Vascularized human cortical organoids (vOrganoids) model cortical development in vivo

Abstract

Modeling the processes of neuronal progenitor proliferation and differentiation to produce mature cortical neuron subtypes is essential for the study of human brain development and the search for potential cell therapies. We demonstrated a novel paradigm for the generation of vascularized organoids (vOrganoids) consisting of typical human cortical cell types and a vascular structure for over 200 days as a vascularized and functional brain organoid model. The observation of spontaneous excitatory postsynaptic currents (sEPSCs), spontaneous inhibitory postsynaptic currents (sIPSCs), and bidirectional electrical transmission indicated the presence of chemical and electrical synapses in vOrganoids. More importantly, singlecell RNA-sequencing analysis illustrated that vOrganoids exhibited robust neurogenesis and that cells of vOrganoids differentially expressed genes (DEGs) related to blood vessel morphogenesis. The transplantation of vOrganoids into the mouse S1 cortex resulted in the construction of functional human-mouse blood vessels in the grafts that promoted cell survival in the grafts. This vOrganoid culture method could not only serve as a model to study human cortical development and explore brain disease pathology but also provide potential prospects for new cell therapies for nervous system disorders and injury.

Cellular and molecular properties of neural progenitors in the developing mammalian hypothalamus

“…Hypothalamic tissues were then dissected under dissection microscope and subjected to tissue dissociation. The hypothalamus tissues were enzymatically digested using a papain-based dissociation protocol previously reported 69 . In short, tissues samples were dissociated into single-cell suspension by digestion buffer (1 mg ml −1 papain in hibernate E medium, Sigma).…”

Electrophysiological Analysis of Brain Organoids: Current Approaches and Advancements

“…An initial strategy used implantation of brain organoids in vivo , resulting in host vascularization of the engrafted organoids, organoid maturation, and prolonged survival ( Mansour et al, 2018 ). This approach has since been improved, incorporating endothelial cells to develop vascular structures in vitro prior to implantation, with implanted organoids developing more complex vasculature and integrating with host vessels, resulting in long-term survival and functional maturation ( Pham et al, 2018 ; Shi et al, 2020 ). Notably, patient-derived hiPSCs were used to generate brain organoids and endothelial cells, supporting this approach to generate patient-specific vascularized brain organoids ( Pham et al, 2018 ).…”

The emerging role of chromatin remodelers in neurodevelopmental disorders: a developmental perspective

“…Similarly, RAB39b loss in 3D organoids has recently been shown to cause hyperproliferation and enlarged organoid size [459]. Studies are currently exploring organoid vascularization to further extend the development and complexity of these organoids [460][461][462], which will allow in the future to study more complex brain phenotypes using these in vitro approaches.…”