Human cerebral organoids establish subcortical projections in the mouse brain after transplantation

Abstract

Numerous studies have used human pluripotent stem cell-derived cerebral organoids to elucidate the mystery of human brain development and model neurological diseases in vitro, but the potential for grafted organoid-based therapy in vivo remains unknown. Here, we optimized a culturing protocol capable of efficiently generating small human cerebral organoids. After transplantation into the mouse medial prefrontal cortex, the grafted human cerebral organoids survived and extended projections over 4.5 mm in length to basal brain regions within 1 month. The transplanted cerebral organoids generated human glutamatergic neurons that acquired electrophysiological maturity in the mouse brain. Importantly, the grafted human cerebral organoids functionally integrated into pre-existing neural circuits by forming bidirectional synaptic connections with the mouse host neurons. Furthermore, compared to control mice, the mice transplanted with cerebral organoids showed an increase in freezing time in response to auditory conditioned stimuli, suggesting the potentiation of the startle fear response. Our study showed that subcortical projections can be established by microtransplantation and may provide crucial insights into the therapeutic potential of human cerebral organoids for neurological diseases.

Brain Organoids: Studying Human Brain Development and Diseases in a Dish

“…For example, most recently, MECP2 knockout neurospheres and cortical organoids were generated for modeling Rett syndrome [144]; Down syndrome cerebral organoid models were established from patient-derived iPSCs [145]; and iPSCderived brain organoids infected by a "clinical-like" human cytomegalovirus (HCMV) strain were utilized for studying HCMV-induced microcephaly [146]. Furthermore, such disease-modeling organoids also provide a platform for drug screening [88,89] and act as a subject in the investigation of potential organoid transplantation therapy for neurological disorders [147][148][149].…”

Neuronal surface autoantibodies in dementia: a systematic review and meta-analysis

“…Consideration should also be given to the emerging notion that in some circumstances, NMDAR antibodies may have a role as endogenous NMDAR antagonists and hence have a protective function [ 40 ]: the possibility that in some cases dementia, serum NMDAR antibodies could represent an adaptive physiological response, potentially even ameliorating clinical severity, is challenging but requires systematic evaluation.…”

The Application of Brain Organoids in Assessing Neural Toxicity

“…Compared with NSC transplantation, organoid transplantation showed increased cell survival, progressive neuronal differentiation, and maturation and formation of robust vascularization and neuronal networks with the host brain ( Daviaud et al, 2018 ; Mansour et al, 2018 ). Our group generated small human cerebral organoids and transplanted them into the mouse medial prefrontal cortex (mPFC) ( Dong et al, 2021 ). The grafts established subcortical projections and formed mutual synaptic connections with host mouse neurons.…”