Publications
2026
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Human Platelet-Derived Extracellular Vesicles Are Internalized by Human Induced Pluripotent Stem Cell-Derived Neurons Under Control and Hypoxic Conditions
Ischaemic brain stroke is among the leading causes of death and disability worldwide. However, the current treatments have a limited time window and regeneration potential. Clinically relevant human platelet-derived extracellular vesicles (EVs) offer potential neuroprotective treatment for stroke. Here, the neuronal uptake of carboxyfluorescein succinimidyl ester (CFSE)-labelled EVs was confirmed by confocal imaging and three-dimensional (3D) image analysis with Imaris software. The results... -
Human cardiac innervation-on-a-chip platform recapitulates neurocardiac interactions and supports future disease modeling
The cardiac autonomic nervous system regulates cardiac function through innervation, and dysfunction of the neuronal and cardiovascular crosstalk has been linked to various pathologies. Here, we present a cardiac innervation-on-a-chip model by combining human induced pluripotent stem cell (hiPSC)-derived cortical neurons, postganglionic sympathetic neurons, and ventricular cardiomyocytes in a compartmentalized microfluidic device called a 3D3C chip to generate physiologically relevant in vitro... -
In vitro identification of kainic acid-induced, concentration-dependent responses in human cortical neuronal networks
Neuronal networks derived from human induced pluripotent stem cells (hiPSCs) have gained attention for their potential use in studying cellular electrophysiology. Similar to in vivo animal models of seizures and epilepsy, neuronal activity can be altered in vitro using kainic acid (KA), a direct agonist of KA glutamate receptors. However, to utilize KA in developing more relevant in vitro seizure models, a better understanding of acute and long-term KA-mediated effects on human neurons is...
2025
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In vitro identification of kainic acid-induced, concentration-dependent responses in human cortical neuronal networks
Neuronal networks derived from human induced pluripotent stem cells (hiPSCs) have gained attention for their potential use in studying cellular electrophysiology. Similar to in vivo animal models of seizures and epilepsy, neuronal activity can be altered in vitro using kainic acid (KA), a direct agonist of KA glutamate receptors. However, to utilize KA in developing more relevant in vitro seizure models, a better understanding of acute and long-term KA-mediated effects on human neurons is... -
Human induced pluripotent stem cell-derived neurons and coculture conditions regulate the adipogenic differentiation and functionality of human adipose stromal/stem cells
CONCLUSIONS: This research provides a novel human cell-based 3D in vitro model to study adipose tissue innervation and neuro-adipose interactions. Here, the novel human cell-based coculture model holds great potential for future mechanistic studies of neuro-adipose regulation. -
Microglia from patients with multiple sclerosis display a cell-autonomous immune activation state
Aberrant and sustained activation of microglia is implicated in the progression and severity of multiple sclerosis (MS). However, whether intrinsic alterations in microglial function impact the pathogenesis of this disease remains unclear. We conducted transcriptomic and functional analyses of microglia-like cells (iMGLs) differentiated from induced pluripotent stem cells (iPSCs) from patients with MS (pwMS) to answer this question. The pwMS showed increased innate immune cell activity via... -
Abnormalities in the functional activity of neural networks in a human iPSC model of Dravet syndrome
Dravet syndrome (DS) is a severe pediatric epilepsy primarily caused by de novo mutation in the SCN1A gene encoding the alpha subunit of the voltage-gated sodium channel. While early in vivo studies linked DS pathology to GABAergic disinhibition, recent studies report altered sodium currents in both inhibitory and excitatory neurons. In vitro models containing both neuronal subtypes may offer deeper insights into functionality of neuronal networks. This study examined the effects of two... -
Modeling neuroinflammatory interactions between microglia and astrocytes in a human iPSC-based coculture platform
CONCLUSIONS: Our results depict an elaborate inflammatory interaction between iPSC-derived microglia and astrocytes via reciprocal molecular signaling. Importantly, the microfluidic coculture platform established in this study provides a more functional and advanced setup for investigating inflammatory glial interactions in vitro. -
Functional 3D Human Neuron-Glioblastoma Model Reveals Cellular Interactions Enabling Drug Safety Assessments
Glioblastoma (GB) cells actively interact with the central nervous system (CNS) tumor microenvironment (TME). These interactions, particularly with neurons, require a better understanding. 3D tumor models replicating the human TME are needed to unravel pathological processes and to test novel treatments for efficacy and safety. We developed a novel 3D human coculture model for studying neuron-GB interactions. The model revealed both structural and functional interactions between cell types.... -
Hyaluronic Acid-Based 3D Bioprinted Hydrogel Structure for Directed Axonal Guidance and Modeling Innervation In Vitro
Neurons form predefined connections and innervate target tissues through elongating axons, which are crucial for the development, maturation, and function of these tissues. However, innervation is often overlooked in tissue engineering (TE) applications. Here, multimaterial 3D bioprinting is used to develop a novel 3D axonal guidance structure in vitro. The approach uses the stiffness difference of acellular hyaluronic acid-based bioink printed as two alternating, parallel-aligned filaments. The...
