A technique to improve effectiveness in cell transplantation for the treatment of stroke or traumatic brain injury. Professor Jun Takahashi, Researcher Bumpei Samata, and Graduate Student Keitaro Yamagami from CiRA’s Department of Clinical Application reported that they published the study in Stem Cells in Translational Medicine, in 2024. Signs of motor function impairment include motor paralysis, which results from a brain being damaged due to any traumatic stroke or brain injury to the motor cortex region.
Treatments, such as drug therapy, surgery, and rehabilitation, are commonly used but the regenerative capacity of the central nervous system (CNS) is low, and therefore curative therapies should be developed. Human induced pluripotent stem cell (iPSC)-derived brain organoid cell transplantation therapy is being regarded as an exciting new therapeutic approach to repair damaged neural circuits and aid in recovery of motor functions. Despite this, with cell transplantation being associated with acute cell death, the success rate has been low.
It is known from previous reports that cell transplants in the immediate aftermath of traumatic brain injury result in worse outcomes for cell engraftment and neuronal axonal extension compared to transplants performed one week later. The research group based its hypotheses on these observations and suggests that brain tissue one week following a traumatic brain injury may be a better environment for cellular transplants than immediately after the injury.
They, therefore, aimed to identify candidate substances that appeared to work within a more permissive environment at the latter time point. Transcriptome analysis of RNA expression in brain tissues immediately and one week after injury revealed several candidate substances. Cell toxicity tests, evaluating your candidate stuff’s ability to protect neurons from oxidative stress, a major cause of cell death in neurons through strokes and traumatic brain injuries, were performed using neurons derived from brain organoids.
Prior studies have established that delaying transplantation by one week enhances outcomes. We hypothesized that brain tissues one-week post-trauma grant a more favorable environment for cell transplantation than completely post-injury. A transcriptomic comparison revealed distinct gene expression profiles between these temporal states. Under oxidative stress conditions in vitro, recombinant human progranulin (rhPGRN) suggestively enhanced the survival of dissociated neurons derived from human induced pluripotent stem cell-based cerebral organoids (COs) (hiPSC-COs), primarily by reducing apoptosis through Akt phosphorylation. Pretreatment with rhPGRN before in vivo transplantation markedly enhanced engraftment efficiency and promoted neurite elongation along host corticospinal tracts.
This study compared the gene expression profiles of mouse brains from the no-delay and 1wpTBI groups to identify other factors that may boost the therapeutic action of cell transplantation. For these brain tissues, gene expression analysis based on cap analysis of gene expression (CAGE) transcriptomics resulted in the detection of 17,621 genes, and the identification of 940 differentially expressed genes (DEGs). Quantified the effect of candidate proteins on neuronal cell survival in a cytotoxicity test using hydroxy peroxide, a reagent commonly used to induce oxidative stress.
Histological analysis three months post-transplantation showed an improved presence of graft-derived sub-cerebral projection neurons; critical for reconstituting neural circuits in rhPGRN-treated groups. These results underscore the potential of rhPGRN as a neurotrophic factor for developing hiPSC-CO-based cell therapies, offering a novel strategy to develop transplantation outcomes and support neural circuit reconstruction in brain injury recovery.
The findings explained a reduction in apoptosis and increased neuron survival through Akt phosphorylation following treatment with progranulin (PGRN), a growth factor. The therapeutic effects of rhPGRN-treated hiPSC-COs were validated in mouse brains by transplanting rhPGRN-treated hiPSC-COs into mouse brains and analyzing micrographs three months post-transplant. Optimal routes of administration that ensure safer and more effective cell transplantation therapies and evaluation of safety (eg: tumor formation) will require further studies.
Reference: Yamagami K, Samata B, Doi D, et al. Progranulin enhances the engraftment of transplanted human iPS cell-derived cerebral neurons. Stem Cells Transl Med. 2024;13(11):1113-1128. doi:10.1093/stcltm/szae066
