases, where the number of patients is increasing and the successful rate in drug discovery is worryingly low. In this review we discuss current iPSC-based OoC as drug screening models and their implication in development of new therapies for neurodegenerative disorders.
Language	English
Publishing date	2022-05-09
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2573915-3
ISSN	2041-7314
ISSN	2041-7314
DOI	10.1177/20417314221095339
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Article ; Online: Development of an Induced Pluripotent Stem Cell-Based Liver-on-a-Chip Assessed with an Alzheimer's Disease Drug.

Fanizza, Francesca / Boeri, Lucia / Donnaloja, Francesca / Perottoni, Simone / Forloni, Gianluigi / Giordano, Carmen / Albani, Diego

ACS biomaterials science & engineering

2023 Volume 9, Issue 7, Page(s) 4415–4430

Abstract: Liver-related drug metabolism is a key aspect of pharmacokinetics and possible toxicity. From this perspective, the availability of advanced in vitro models for drug testing is still an open need, also to the end of reducing the burden of in vivo ... ...

Abstract	Liver-related drug metabolism is a key aspect of pharmacokinetics and possible toxicity. From this perspective, the availability of advanced in vitro models for drug testing is still an open need, also to the end of reducing the burden of in vivo experiments. In this scenario, organ-on-a-chip is gaining attention as it couples a state-of-the art in vitro approach to the recapitulation of key in vivo physiological features such as fluidodynamics and a tri-dimensional cytoarchitecture. We implemented a novel liver-on-a-chip (LoC) device based on an innovative dynamic device (MINERVA 2.0) where functional hepatocytes (iHep) have been encapsulated into a 3D hydrogel matrix interfaced through a porous membrane with endothelial cells (iEndo)]. Both lines were derived from human-induced pluripotent stem cells (iPSCs), and the LoC was functionally assessed with donepezil, a drug approved for Alzheimer's disease therapy. The presence of iEndo and a 3D microenvironment enhanced the expression of liver-specific physiologic functions as in iHep, after 7 day perfusion, we noticed an increase of albumin, urea production, and cytochrome CYP3A4 expression compared to the iHep static culture. In particular, for donepezil kinetics, a computational fluid dynamic study conducted to assess the amount of donepezil diffused into the LoC indicated that the molecule should be able to pass through the iEndo and reach the target iHep construct. Then, we performed experiments of donepezil kinetics that confirmed the numerical simulations. Overall, our iPSC-based LoC reproduced the in vivo physiological microenvironment of the liver and was suitable for potential hepatotoxic screening studies.
MeSH term(s)	Humans ; Induced Pluripotent Stem Cells ; Alzheimer Disease/drug therapy ; Donepezil ; Endothelial Cells ; Liver ; Lab-On-A-Chip Devices
Chemical Substances	Donepezil (8SSC91326P)
Language	English
Publishing date	2023-06-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2373-9878
ISSN (online)	2373-9878
DOI	10.1021/acsbiomaterials.3c00346
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Article ; Online: Microbiota-Host Immunity Communication in Neurodegenerative Disorders: Bioengineering Challenges for In Vitro Modeling.

Boeri, Lucia / Perottoni, Simone / Izzo, Luca / Giordano, Carmen / Albani, Diego

Advanced healthcare materials

2021 Volume 10, Issue 7, Page(s) e2002043

Abstract: Human microbiota communicates with its host by secreting signaling metabolites, enzymes, or structural components. Its homeostasis strongly influences the modulation of human tissue barriers and immune system. Dysbiosis-induced peripheral immunity ... ...