2024
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Hyaluronic Acid-Based 3D Bioprinted Hydrogel Structure for Directed Axonal Guidance and Modeling Innervation In Vitro
Neurons form predefined connections and innervate target tissues through elongating axons, which are crucial for the development, maturation, and function of these tissues. However, innervation is often overlooked in tissue engineering (TE) applications. Here, multimaterial 3D bioprinting is used to develop a novel 3D axonal guidance structure in vitro. The approach uses the stiffness difference of acellular hyaluronic acid-based bioink printed as two alternating, parallel-aligned filaments. The... -
Exploring Kainic Acid-Induced Alterations in Circular Tripartite Networks with Advanced Analysis Tools
Brain activity implies the orchestrated functioning of interconnected brain regions. Typical in vitro models aim to mimic the brain using single human pluripotent stem cell-derived neuronal networks. However, the field is constantly evolving to model brain functions more accurately through the use of new paradigms, e.g., brain-on-a-chip models with compartmentalized structures and integrated sensors. These methods create novel data requiring more complex analysis approaches. The previously... -
Human tripartite cortical network model for temporal assessment of alpha-synuclein aggregation and propagation in Parkinson's Disease
Previous studies have shown that aggregated alpha-synuclein (α-s) protein, a key pathological marker of Parkinson's disease (PD), can propagate between cells, thus participating in disease progression. This prion-like propagation has been widely studied using in vivo and in vitro models, including rodent and human cell cultures. In this study, our focus was on temporal assessment of functional changes during α-s aggregation and propagation in human induced pluripotent stem cell (hiPSC)-derived...
2023
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Simultaneous induction of vasculature and neuronal network formation on a chip reveals a dynamic interrelationship between cell types
CONCLUSIONS: Overall, our study provides a novel human neurovascular network model that is applicable for creating in vivo-like tissue models with intrinsic neurovascular interactions. The 3D neurovascular network model on chip forms an initial platform for the development of vascularized and innervated organ-on-chip and further body-on-chip concepts and offers the possibility for mechanistic studies on neurovascular communication both under healthy and in disease conditions. Video Abstract.
2022
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Hyaluronic acid based next generation bioink for 3D bioprinting of human stem cell derived corneal stromal model with innervation
Corneal transplantation remains gold standard for the treatment of severe cornea diseases, however, scarcity of donor cornea is a serious bottleneck. 3D bioprinting holds tremendous potential for cornea tissue engineering (TE). One of the key technological challenges is to design bioink compositions with ideal printability and cytocompatibility. Photo-crosslinking and ionic crosslinking are often used for the stabilization of 3D bioprinted structures, which can possess limitations on biological... -
Effect of cell culture media on extracellular vesicle secretion from mesenchymal stromal cells and neurons
CONCLUSIONS: We demonstrated successful EV isolation from MSC and neuronal cells using an ultrafiltration-SEC method. The EV yield from MSC and neuronal cultures exhibited a large batch effect, apparently related to the culture media used, highlighting the importance of including NCC as a negative control in all cell culture experiments. -
Practical guide for preparation, computational reconstruction and analysis of 3D human neuronal networks in control and ischaemic conditions
To obtain commensurate numerical data of neuronal network morphology in vitro, network analysis needs to follow consistent guidelines. Important factors in successful analysis are sample uniformity, suitability of the analysis method for extracting relevant data and the use of established metrics. However, for the analysis of 3D neuronal cultures, there is little coherence in the analysis methods and metrics used in different studies. Here, we present a framework for the analysis of neuronal... -
Establishment of a human induced pluripotent stem cell line (TAUi008-A) derived from a multiple sclerosis patient
