Modeling of the brain-lung axis using organoids in traumatic brain injury: an updated review

Abstract

Clinical outcome after traumatic brain injury (TBI) is closely associated conditions of other organs, especially lungs as well as degree of brain injury. Even if there is no direct lung damage, severe brain injury can enhance sympathetic tones on blood vessels and vascular resistance, resulting in neurogenic pulmonary edema. Conversely, lung damage can worsen brain damage by dysregulating immunity. These findings suggest the importance of brain-lung axis interactions in TBI. However, little research has been conducted on the topic. An advanced disease model using stem cell technology may be an alternative for investigating the brain and lungs simultaneously but separately, as they can be potential candidates for improving the clinical outcomes of TBI.In this review, we describe the importance of brain-lung axis interactions in TBI by focusing on the concepts and reproducibility of brain and lung organoids in vitro. We also summarize recent research using pluripotent stem cell-derived brain organoids and their preclinical applications in various brain disease conditions and explore how they mimic the brain-lung axis. Reviewing the current status and discussing the limitations and potential perspectives in organoid research may offer a better understanding of pathophysiological interactions between the brain and lung after TBI.

Keywords: Brain organoids; Brain-lung axis; Lung organoids; Organ-on-a-chip; Traumatic brain injury.

Fig. 1

Schematic representation of brain-lung interactions after traumatic brain injury (TBI) and the concept of different organ models to study simultaneous interactions including bottom-up and top-down pathways of brain and lung axis

Fig. 2

Cerebral organoid culture concept using human pluripotent stem cells. (A) Schematic illustration of 3D dynamic culture platforms for cerebral organoids (COs). hPSCs, human pluripotent stem cells. (B) Representative images showing various morphological changes at each stage. Scale bars are 300 μm. EB, embryonic bodies. Reproduced with permission [16]. Copyright 2022, Elsevier. (C) Schematic timeline of generating COs. bFGF, basic fibroblast growth factor. (D) Immunofluorescence staining for SOX2, Ki67, DCX and nestin in COs. Scale bars are 200 μm. All cell nuclei were stained with DAPI. SOX2, SRY-Box transcription factor; Ki67, proliferation marker; Doublecortin (DCX), neuronal precursor cell marker; nestin, neural stem cell marker; V, ventricle-like structures. DAPI, 4′,6-diamidino-2-phenylindole. Reproduced with permission [16]. Copyright 2022, Elsevier

Fig. 3

Culture of lung organoids using various cell lines and methods. A. Lung cancer organoids (LCOs) generated using Matrigel and minimum basal medium for the lung cancer biobank. Representative images of LCOs cultured long-term. Reproduced with permission [52]. Copyright 2019, Nature Publishing Group. (B) Bright-field images of lung organoids derived from the HTII-280 + fraction cultured in a complete alveolar medium. Reproduced with permission [61]. Copyright 2022, American Physiological Society. (C) Lung organoids from cryobiopsy specimens. Hematoxylin and eosin (H&E) staining and immunohistochemical (IHC) staining of LCOs. IHC staining profiles, including TTF-1, p40, and PD-L1. Reproduced with permission [62]. Copyright 2023, MDPI. (D) Human induced pluripotent stem cell (iPSC) differentiation into 3D lung organoids for modeling SARS-CoV-2 infection. Representative phase-contrast image of lung organoids at 60 days. H&E staining of 60-day lung organoids showing alveolar-like morphology. Scale bars represent 200 μm (left) and 100 μm (right). Reproduced with permission [65]. Copyright 2021, Elsevier

Fig. 4

Microfluidic technique for the co-culture of different cells and organoids with in situ monitoring. (A) Schematic illustration of the parallel-type of microfluidic cell culture device with micro-pillar structures for investigating the interactions of different cell lines. (B) The parallel-type chip with structural modification for the development of more elaborate physiological environments. (C) Schematic representation of the vertical-type microfluidic cell culture device comprising the upper and lower cell culture chambers. (D) External stimulus-induced microfluidic cell culture device for the recapitulation of dynamic physiological environments