Abstract	Human microbiota communicates with its host by secreting signaling metabolites, enzymes, or structural components. Its homeostasis strongly influences the modulation of human tissue barriers and immune system. Dysbiosis-induced peripheral immunity response can propagate bacterial and pro-inflammatory signals to the whole body, including the brain. This immune-mediated communication may contribute to several neurodegenerative disorders, as Alzheimer's disease. In fact, neurodegeneration is associated with dysbiosis and neuroinflammation. The interplay between the microbial communities and the brain is complex and bidirectional, and a great deal of interest is emerging to define the exact mechanisms. This review focuses on microbiota-immunity-central nervous system (CNS) communication and shows how gut and oral microbiota populations trigger immune cells, propagating inflammation from the periphery to the cerebral parenchyma, thus contributing to the onset and progression of neurodegeneration. Moreover, an overview of the technological challenges with in vitro modeling of the microbiota-immunity-CNS axis, offering interesting technological hints about the most advanced solutions and current technologies is provided.
MeSH term(s)	Bioengineering ; Communication ; Gastrointestinal Microbiome ; Humans ; Microbiota ; Neurodegenerative Diseases
Language	English
Publishing date	2021-03-04
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2649576-4
ISSN	2192-2659 ; 2192-2640
ISSN (online)	2192-2659
ISSN	2192-2640
DOI	10.1002/adhm.202002043
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Article: Unravelling the mechanotransduction pathways in Alzheimer's disease.

Donnaloja, Francesca / Limonta, Emma / Mancosu, Christian / Morandi, Francesco / Boeri, Lucia / Albani, Diego / Raimondi, Manuela Teresa

Journal of biological engineering

2023 Volume 17, Issue 1, Page(s) 22

Abstract: Alzheimer's disease (AD) represents one of the most common and debilitating neurodegenerative disorders. By the end of 2040, AD patients might reach 11.2 million in the USA, around 70% higher than 2022, with severe consequences on the society. As now, we ...

Abstract	Alzheimer's disease (AD) represents one of the most common and debilitating neurodegenerative disorders. By the end of 2040, AD patients might reach 11.2 million in the USA, around 70% higher than 2022, with severe consequences on the society. As now, we still need research to find effective methods to treat AD. Most studies focused on the tau and amyloid hypothesis, but many other factors are likely involved in the pathophysiology of AD. In this review, we summarize scientific evidence dealing with the mechanotransduction players in AD to highlight the most relevant mechano-responsive elements that play a role in AD pathophysiology. We focused on the AD-related role of extracellular matrix (ECM), nuclear lamina, nuclear transport and synaptic activity. The literature supports that ECM alteration causes the lamin A increment in the AD patients, leading to the formation of nuclear blebs and invaginations. Nuclear blebs have consequences on the nuclear pore complexes, impairing nucleo-cytoplasmic transport. This may result in tau hyperphosphorylation and its consequent self-aggregation in tangles, which impairs the neurotransmitters transport. It all exacerbates in synaptic transmission impairment, leading to the characteristic AD patient's memory loss. Here we related for the first time all the evidence associating the mechanotransduction pathway with neurons. In addition, we highlighted the entire pathway influencing neurodegenerative diseases, paving the way for new research perspectives in the context of AD and related pathologies.
Language	English
Publishing date	2023-03-28
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2391582-1
ISSN	1754-1611
ISSN	1754-1611
DOI	10.1186/s13036-023-00336-w
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Article ; Online: An Organ-On-A-Chip Engineered Platform to Study the Microbiota-Gut-Brain Axis in Neurodegeneration.

Raimondi, Manuela Teresa / Albani, Diego / Giordano, Carmen

Trends in molecular medicine

2019 Volume 25, Issue 9, Page(s) 737–740

Abstract: After decades of research, the etiology of neurodegenerative disorders such as Alzheimer's or Parkinson's disease is still mostly unknown. Recent findings indicate that the microorganisms in the human gut might be involved in neurodegenerative pathways. ... ...

Abstract	After decades of research, the etiology of neurodegenerative disorders such as Alzheimer's or Parkinson's disease is still mostly unknown. Recent findings indicate that the microorganisms in the human gut might be involved in neurodegenerative pathways. Here, we discuss an innovative groundbreaking bioengineering approach that could make a difference in this intriguing scenario.
MeSH term(s)	Brain/metabolism ; Disease Susceptibility ; Gastrointestinal Microbiome ; Humans ; In Vitro Techniques ; Intestines ; Lab-On-A-Chip Devices ; Microbiota ; Neurodegenerative Diseases/etiology ; Neurodegenerative Diseases/metabolism ; Neurodegenerative Diseases/pathology ; Precision Medicine ; Tissue Culture Techniques
Language	English
Publishing date	2019-08-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2036490-8
ISSN	1471-499X ; 1471-4914
ISSN (online)	1471-499X
ISSN	1471-4914
DOI	10.1016/j.molmed.2019.07.006
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Article: A miniaturized hydrogel-based

