Abstract
Mitochondrial health plays a crucial role in human brain development and diseases. However, the evaluation of mitochondrial health in the brain is not incorporated into clinical practice due to ethical and logistical concerns. As a result, the development of targeted mitochondrial therapeutics remains a significant challenge due to the lack of appropriate patient-derived brain tissues. To address these unmet needs, we developed cerebral organoids (COs) from induced pluripotent stem cells (iPSCs) derived from human peripheral blood mononuclear cells (PBMCs) and monitored mitochondrial health from the primary, reprogrammed and differentiated stages. Our results show preserved mitochondrial genetics, function and treatment responses across PBMCs to iPSCs to COs, and measurable neuronal activity in the COs. We expect our approach will serve as a model for more widespread evaluation of mitochondrial health relevant to a wide range of human diseases using readily accessible patient peripheral (PBMCs) and stem-cell derived brain tissue samples.
Highlights
Mitochondrial health plays a crucial role in human brain development and diseases
We developed a human-derived cerebral organoids (COs) model that allows for the assessment of mitochondrial health at the primary, reprogrammed, and differentiated stages, using induced pluripotent stem cells (iPSCs) derived from peripheral blood mononuclear cells (PBMCs) and compared and validated these by comparison to COs derived from human embryonic stem cells
Generation of cerebral organoids using iPSCs derived from PBMCs
Summary
Mitochondrial health plays a crucial role in human brain development and diseases. the evaluation of mitochondrial health in the brain is not incorporated into clinical practice due to ethical and logistical concerns. The development of targeted mitochondrial therapeutics remains a significant challenge due to the lack of appropriate patient-derived brain tissues To address these unmet needs, we developed cerebral organoids (COs) from induced pluripotent stem cells (iPSCs) derived from human peripheral blood mononuclear cells (PBMCs) and monitored mitochondrial health from the primary, reprogrammed and differentiated stages. Our results show preserved mitochondrial genetics, function and treatment responses across PBMCs to iPSCs to COs, and measurable neuronal activity in the COs. We expect our approach will serve as a model for more widespread evaluation of mitochondrial health relevant to a wide range of human diseases using readily accessible patient peripheral (PBMCs) and stem-cell derived brain tissue samples. We expect our approach to be a starting point for more sophisticated patient-derived brain models to investigate mitochondrial health and neuronal activity in a wide range of human diseases—a way forward in developing a standard of care for mitochondrial medicine
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