The human body's capacity for tissue repair varies; for instance, the eye's cornea can heal minor abrasions within a day, whereas adult brain cells are stable and generally do not regenerate. Scientific efforts are focused on utilizing stem cell therapy to facilitate brain regeneration following injuries such as concussion or stroke. Previous challenges in this area have included integrating regenerated cells into existing neural circuits to restore functions like memory or motor skills, and the brain's environment post-injury.
Research Findings
On January 8, 2026, scientists from Sanford Burnham Prebys Medical Discovery Institute and Duke-National University of Singapore (NUS) Medical School published findings in Cell Stem Cell regarding a human stem cell-derived therapy. When transplanted into mice, these cells matured, integrated into existing circuits, and restored function. The researchers traced these cells and sequenced their gene expression patterns to understand their integration into the nervous system.
Challenges in Brain Regeneration
Post-stroke, the adult brain presents an environment that impedes stem cell integration. Su-Chun Zhang, MD, PhD, from Sanford Burnham Prebys, noted the presence of a cyst, a cavity filled with inflammatory molecules, and scar tissue surrounding the damaged area. This scar tissue acts as a barrier to regeneration. Current strategies often involve grafting new cells adjacent to the damaged region, aiming to bypass the primary injury. Zhang's team focused on direct intervention within the damaged region.
Therapeutic Approach and Results
Zhang's team developed a method to support the survival of therapeutic cells transplanted directly into the stroke cavity. Utilizing a combination of small molecule drugs and structural proteins, the transplanted cells survived, grew, and filled the damaged area. These cells subsequently developed into neurons capable of penetrating the scar tissue and forming new connections, thereby reconstructing disrupted circuits.
Neuron Integration and Guidance
The research demonstrated that various types of transplanted neurons located their appropriate partners within the mature brain environment, forming specific connections. Three-dimensional reconstruction of the transplanted neurons revealed projection patterns consistent with normal neurons in the pathway between the cerebral cortex and spinal cord.
To understand neuron navigation, the scientists used genetic barcoding to label and trace transplanted cells, combined with gene expression profiling. This revealed that each cell type possesses a distinct genetic code that guides its projections to specific brain and spinal cord regions once it differentiates into a neuron. This suggests that appropriately selected transplanted cells inherently possess the information to repair lost functions.
Neuron Subtypes and Future Directions
Machine learning was employed to identify four distinct neuronal subtypes developing from the transplanted cells. Each subtype exhibited unique gene expression patterns related to axon growth, explaining their consistent projection to specific brain regions. The study also investigated the role of transcription factor proteins in guiding axonal projection patterns. For example, stem cells modified without the Ctip2 transcription factor exhibited altered projection patterns, with more axons forming connections in the hippocampus and amygdala.
Understanding these neuronal subtypes may allow for the selection of specific cell types for targeted circuit reconstruction in patients. This research contributes to the development of cell therapy for neurological conditions such as stroke.
Contributors
Zhifu Wang, PhD, and Danyi Zheng, PhD, are co-first authors of the study. Additional authors include Phil Jun Kang, Shu-Min Chou, and Fei Ye. The National Medical Research Council of Singapore and Duke-NUS Medical School provided funding for the study. The study's DOI is 10.1016/j.stem.2025.12.008.