Cerebral Organoids Repair Ischemic Stroke Brain Injury

Abstract

Stroke is the second leading cause of death and main cause of disability worldwide, but with few effective therapies. Although stem cell-based therapy has been proposed as an exciting regenerative medicine strategy for brain injury, there are limitations. The developed cerebral organoids (COs) represent a promising transplantation source for stroke that remains to be answered. Here, we transplanted COs at 55 days and explored the feasibility in the rat middle cerebral artery occlusion (MCAO) model of stroke. COs transplantation at 6 h or even 24 h after MCAO significantly reduces brain infarct volume and improves neurological motor function. Transplanted COs show the potential of multilineage differentiation to mimic in vivo cortical development, support motor cortex region-specific reconstruction, form neurotransmitter-related neurons, and achieve synaptic connection with host brain via in situ differentiation and cell replacement in stroke. Cells from transplanted COs show extensive migration into different brain regions along corpus callosum. The mechanisms underlying COs transplantation therapy are also associated with enhanced neurogenesis, synaptic reconstruction, axonal regeneration and angiogenesis, and decreased neural apoptosis with more survival neurons after stroke. Moreover, COs transplantation promotes predominantly exogenous neurogenesis in the transplantation periphery of ipsilateral cortex and predominantly endogenous neurogenesis in the hippocampus and subventricular zone. Together, we demonstrate the efficacy and underlying mechanisms of COs transplantation in stroke. This preliminary but promising study provides first-hand preclinical evidence for COs transplantation as a potential and effective intervention for stroke treatment.

Clinical Application of Human Induced Pluripotent Stem Cell-Derived Organoids as an Alternative to Organ Transplantation

“…Organoids were transplanted at 55 days in the rat middle cerebral artery occlusion, and results, 6 h–24 h later, demonstrated that cerebral organoids were able to differentiate and migrate into different brain regions. Also, they observed reduced brain damage volume, synaptic reconstruction, and neurological motor function recovery, among other neurological improvements, likely due to cell survival and vascularization, cell multilineage differentiation, and cellular replacement after stroke [ 65 ].…”

Cerebral organoids and their potential for studies of brain diseases in domestic animals

“…Today, they are the closest in vitro model of the human brain. They have assisted in the understanding of several neurological diseases: those of embryonic origin such as autism [ 42 , 56 , 57 ], genetic or viral-induced microencephaly [ 30 , 35 , 58 ], lissencephaly and Miller-Dieker syndrome [ 59 , 60 ], but also those of the aging brain such as Parkinson’s disease [ 61 – 63 ], Alzheimer’s disease [ 64 ], stroke [ 65 , 66 ] and brain tumors such as glioblastomas [ 67 – 69 ]. They are also expected to be more predictive for drug development.…”

Regenerative Rehabilitation for Stroke Recovery by Inducing Synergistic Effects of Cell Therapy and Neurorehabilitation on Motor Function: A Narrative Review of Pre-Clinical Studies

“…Therefore, brain organoids are expected to be plausible cell sources for transplantation. A study by Wang et al exploring the effects of brain organoid transplantation in a rat model of middle cerebral artery occlusion (MCAO) found that cerebral infarct volume was greatly reduced and neuromotor function was improved [23]. The transplanted brain organoids imitated cortical development and supported motor-cortex-specific reconstruction.…”