Tunesi, Marta / Izzo, Luca / Raimondi, Ilaria / Albani, Diego / Giordano, Carmen

Journal of tissue engineering

2020 Volume 11, Page(s) 2041731420945633

Abstract: Recent findings have highlighted an interconnection between intestinal microbiota and the brain, referred to as microbiota-gut-brain axis, and suggested that alterations in microbiota composition might affect brain functioning, also in Alzheimer's ... ...

Abstract	Recent findings have highlighted an interconnection between intestinal microbiota and the brain, referred to as microbiota-gut-brain axis, and suggested that alterations in microbiota composition might affect brain functioning, also in Alzheimer's disease. To investigate microbiota-gut-brain axis biochemical pathways, in this work we developed an innovative device to be used as modular unit in an engineered multi-organ-on-a-chip platform recapitulating
Language	English
Publishing date	2020-08-18
Publishing country	England
Document type	Journal Article
ZDB-ID	2573915-3
ISSN	2041-7314
ISSN	2041-7314
DOI	10.1177/2041731420945633
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Article: 3D brain tissue physiological model with co-cultured primary neurons and glial cells in hydrogels.

Raimondi, Ilaria / Tunesi, Marta / Forloni, Gianluigi / Albani, Diego / Giordano, Carmen

Journal of tissue engineering

2020 Volume 11, Page(s) 2041731420963981

Abstract: Recently, researchers have focused on the role of gut microbiota on human health and reported the existence of a bidirectional relationship between intestinal microbiota and the brain, referred to as microbiota-gut-brain axis (MGBA). In this context, the ...

Abstract	Recently, researchers have focused on the role of gut microbiota on human health and reported the existence of a bidirectional relationship between intestinal microbiota and the brain, referred to as microbiota-gut-brain axis (MGBA). In this context, the development of an organ-on-a-chip platform recapitulating the main players of the MGBA would help in the investigations of the biochemical mechanisms involved. In this work, we focused on the development of a new, hydrogel-based, 3D brain-like tissue model to be hosted in the brain compartment of the aforementioned platform. We previously cultured primary mouse microglial cells, cortical neurons and astrocytes independently, once embedded or covered by a millimeter layer of two selected collagen-based hydrogels. We evaluated cell metabolic activity up to 21 days, cell morphology, spatial distribution and synapse formation. Then, we exploited the best performing culturing condition and developed a more complex brain-like tissue model based on the co-culture of cortical neurons and glial cells in physiological conditions. The obtained results indicate that our 3D hydrogel-based brain tissue model is suitable to recapitulate in vitro the key biochemical parameters of brain tissue.
Language	English
Publishing date	2020-10-14
Publishing country	England
Document type	Journal Article
ZDB-ID	2573915-3
ISSN	2041-7314
ISSN	2041-7314
DOI	10.1177/2041731420963981
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Article: Molecular Analysis of the E2F/DP Gene Family of

Perrotta, Lara / Giordo, Roberta / Francis, Dennis / Rogers, Hilary J / Albani, Diego

Frontiers in plant science

2021 Volume 12, Page(s) 652570

Abstract: E2F transcription factors are key components of the RB/E2F pathway that, through the action of cyclin-dependent kinases, regulates cell cycle progression in both plants and animals. Moreover, plant and animal E2Fs have also been shown to regulate other ... ...

