Organoid models of breathing disorders reveal patterning defect of hindbrain neurons caused by PHOX2B-PARMs

Kathy Nga-Chu Lui, Zhixin Li, Frank Pui-Ling Lai, Sin-Ting Lau and Elly Sau-Wai Ngan

Stem Cell Reports, ISSCR, June 22, 2023


Scientists use Axion’s Maestro MEA to assess hypercapnia response in hPSC-derived brainstem organoids in vitro.  

Developing biologically relevant in vitro models for congenital central hypoventilation syndrome (CCHS)—a breathing disorder caused by a mutation in the PHOX2B gene—is challenging, but three-dimensional organoids are helping to bridge that gap. In this study, scientists take a multiplatform approach to investigate the pathogenesis of CCHS using human pluripotent stem cell (hPSC)-based brainstem organoids (HBSO) and hPSC-based cerebral organoids (HCO) with cytoarchitectures similar to the retrotrapezoid nucleus (RTN) respiratory center. To assess hypercapnia response of dissociated HBSO neurons in vitro, the researchers used Axion’s noninvasive Maestro multielectrode array (MEA) platform, finding increased activity in response to elevated carbon dioxide (CO2)—an effect that was reversed via the RTN-specific inhibitor retigabine, suggesting that RTN neurons are present in HBSOs. Overall, the researchers propose that “HBSOs and HCOs comprise enriched hindbrain neurons and self-assembled multicomponent structures, respectively, and complementary uses of these two models allow us to unambiguously reveal the detrimental effects of PHOX2B-PARMs in hindbrain development.”