Multiple sclerosis (MS) is a complex autoimmune disease of the central nervous system where the main pathogenetic events include demyelination and axonal degeneration. Here, we generated a human induced pluripotent stem cell (hiPSC) line from peripheral blood mononuclear cells of an MS patient utilizing Sendai virus reprogramming. The produced hiPSC line expressed pluripotency markers, differentiated into three germ layers, showed a normal karyotype and was free of virus vectors, transgenes and... -
Corrigendum to 'Bidirectional cell-matrix interaction dictates neuronal network formation in a brain mimetic 3D scaffold' [Acta Biomaterialia (2022) 314-323]
No abstract -
Comparative microelectrode array data of the functional development of hPSC-derived and rat neuronal networks
We present a dataset of microelectrode array (MEA) recordings from human pluripotent stem cell (hPSC)-derived and rat embryonic cortical neurons during their in vitro maturation. The data were prepared to assess extracellularly recorded spontaneous activity and to compare the functional development of these neuronal networks. In addition to recordings of spontaneous activity, we provide pharmacological responses of hPSC-derived and rat cortical cultures at their mature stage. Together with the... -
Human Neurons Form Axon-Mediated Functional Connections with Human Cardiomyocytes in Compartmentalized Microfluidic Chip
The cardiac autonomic nervous system (cANS) regulates cardiac function by innervating cardiac tissue with axons, and cardiomyocytes (CMs) and neurons undergo comaturation during the heart innervation in embryogenesis. As cANS is essential for cardiac function, its dysfunctions might be fatal; therefore, cardiac innervation models for studying embryogenesis, cardiac diseases, and drug screening are needed. However, previously reported neuron-cardiomyocyte (CM) coculture chips lack studies of... -
A kainic acid-induced seizure model in human pluripotent stem cell-derived cortical neurons for studying the role of IL-6 in the functional activity
Human pluripotent stem cell (hPSC)-derived neural cultures have attracted interest for modeling epilepsy and seizure-like activity in vitro. Clinical and experimental evidence have shown that the multifunctional inflammatory cytokine interleukin (IL)-6 plays a significant role in epilepsy. However, the role of IL-6 in neuronal networks remains unclear. In this study, we modelled seizure-like activity in hPSC-derived cortical neurons using kainic acid (KA) and explored the effects of IL-6 and its... -
Bidirectional cell-matrix interaction dictates neuronal network formation in a brain-mimetic 3D scaffold
Human pluripotent stem cells (hPSC) derived neurons are emerging as a powerful tool for studying neurobiology, disease pathology, and modeling. Due to the lack of platforms available for housing and growing hPSC-derived neurons, a pressing need exists to tailor a brain-mimetic 3D scaffold that recapitulates tissue composition and favourably regulates neuronal network formation. Despite the progress in engineering biomimetic scaffolds, an ideal brain-mimetic scaffold is still elusive. We...
2021
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Hyaluronic Acid-Based 3D Bioprinted Hydrogel Structure for Directed Axonal Guidance and Modeling Innervation In Vitro
Neurons form predefined connections and innervate target tissues through elongating axons, which are crucial for the development, maturation, and function of these tissues. However, innervation is often overlooked in tissue engineering (TE) applications. Here, multimaterial 3D bioprinting is used to develop a novel 3D axonal guidance structure in vitro. The approach uses the stiffness difference of acellular hyaluronic acid-based bioink printed as two alternating, parallel-aligned filaments. The... -
Bidirectional cell-matrix interaction dictates neuronal network formation in a brain-mimetic 3D scaffold
Human pluripotent stem cells (hPSC) derived neurons are emerging as a powerful tool for studying neurobiology, disease pathology, and modeling. Due to the lack of platforms available for housing and growing hPSC-derived neurons, a pressing need exists to tailor a brain-mimetic 3D scaffold that recapitulates tissue composition and favourably regulates neuronal network formation. Despite the progress in engineering biomimetic scaffolds, an ideal brain-mimetic scaffold is still elusive. We... -
Novel method to produce a layered 3D scaffold for human pluripotent stem cell-derived neuronal cells
CONCLUSIONS: We introduced a method to produce layered 3D scaffolds to mimic the cell guiding cues in CNS by alternating the soft hydrogel matrix and fibrous guidance cues. The produced scaffold successfully enabled the long-term culture of hPSC-derived neuronal cells. This layered 3D scaffold is a useful model for in vitro and in vivo neuronal TE applications.
