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.
Highlights
Stroke is the second leading cause of death worldwide, endangering public health but with few effective therapies
As oligodendrocyte survival is closely related to the production of myelin sheaths and preservation of axon function [32], we introduced adult oligodendrocyte-precursor cell (OPCs) marker platelet-derived growth factor receptor α (PDGFRα) and oligodendrocyte-lineage cell marker Nkx2.2 to explore the role of cerebral organoids (COs) transplantation on oligodendrogenesis after stroke
With TUNEL staining for cell apoptosis and Nissl’s staining for survival neurons, we found that COs transplantation significantly decreased TUNEL positive cells and increased Nissl’s positive neurons at 7 and 28 dpi in the transplantation periphery of ipsilateral cortex after middle cerebral artery occlusion (MCAO) (Fig. S5), demonstrating decreased neural apoptosis and more survival neurons mediated by COs transplantation
Summary
Stroke is the second leading cause of death worldwide, endangering public health but with few effective therapies. The recent generation of three-dimensional cerebral organoids (COs) from human pluripotent stem cells overcomes the limitations of stem cell-based transplantation therapy to a certain extent and shows advantages in diverse cell types (including but not limited to, NPCs, NSCs, mature and immature neurons, glia cells), rich cell source, considerable cell number, and controllable degree of cell differentiation and Transl. The COs show neural connectivity and brain functionality in vitro that recapitulates in vivo features of brain development and maturation [6, 8,9,10], providing possibility for directly repairing and replacing damaged brain tissue after stroke. Compared to NPC transplantation, transplanted COs exhibit more cell survival number and better vascularization with host brain and harbor a large NSC pool with multilineage neurodifferentiation [12]. COs represent a promising alternative source of NSCs to be a potential transplantation donor for stroke
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