Williams, N. P. | Search bioRxiv

bioRxiv2025

Intracortical Microstimulation Induces Rapid Microglia Process Convergence

Intracortical microstimulation (ICMS) has demonstrated the potential to restore vision and hearing by stimulating relevant cortical regions in both animals and humans, offering significant clinical promise for sensory restoration. While the neuronal response to ICMS has been extensively studied at the cellular level through electrophysiology and two-photon (2P) imaging, the response of non-neuronal cells, particularly microglia, as well as the effects of ICMS on blood-brain barrier (BBB) integrity remain poorly understood. In this study, we applied ICMS under 2P imaging in dual-reporter mice, with green fluorescent protein labeling microglia and a red fluorescent Ca2+ indicator labeling neurons. We also monitored vascular dye leakage to assess BBB integrity throughout the experiment. Using clinically relevant waveform parameters, we tested a range of current amplitudes. Surprisingly, we found that microglia responded rapidly, within 15 minutes of stimulation, by converging their processes (MPC) on areas of high neural activity. The prevalence of MPC increased with higher current amplitudes, but intriguingly, it did not correlate with the strength of the local electric field. Additionally, vascular dye penetration into brain tissue was higher in stimulated animals than in controls and increased with current amplitude. This study reveals a rapid microglia and BBB response to ICMS that has not been reported previously, underscoring the need for further research to fully characterize the biological response to ICMS and establish improved safety standards.

bioengineering↗

bioRxiv2022

Perpendicular Shear Stresses Drive Transmural Helical Remodeling in Engineered Human Ventricular Models

Tissue engineering with human induced pluripotent stem cell-derived cardiomyocytes enables unique opportunities for creating physiological models of the heart in vitro. However, there are few approaches available that can recapitulate the complex structure-function relationships that govern cardiac function at the macroscopic organ level. Here, we report a down-scaled, conical human 3D ventricular model with controllable cellular organization using multilayered, patterned cardiac sheets. Tissue engineered ventricles whose cardiomyocytes were pre-aligned parallel or perpendicular to the long axis outperformed those whose cardiomyocytes were angled or randomly oriented. Notably, the inner layers of perpendicular cardiac sheets realigned over 4 days into a parallel orientation, creating a helical transmural architecture, whereas minimal remodeling occurred in the parallel or angled sheets. Finite element analysis of engineered ventricles demonstrated that circumferential alignment leads to maximal perpendicular shear stress at the inner layer, whereas longitudinal orientation leads to maximal parallel stress. We hypothesize that cellular remodeling occurs to reduce perpendicular shear stresses in myocardium. This advanced platform provides evidence that physical forces such as shear stress drive self-organization of cardiac architecture.

bioengineering↗