Stem cell therapy for stroke

Some parts of our bodies bounce back from injury in fairly short order. The outer protective layer of the eye—called the cornea—can heal from minor scratches within a single day.

But the brain works differently and is not one of these fast-healing tissues or organs. Adult brain cells are stable and last for a lifetime barring trauma or disease, whereas some cells lining our guts last only five days and must be continually replaced.

Scientists and physicians are trying to use stem cell therapy to boost the brain's ability to regenerate damage due to concussion or stroke. So far, these treatments have been stymied by changes in the brain due to injury, as well as difficulties with integrating regenerated cells into existing brain circuits to restore functions such as memory retention or motor skills.

Scientists recently published findings in Cell Stem Cell from testing a therapy derived from human stem cells.

When transplanted into mice, the cells matured, integrated into existing circuits and restored function. By tracing the cells and sequencing their gene expression patterns, the researchers also revealed how transplanted cells find where they need to go and form connections with the nervous system.

The first challenge faced by hopeful regenerative medicine therapies for stroke and other forms of brain damage is the lack of a nurturing environment. Whereas the developing brain is a welcoming and instructive place for stem cells forming neurons and wiring the nervous system's circuits, therapeutic cells arriving after a stroke find more hostility than hospitality.

In the adult brain after a stroke, you see the formation of a cyst, a cavity that is filled with all sorts of inflammatory molecules, so it is a bit like the therapeutic cells are swimming in a dangerous swamp full of threats.

If that wasn't enough, scar tissue surrounds the cavity to protect the brain from further damage, but it also forms a barrier against any potential regeneration.

Some cell therapy strategists try grafting new cells next to the damaged region of the brain where it is easier for the cells to survive and grow. The goal is to eventually reestablish circuits by bypassing the damaged region. Researchers now think that this trauma needs to be healed rather than side-stepped to reach the potential benefits of regenerative medicine.

Following a stroke, the damaged lesion is often very large and presents an immense challenge to efforts to functionally reconnect the brain to the brain stem and spinal cord.

The research team of this paper sought to span this gap by developing a method to support the survival of therapeutic cells grafted directly into the harsh environment of the stroke cavity. Using a mixture of small molecule drugs and structural proteins, the scientists found that transplanted cells succeeded in surviving and growing to fill the damaged region.

Once transplanted cells could survive and become neurons, then they started asking whether those neurons can break through the scar tissue and grow functioning nerves by making new connections and reconstructing the disrupted circuits.

While the researchers had proven it was possible to transplant cells and grow new neurons, they knew it would be of little benefit if they didn't form the correct kinds of connections. 

They found that different types of transplanted neurons found their own partners even in the complicated context of the mature brain environment. After conducting three-dimensional reconstruction of the transplanted neurons, the scientists observed that the patterns of long, spiny projections neurons use to form connections in the nervous system resembled the patterns seen in normal neurons populating the pathway between the cerebral cortex and spinal cord.

Next, the scientists sought to better understand the navigational abilities of these regenerated neurons. They used a genetic bar code to label and trace the transplanted cells. This data was combined with the results of sequencing the transplanted cells' gene expression profiles.

They revealed that each cell type has its own code and, once the cells become neurons, this code tells each cell to send its projections or axons to different parts of the brain and spinal cord.

It's the first time this striking phenomenon has been reported, and it is significant because it basically tells us that if we have the right types of transplanted cells, they already know where to go and what to do to repair what has been lost.

The scientists used machine learning to identify four subtypes of neurons that develop from transplanted therapeutic cells. Each subtype has a distinct expression of genes known to guide the growth of axons, which explains why most neurons of a particular subtype send axons to form circuits with the same brain region.

The research team also validated how axonal projection patterns are affected by transcription factor proteins that modify gene expression. 

By learning more about these subtypes of transplanted neurons, scientists may be able to predict their projections and connectivity in order to select appropriate neuronal cell types for targeted circuit reconstruction in patients.

This opens a promising future for cell therapy to help the millions of people that suffer from stroke and other devastating neurological conditions.

Transcriptional code for Circuit Integration in the Injured Brain by Transplanted Human Neurons, Cell Stem Cell (2026). DOI: 10.1016/j.stem.2025.12.008. www.cell.com/cell-stem-cell/fu … 1934-5909(25)00442-4