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A proof of concept 'phase zero' study of neurodevelopment using brain organoid models with Vis/near-infrared spectroscopy and electrophysiology.

ABSTRACT: Homeostatic control of neuronal excitability by modulation of synaptic inhibition (I) and excitation (E) of the principal neurons is important during brain maturation. The fundamental features of in-utero brain development, including local synaptic E-I ratio and bioenergetics, can be modeled by cerebral organoids (CO) that have exhibited highly regular nested oscillatory network events. Therefore, we evaluated a 'Phase Zero' clinical study platform combining broadband Vis/near-infrared(NIR) spectroscopy and electrophysiology with studying E-I ratio based on the spectral exponent of local field potentials and bioenergetics based on the activity of mitochondrial Cytochrome-C Oxidase (CCO). We found a significant effect of the age of the healthy controls iPSC CO from 23 days to 3 months on the CCO activity (chi-square (2, N?=?10)?=?20, p?=?4.5400e-05), and spectral exponent between 30-50 Hz (chi-square (2, N?=?16)?=?13.88, p?=?0.001). Also, a significant effect of drugs, choline (CHO), idebenone (IDB), R-alpha-lipoic acid plus acetyl-L-carnitine (LCLA), was found on the CCO activity (chi-square (3, N?=?10)?=?25.44, p?=?1.2492e-05), spectral exponent between 1 and 20 Hz (chi-square (3, N?=?16)?=?43.5, p?=?1.9273e-09) and 30-50 Hz (chi-square (3, N?=?16)?=?23.47, p?=?3.2148e-05) in 34 days old CO from schizophrenia (SCZ) patients iPSC. We present the feasibility of a multimodal approach, combining electrophysiology and broadband Vis-NIR spectroscopy, to monitor neurodevelopment in brain organoid models that can complement traditional drug design approaches to test clinically meaningful hypotheses.

SUBMITTER: Dutta A

PROVIDER: S-EPMC7710726 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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A proof of concept 'phase zero' study of neurodevelopment using brain organoid models with Vis/near-infrared spectroscopy and electrophysiology.

Dutta Anirban A Karanth Sneha Sudhakar SS Bhattacharya Mahasweta M Liput Michal M Augustyniak Justyna J Cheung Mancheung M Stachowiak Ewa K EK Stachowiak Michal K MK

Scientific reports 20201202 1

Homeostatic control of neuronal excitability by modulation of synaptic inhibition (I) and excitation (E) of the principal neurons is important during brain maturation. The fundamental features of in-utero brain development, including local synaptic E-I ratio and bioenergetics, can be modeled by cerebral organoids (CO) that have exhibited highly regular nested oscillatory network events. Therefore, we evaluated a 'Phase Zero' clinical study platform combining broadband Vis/near-infrared(NIR) spec ...[more]

PMID: 33268815

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Project description:PurposeAberrantly expressed glycans in cancer are of particular interest for tumor targeting. This proof-of-concept in vivo study aims to validate the use of aberrant Lewis glycans as target for antibody-based, real-time imaging of gastrointestinal cancers.ProceduresImmunohistochemical (IHC) staining with monoclonal antibody FG88.2, targeting Lewisa/c/x, was performed on gastrointestinal tumors and their healthy counterparts. Then, FG88.2 and its chimeric human/mouse variant CH88.2 were conjugated with near-infrared fluorescent (NIRF) IRDye 800CW for real-time imaging. Specific binding was evaluated in vitro on human gastrointestinal cancer cell lines with cell-based plate assays, flow cytometry, and immune-fluorescence microscopy. Subsequently, mice bearing human colon and pancreatic subcutaneous tumors were imaged in vivo after intravenous administration of 1 nmol (150 μg) CH88.2-800CW with the clinical Artemis NIRF imaging system using the Pearl Trilogy small animal imager as reference. One week post-injection of the tracer, tumors and organs were resected and tracer uptake was analyzed ex vivo.ResultsIHC analysis showed strong FG88.2 staining on colonic, gastric, and pancreatic tumors, while staining on their normal tissue counterparts was limited. Next, human cancer cell lines HT-29 (colon) and BxPC-3 and PANC-1 (both pancreatic) were identified as respectively high, moderate, and low Lewisa/c/x-expressing. Using the clinical NIRF camera system for tumor-bearing mice, a mean tumor-to-background ratio (TBR) of 2.2 ± 0.3 (Pearl: 3.1 ± 0.8) was observed in the HT-29 tumors and a TBR of 1.8 ± 0.3 (Pearl: 1.9 ± 0.5) was achieved in the moderate expression BxPC-3 model. In both models, tumors could be adequately localized and delineated by NIRF for up to 1 week. Ex vivo analysis confirmed full tumor penetration of the tracer and low fluorescence signals in other organs.ConclusionsUsing a novel chimeric Lewisa/c/x-targeting tracer in combination with a clinical NIRF imager, we demonstrate the potential of targeting Lewis glycans for fluorescence-guided surgery of gastrointestinal tumors.

Dataset Information

A proof of concept 'phase zero' study of neurodevelopment using brain organoid models with Vis/near-infrared spectroscopy and electrophysiology.

Publications

A proof of concept 'phase zero' study of neurodevelopment using brain organoid models with Vis/near-infrared spectroscopy and electrophysiology.

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