2020
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Novel method to produce a layered 3D scaffold for human pluripotent stem cell-derived neuronal cells
CONCLUSIONS: We introduced a method to produce layered 3D scaffolds to mimic the cell guiding cues in CNS by alternating the soft hydrogel matrix and fibrous guidance cues. The produced scaffold successfully enabled the long-term culture of hPSC-derived neuronal cells. This layered 3D scaffold is a useful model for in vitro and in vivo neuronal TE applications. -
<em>In Vitro</em> Oxygen-Glucose Deprivation-Induced Stroke Models with Human Neuroblastoma Cell- and Induced Pluripotent Stem Cell-Derived Neurons
Stroke is a devastating neurological disorder and one of the leading causes of mortality and disability. To understand the cellular and molecular mechanisms of stroke and to develop novel therapeutic approaches, two different in vitro human cell-based stroke models were established using oxygen-glucose deprivation (OGD) conditions. In addition, the effect of adipose stem cells (ASCs) on OGD-induced injury was studied. In the present study, SH-SY5Y human neuroblastoma cells and human induced... -
A modular brain-on-a-chip for modelling epileptic seizures with functionally connected human neuronal networks
Epilepsies are a group of neurological disorders characterised by recurrent epileptic seizures. Seizures, defined as abnormal transient discharges of neuronal activity, can affect the entire brain circuitry or remain more focal in the specific brain regions and neuronal networks. Human pluripotent stem cell (hPSC)-derived neurons are a promising option for modelling epilepsies, but as such, they do not model groups of connected neuronal networks or focal seizures. Our solution is a Modular... -
Covalent immobilization of luminescent oxygen indicators reduces cytotoxicity
Luminescence-based oxygen sensing is a widely used tool in cell culture applications. In a typical configuration, the luminescent oxygen indicators are embedded in a solid, oxygen-permeable matrix in contact with the culture medium. However, in sensitive cell cultures even minimal leaching of the potentially cytotoxic indicators can become an issue. One way to prevent the leaching is to immobilize the indicators covalently into the supporting matrix. In this paper, we report on a method where... -
Transparent Microelectrode Arrays Fabricated by Ion Beam Assisted Deposition for Neuronal Cell in Vitro Recordings
Microelectrode array (MEA) is a tool used for recording bioelectric signals from electrically active cells in vitro. In this paper, ion beam assisted electron beam deposition (IBAD) has been used for depositing indium tin oxide (ITO) and titanium nitride (TiN) thin films which are applied as transparent track and electrode materials in MEAs. In the first version, both tracks and electrodes were made of ITO to guarantee full transparency and thus optimal imaging capability. In the second version,...
2019
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Microglia from patients with multiple sclerosis display a cell-autonomous immune activation state
Aberrant and sustained activation of microglia is implicated in the progression and severity of multiple sclerosis (MS). However, whether intrinsic alterations in microglial function impact the pathogenesis of this disease remains unclear. We conducted transcriptomic and functional analyses of microglia-like cells (iMGLs) differentiated from induced pluripotent stem cells (iPSCs) from patients with MS (pwMS) to answer this question. The pwMS showed increased innate immune cell activity via... -
Functional characterization of human pluripotent stem cell-derived cortical networks differentiated on laminin-521 substrate: comparison to rat cortical cultures
Human pluripotent stem cell (hPSC)-derived neurons provide exciting opportunities for in vitro modeling of neurological diseases and for advancing drug development and neurotoxicological studies. However, generating electrophysiologically mature neuronal networks from hPSCs has been challenging. Here, we report the differentiation of functionally active hPSC-derived cortical networks on defined laminin-521 substrate. We apply microelectrode array (MEA) measurements to assess network events and... -
Co-stimulation with IL-1β and TNF-α induces an inflammatory reactive astrocyte phenotype with neurosupportive characteristics in a human pluripotent stem cell model system
Astrocyte reactivation has been discovered to be an important contributor to several neurological diseases. In vitro models involving human astrocytes have the potential to reveal disease-specific mechanisms of these cells and to advance research on neuropathological conditions. Here, we induced a reactive phenotype in human induced pluripotent stem cell (hiPSC)-derived astrocytes and studied the inflammatory natures and effects of these cells on human neurons. Astrocytes responded to... -
Screening of Hydrogels for Human Pluripotent Stem Cell-Derived Neural Cells: Hyaluronan-Polyvinyl Alcohol-Collagen-Based Interpenetrating Polymer Network Provides an Improved Hydrogel Scaffold
