Characterization of neural mechanotransduction response in human traumatic brain injury organoid model

Abstract

The ability to model physiological systems through 3D neural in-vitro systems may enable new treatments for various diseases while lowering the need for challenging animal and human testing. Creating such an environment, and even more impactful, one that mimics human brain tissue under mechanical stimulation, would be extremely useful to study a range of human-specific biological processes and conditions related to brain trauma. One approach is to use human cerebral organoids (hCOs) in-vitro models. hCOs recreate key cytoarchitectural features of the human brain, distinguishing themselves from more traditional 2D cultures and organ-on-a-chip models, as well as in-vivo animal models. Here, we propose a novel approach to emulate mild and moderate traumatic brain injury (TBI) using hCOs that undergo strain rates indicative of TBI. We subjected the hCOs to mild (2 s$$^{-1}$$ - 1 ) and moderate (14 s$$^{-1}$$ - 1 ) loading conditions, examined the mechanotransduction response, and investigated downstream genomic effects and regulatory pathways. The revealed pathways of note were cell death and metabolic and biosynthetic pathways implicating genes such as CARD9, ENO1, and FOXP3, respectively. Additionally, we show a steeper ascent in calcium signaling as we imposed higher loading conditions on the organoids. The elucidation of neural response to mechanical stimulation in reliable human cerebral organoid models gives insights into a better understanding of TBI in humans.

Transforming growth factor-β1 protects mechanically injured cortical murine neurons by reducing trauma-induced autophagy and apoptosis

“…The objective of our study was to investigate the protective effect of TGF-β1 on mechanically injured neurons using an in vitro neuronal scratch cell model and explore its molecular mechanism. This cellular model, which is based on mechanical injury to primary cultured neurons, has been used in numerous studies and provides an essential tool for the treatment of TBI ( Ni et al, 2019 ; Beltrán et al, 2023 ; Wang et al, 2024 ), that can reproduce neurological injuries such as stab wounds, penetrating skull frcatures, and gunshot that result in transection of the cell body ( Morrison et al, 1998 ). We found that treatment with TGF-β1 (10 ng/mL) for 24 h significantly inhibited LDH release induced by mechanically injured cortical neurons and reduced cytotoxicity in our in vitro model, consistent with our previous findings ( Li et al, 2022 ).…”