Yu-Ping Shen - Institutionen för kliniska vetenskaper, Lund

Title: Filling the gap in stroke research from animal to human – a deeper understanding of the cortical stroke model and stem cell-derived transplantation

Main supervisor: Zaal Kokaia

Reviewers: Saema Ansar, Marion Moseby Knappe

Background

Stroke is a leading cause of death and disability, which is caused by an interrupted blood supply and results in focal brain damage. Thousands of interventions have demonstrated encouraging effects in various preclinical studies, and over 200 drugs have been tested clinically. However, only one has translated successfully. To fill the gap of translational

differences, better understanding of current preclinical models, novel intervention approaches, and a human tissue-based platform is potentially required.

Preliminary results

Behavioral tests in cortical ischemic stroke rats – short- and long–term functional impairments:

We observed that rats with a large stroke exhibited long-term forelimb impairment in the stepping test and ladder rung test. Most stroke-affected animals showed a decrease in grip strength of the affected forelimb up to 1 month. Meanwhile, the cylinder test only detected short-term asymmetry in large stroke rats. No significant long-term impairment was found in rats with a small stroke.

Secondary thalamic degeneration following cortical stroke:

The ipsilateral thalamus demonstrated reduced volume, neuronal loss, and increased activated microglia following stroke. The dynamics of tractographic parameters further

indicated the axonal injury and demyelination process of the fiber tract connecting with the thalamus. Furthermore, human-induced pluripotent stem cell-derived neural progenitors transplantation has been shown to have the capability to rescue neuronal loss in the thalamus.

Review of brain organoid transplantation:

This comprehensive review summarized pre-transplantation statements, transplantation procedures, post-transplantation outcomes, current applications, and future challenges, as well as perspectives. The results demonstrated its strong potential for in vivoapplications and broad applicability, although significant challenges and ethical issues remain.

Human cortical organoid transplantation onto human organotypic cortical slices ex vivo:

To investigate if the organoids could integrate into the host neuronal circuits in the human-to-human platform. Our preliminary results showed the graft could send robust fiber

projections over the host slices within one month. Further experiments to assess functional integration are ongoing.

We have explored the nature of the rat cortical stroke model, organoid transplantation, and applied it to a human brain platform. These results could provide a substantial foundation to bridge the gap between the bench and the clinic.

Publications

Shen, Y.-P.; Kokaia, Z. Brain Organoid Transplantation: A Comprehensive Guide to the

Latest Advances and Practical Applications—A Systematic Review. Cells 2025, 14, 1074. https://doi.org/10.3390/cells14141074