Context matters: hPSC-derived microglia thrive in a humanized brain environment in vivo

Induced pluripotent stem cells (iPSCs): molecular mechanisms of induction and applications

“…216 Organoid maturation can be further improved by transplantation in vivo, leading to organoid vascularization, improved nutrient exchange, and exposure to physiologically-relevant systemic factors. [217][218][219][220][221][222][223] For example, orthotopically transplanted lacrimal gland organoids functionally mature to produce tear-film proteins and resemble primary human tissue. 217 Somatic cells are also exposed to tissue-specific mechanical and environmental conditioning, which may be partially recreated in vitro.…”

“…303 A powerful approach of iPSCbased modeling of neurological disorders is whole brain organoid transplantation in vivo, which not only creates a complex physiological milieu for the transplanted human cells, but also preserves human cell-specific organoid environment. 218,220,222,223,304,305 Although neurological disorders have successfully been modeled using brain organoids in vitro, one important limitation of the brain organoid technology is their lack of vascularization, leading to poor nutrient and oxygen exchange, cellular stress, necrosis of the organoid core, and incomplete organoid maturation. 306 Remarkably, brain organoid transplantation in vivo promotes robust organoid vascularization by the host vasculature and substantially improves organoid characteristics, including neuron maturation and microglia survival.…”

“…306 Remarkably, brain organoid transplantation in vivo promotes robust organoid vascularization by the host vasculature and substantially improves organoid characteristics, including neuron maturation and microglia survival. 218,220,222,223,304,305 An in vivo brain organoid model of Timothy syndrome reveals abnormal neuronal morphology and increased frequency of excitatory postsynaptic potentials, whereas a model of ASD indicates microglia activation. 220,222 Overall, iPSC-derived cellular models of neurological disorders reveal complex molecular, cellular, and electrophysiological disease-related phenotypes.…”

Myelin organoids for the study of Alzheimer's disease

“…Finally, various myelinoids discussed earlier can be transplanted in vivo to promote advanced myelinoid maturation and vascularization ( Figure 1F ). Indeed, brain organoid transplantation paradigm has recently emerged as a powerful approach to achieve improved organoid maturation, revealing subtle disease phenotypes that are not recapitulated in vitro (Mansour et al, 2018 ; Revah et al, 2022 ; Cerneckis and Shi, 2023b ; Schafer et al, 2023 ). It can be expected that xenotransplanted myelinoids will contain a robust pool of OPCs and mature oligodendrocytes as well as exhibit improved myelination patterns, making them especially suitable for modeling myelin dysfunction in AD.…”

Developing a human iPSC-derived three-dimensional myelin spheroid platform for modeling myelin diseases

“… 6 , 7 , 8 hiPSC-derived three-dimensional (3D) spheroids or organoids have been used to study brain development and disorders in our group and others. 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 However, it has been difficult to recapitulate mature myelination in these 3D structures. To address this limitation, methods have been developed to generate 3D oligospheres with mature oligodendrocytes and myelination.…”