Development of improved iPSC-based tools
Morphogen-Gradient Induced Brain Organoids (MIBOs)
Human iPSC-derived brain organoids hold great promise for modeling early brain development and disease, yet current brain/neural organoid systems often lack reproducible spatial patterning. Standard 3D forebrain organoids are intended to mimic developing telencephalon and diencephalon, but they frequently show poor anterior-posterior (A–P) and dorsal-ventral (D–V) organization. This leads to variability in regional identity across batches and limits their utility for standardized, reproducible applications.
To address this challenge, in collaboration with the Sun Lab at UMass Amherst, we developed a novel localized passive diffusion device (LPaD) that enables controlled D–V patterning in 3D human forebrain organoids by establishing a sustained Sonic hedgehog (Shh) gradient using the small molecule Purmorphamine (Pur) (Pavon et al., 2024). This method allows us to reproducibly generate patterned forebrain organoids with defined D–V axes, giving rise to distinct ventral telencephalic regions, including the medial, lateral, and caudal ganglionic eminences (MGE, LGE, and CGE).
We term these patterned structures Morphogen-Gradient Induced Brain Organoids (MIBOs). MIBOs can be removed from the engineered devices and maintained long term—up to 200 days—while retaining functional properties, offering a scalable and reproducible platform for studying human brain development and disease in a region-specific context.
See publications related to this research focus:
Pavon et al., 2024 Cell Reports Methods
Pavon et al., 2024 Frontiers in Genetics
Synaptic Modulation and Functional Screening Platforms
In addition to our work with brain organoids, we have developed human iPSC-derived 2D induced neuronal (iN) culture systems optimized for studying synaptic function within defined cortical microcircuits. These cellular tools specifically enable the formation and functional analysis of excitatory and inhibitory neuronal networks in vitro, providing a tractable platform to model key aspects of human cortical circuitry (Zhang et al., 2013 Neuron; Pak et al., 2015 Cell Stem Cell; Yi et al., 2016 Science; Pak et al., 2021 PNAS; McSweeney et al., 2023 Methods Mol. Biol.; English et al., 2023 Methods Mol. Biol.).
We continue to refine and expand these platforms to more accurately capture human synaptic function and neurodevelopment, recreating microcircuits that allow us to probe synaptic modulation, plasticity, and network-level activity. These systems form the basis for high-content functional screening approaches aimed at identifying synaptic deficits in neurodevelopmental and neuropsychiatric disorders and testing potential therapeutic strategies in a human-relevant cellular context.
