Targeted mechanical stimulation via magnetic nanoparticles guides in vitro tissue development

Tissues take shape through a series of morphogenetic movements guided by local cell-scale mechanical forces. Current in vitro approaches to recapitulate tissue mechanics rely on uncontrolled self-organization or on the imposition of extrinsic and homogenous forces using matrix or instrument-driven stimulation, thereby failing to recapitulate highly localized and spatially varying forces. Here we develop a method for targeted mechanical stimulation of organoids using embedded magnetic nanoparticles. We show that magnetic clusters within organoids can be produced by sequential aggregation of magnetically labeled and non-labeled human pluripotent stem cells. These clusters impose local mechanical forces on the surrounding cells in response to applied magnetic fields. We show that precise, spatially defined actuation provides short-term mechanical tissue perturbations as well as long-term cytoskeleton remodeling in these organoids, which we term "magnetoids". We demonstrate that targeted magnetic nanoparticle-driven actuation guides asymmetric tissue growth and proliferation, leading to enhanced patterning in human neural magnetoids. This approach, enabled by nanoparticle technology, allows for precise and locally controllable mechanical actuation in human neural tube organoids, and could be widely applicable to interrogate the role of local mechanotransduction in developmental and disease model systems.