Abstract	E2F transcription factors are key components of the RB/E2F pathway that, through the action of cyclin-dependent kinases, regulates cell cycle progression in both plants and animals. Moreover, plant and animal E2Fs have also been shown to regulate other cellular functions in addition to cell proliferation. Based on structural and functional features, they can be divided into different classes that have been shown to act as activators or repressors of E2F-dependent genes. Among the first plant E2F factors to be reported, we previously described DcE2F1, an activating E2F which is expressed in cycling carrot (
Language	English
Publishing date	2021-03-12
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2711035-7
ISSN	1664-462X
ISSN	1664-462X
DOI	10.3389/fpls.2021.652570
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Article: The microbiota-gut-brain axis and epilepsy from a multidisciplinary perspective: Clinical evidence and technological solutions for improvement of in vitro preclinical models.

Fusco, Federica / Perottoni, Simone / Giordano, Carmen / Riva, Antonella / Iannone, Luigi Francesco / De Caro, Carmen / Russo, Emilio / Albani, Diego / Striano, Pasquale

Bioengineering & translational medicine

2022 Volume 7, Issue 2, Page(s) e10296

Abstract: Epilepsy is a common neurological disease characterized by the enduring predisposition of the brain to generate seizures. Among the recognized causes, a role played by the gut microbiota in epilepsy has been hypothesized and supported by new ... ...

Abstract	Epilepsy is a common neurological disease characterized by the enduring predisposition of the brain to generate seizures. Among the recognized causes, a role played by the gut microbiota in epilepsy has been hypothesized and supported by new investigative approaches. To dissect the microbiota-gut-brain (MGB) axis involvement in epilepsy, in vitro modeling approaches arouse interest among researchers in the field. This review summarizes, first of all, the evidence of a role of the MGB axis in epilepsy by providing an overview of the recent clinical and preclinical studies and showing how dietary modification, microbiome supplementations, and hence, microbiota alterations may have an impact on seizures. Subsequently, the currently available strategies to study epilepsy on animal and in vitro models are described, focusing attention on these latter and the technological challenges for integration with already existing MGB axis models. Finally, the implementation of existing epilepsy in vitro systems is discussed, offering a complete overview of the available technological tools which may improve reliability and clinical translation of the results towards the development of innovative therapeutic approaches, taking advantage of complementary technologies.
Language	English
Publishing date	2022-02-25
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2380-6761
ISSN	2380-6761
DOI	10.1002/btm2.10296
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Article ; Online: Using integrated meta-omics to appreciate the role of the gut microbiota in epilepsy.

Boeri, Lucia / Donnaloja, Francesca / Campanile, Marzia / Sardelli, Lorenzo / Tunesi, Marta / Fusco, Federica / Giordano, Carmen / Albani, Diego

Neurobiology of disease

2022 Volume 164, Page(s) 105614

Abstract: The way the human microbiota may modulate neurological pathologies is a fascinating matter of research. Epilepsy is a common neurological disorder, which has been largely investigated in correlation with microbiota health and function. However, the ... ...

Abstract	The way the human microbiota may modulate neurological pathologies is a fascinating matter of research. Epilepsy is a common neurological disorder, which has been largely investigated in correlation with microbiota health and function. However, the mechanisms that regulate this apparent connection are scarcely defined, and extensive effort has been conducted to understand the role of microbiota in preventing and reducing epileptic seizures. Intestinal bacteria seem to modulate the seizure frequency mainly by releasing neurotransmitters and inflammatory mediators. In order to elucidate the complex microbial contribution to epilepsy pathophysiology, integrated meta-omics could be pivotal. In fact, the combination of two or more meta-omics approaches allows a multifactorial study of microbial activity within the frame of disease or drug treatments. In this review, we provide information depicting and supporting the use of multi-omics to study the microbiota-epilepsy connection. We described different meta-omics analyses (metagenomics, metatranscriptomics, metaproteomics and metabolomics), focusing on current technical challenges in stool collection procedures, sample extraction methods and data processing. We further discussed the current advantages and limitations of using the integrative approach of multi-omics in epilepsy investigations.
MeSH term(s)	Epilepsy/microbiology ; Gastrointestinal Microbiome ; Humans ; Metagenome ; Metagenomics
Language	English
Publishing date	2022-01-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1211786-9
ISSN	1095-953X ; 0969-9961
ISSN (online)	1095-953X
ISSN	0969-9961
DOI	10.1016/j.nbd.2022.105614
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