Neural cortical organoids from self-assembling human iPSC as a model to investigate neurotoxicity in brain ischemia

Paola, Massimiliano De; Pischiutta, Francesca; Comolli, Davide; Mariani, Alessandro; Kelk, Joe; Lisi, Ilaria; Cerovic, Milica; Fumagalli, Stefano; Forloni, Gianluigi; Zanier, Elisa R.

doi:10.1177/0271678x231152023

Cited by 10 publications

(3 citation statements)

References 55 publications

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“…We quantified the complexity of neuronal arborizations in terms of number, size and density of branches on MAP-2 stained slices, by using an originally developed ImageJ algorithm to segment and skeletonize the signal as previously described ( De Paola et al, 2023 ). Briefly, the background was normalized imposing a minimum gray value of 1,200, and the image was corrected with a median filter with a radius of 5 and binarized over the z stack by the Li method ( Li and Tam, 1998 ).…”

Section: Methodsmentioning

confidence: 99%

A novel organotypic cortical slice culture model for traumatic brain injury: molecular changes induced by injury and mesenchymal stromal cell secretome treatment

Pischiutta

Cavaleiro

Caruso

et al. 2023

Front. Cell. Neurosci.

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Traumatic brain injury (TBI) is a major worldwide neurological disorder with no neuroprotective treatment available. Three-dimensional (3D) in vitro models of brain contusion serving as a screening platform for drug testing are lacking. Here we developed a new in vitro model of brain contusion on organotypic cortical brain slices and tested its responsiveness to mesenchymal stromal cell (MSC) derived secretome. A focal TBI was induced on organotypic slices by an electromagnetic impactor. Compared to control condition, a temporal increase in cell death was observed after TBI by propidium iodide incorporation and lactate dehydrogenase release assays up to 48 h post-injury. TBI induced gross neuronal loss in the lesion core, with disruption of neuronal arborizations measured by microtubule-associated protein-2 (MAP-2) immunostaining and associated with MAP-2 gene down-regulation. Neuronal damage was confirmed by increased levels of neurofilament light chain (NfL), microtubule associated protein (Tau) and ubiquitin C-terminal hydrolase L1 (UCH-L1) released into the culture medium 48 h after TBI. We detected glial activation with microglia cells acquiring an amoeboid shape with less ramified morphology in the contusion core. MSC-secretome treatment, delivered 1 h post-injury, reduced cell death in the contusion core, decreased NfL release in the culture media, promoted neuronal reorganization and improved microglia survival/activation. Our 3D in vitro model of brain contusion recapitulates key features of TBI pathology. We showed protective effects of MSC-secretome, suggesting the model stands as a tractable medium/high throughput, ethically viable, and pathomimetic biological asset for testing new cell-based therapies.

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Section: Methodsmentioning

confidence: 99%

A novel organotypic cortical slice culture model for traumatic brain injury: molecular changes induced by injury and mesenchymal stromal cell secretome treatment

Pischiutta

Cavaleiro

Caruso

et al. 2023

Front. Cell. Neurosci.

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“…and expanded by dissociation with Versene 1x (Thermo Fisher Scientific). Neural precursor cells (NPCs) were derived from iPSC as previously described, [ 44 ] by blocking TGF‐β/BMP‐dependent signaling using small molecules in defined commercial medium (STEMdiff SMADi Induction Kit, STEMCELLS Technologies).…”

Section: Methodsmentioning

confidence: 99%

Synergistic Pharmacological Therapy to Modulate Glial Cells in Spinal Cord Injury

Veneruso,

Petillo,

Pizzetti

et al. 2023

Advanced Materials

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Current treatments for modulating the glial‐mediated inflammatory response after spinal cord injury (SCI) have limited ability to improve recovery. This is quite likely due to the lack of a selective therapeutic approach acting on microgliosis and astrocytosis, the glia components most involved after trauma, while maximizing efficacy and minimizing side effects. A new nanogel that can selectively release active compounds in microglial cells and astrocytes is developed and characterized. The degree of selectivity and subcellular distribution of the nanogel is evaluated by applying an innovative super‐resolution microscopy technique, expansion microscopy. Two different administration schemes are then tested in a SCI mouse model: in an early phase, the nanogel loaded with Rolipram, an anti‐inflammatory drug, achieves significant improvement in the animal's motor performance due to the increased recruitment of microglia and macrophages that are able to localize the lesion. Treatment in the late phase, however, gives opposite results, with worse motor recovery because of the widespread degeneration. These findings demonstrate that the nanovector can be selective and functional in the treatment of the glial component in different phases of SCI. They also open a new therapeutic scenario for tackling glia‐mediated inflammation after neurodegenerative events in the central nervous system.

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“…These models use 2-8 h of OGD with O 2 (0.1%), CO 2 (5.0%), and N 2 (95.0%) gas levels and deoxygenated glucose-free medium to induce ischemia[ 95 ]. It has also been discovered that hypoxic conditions can reduce the number of progenitors and impair the differentiation of immature neurons during the development stage of brain organoids[ 96 , 97 ]. Ventral forebrain tissue-like medial ganglionic eminence (MGE) organoids are usually patterned by high Shh and low Wnt signals[ 85 , 98 ].…”

Section: Brain Organoid Development From Hpscsmentioning

confidence: 99%

Neural lineage differentiation of human pluripotent stem cells: Advances in disease modeling

Yan¹,

Qian²,

Woodard³

et al. 2023

World J Stem Cells

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Brain diseases affect 1 in 6 people worldwide. These diseases range from acute neurological conditions such as stroke to chronic neurodegenerative disorders such as Alzheimer’s disease. Recent advancements in tissue-engineered brain disease models have overcome many of the different shortcomings associated with the various animal models, tissue culture models, and epidemiologic patient data that are commonly used to study brain disease. One innovative method by which to model human neurological disease is via the directed differentiation of human pluripotent stem cells (hPSCs) to neural lineages including neurons, astrocytes, and oligodendrocytes. Three-dimensional models such as brain organoids have also been derived from hPSCs, offering more physiological relevance due to their incorporation of various cell types. As such, brain organoids can better model the pathophysiology of neural diseases observed in patients. In this review, we will emphasize recent developments in hPSC-based tissue culture models of neurological disorders and how they are being used to create neural disease models.

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Neural cortical organoids from self-assembling human iPSC as a model to investigate neurotoxicity in brain ischemia

Cited by 10 publications

References 55 publications

A novel organotypic cortical slice culture model for traumatic brain injury: molecular changes induced by injury and mesenchymal stromal cell secretome treatment

A novel organotypic cortical slice culture model for traumatic brain injury: molecular changes induced by injury and mesenchymal stromal cell secretome treatment

Synergistic Pharmacological Therapy to Modulate Glial Cells in Spinal Cord Injury

Neural lineage differentiation of human pluripotent stem cells: Advances in disease modeling

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