There is a clear need for novel in vitro models, especially for neuronal applications. Development of in vitro models is a multiparameter task consisting of cell-, biomaterial-, and environment-related parameters. Here, three different human origin neuronal cell sources are studied and cultured in various hydrogel 3D scaffolds. For the efficient evaluation of complex results, an indexing method for data is developed and used in principal component analysis (PCA). It is found that no single... -
Advances in Human Stem Cell-Derived Neuronal Cell Culturing and Analysis
This chapter provides an overview of the current stage of human in vitro functional neuronal cultures, their biological application areas, and modalities to analyze their behavior. During the last 10 years, this research area has changed from being practically non-existent to one that is facing high expectations. Here, we present a case study as a comprehensive short history of this process based on extensive studies conducted at NeuroGroup (University of Tampere) and Computational Biophysics... -
Catalytically inactive carbonic anhydrase-related proteins enhance transport of lactate by MCT1
Carbonic anhydrases (CA) catalyze the reversible hydration of CO(2) to protons and bicarbonate and thereby play a fundamental role in the epithelial acid/base transport mechanisms serving fluid secretion and absorption for whole-body acid/base regulation. The three carbonic anhydrase-related proteins (CARPs) VIII, X, and XI, however, are catalytically inactive. Previous work has shown that some CA isoforms noncatalytically enhance lactate transport through various monocarboxylate transporters... -
Microelectrode Array With Transparent ALD TiN Electrodes
Low noise platinum black or sputtered titanium nitride (TiN) microelectrodes are typically used for recording electrical activity of neuronal or cardiac cell cultures. Opaque electrodes and tracks, however, hinder the visibility of the cells when imaged with inverted microscope, which is the standard method of imaging cells plated on microelectrode array (MEA). Even though transparent indium tin oxide (ITO) electrodes exist, they cannot compete in impedance and noise performance with... -
Effects of inflammatory cytokines IFN-γ, TNF-α and IL-6 on the viability and functionality of human pluripotent stem cell-derived neural cells
Multiple Sclerosis (MS) is an inflammatory neurodegenerative disease, where neural progenitor cell (NPC) transplantation has been suggested as a potential neuroprotective therapeutic strategy. Since the effect of inflammation on NPCs is poorly known, their effect on the survival and functionality of human NPCs were studied. Treatment with interleukin (IL)-6, tumor necrosis factor (TNF)-α and interferon (IFN)-γ did not induced cytotoxicity, but IFN-γ treatment showed decreased proliferation and...
2018
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Ion Beam Assisted E-Beam Deposited TiN Microelectrodes-Applied to Neuronal Cell Culture Medium Evaluation
Microelectrode material and cell culture medium have significant roles in the signal-to-noise ratio and cell well-being in in vitro electrophysiological studies. Here, we report an ion beam assisted e-beam deposition (IBAD) based process as an alternative titanium nitride (TiN) deposition method for sputtering in the fabrication of state-of-the-art TiN microelectrode arrays (MEAs). The effects of evaporation and nitrogen flow rates were evaluated while developing the IBAD TiN deposition process.... -
Effects of inflammatory cytokines IFN-γ, TNF-α and IL-6 on the viability and functionality of human pluripotent stem cell-derived neural cells
Multiple Sclerosis (MS) is an inflammatory neurodegenerative disease, where neural progenitor cell (NPC) transplantation has been suggested as a potential neuroprotective therapeutic strategy. Since the effect of inflammation on NPCs is poorly known, their effect on the survival and functionality of human NPCs were studied. Treatment with interleukin (IL)-6, tumor necrosis factor (TNF)-α and interferon (IFN)-γ did not induced cytotoxicity, but IFN-γ treatment showed decreased proliferation and... -
GABA and Gap Junctions in the Development of Synchronized Activity in Human Pluripotent Stem Cell-Derived Neural Networks
The electrical activity of the brain arises from single neurons communicating with each other. However, how single neurons interact during early development to give rise to neural network activity remains poorly understood. We studied the emergence of synchronous neural activity in human pluripotent stem cell (hPSC)-derived neural networks simultaneously on a single-neuron level and network level. The contribution of gamma-aminobutyric acid (GABA) and gap junctions to the development of... -
Effect of prolonged differentiation on functional maturation of human pluripotent stem cell-derived neuronal cultures
Long-term neural differentiation of human pluripotent stem cells (hPSCs) is associated with enhanced neuronal maturation, which is a necessity for creation of representative in vitro models. It also induces neurogenic-to-gliogenic fate switch, increasing proportion of endogenous astrocytes formed from the common neural progenitors. However, the significance of prolonged differentiation on the neural cell type composition and functional development of hPSC-derived neuronal cells has not been well...