Cell Therapy Aids Stroke-Damaged Brain Repair, Restores 90% of Motor Function

Most stroke victims don’t receive treatment fast enough to prevent brain damage, but scientists at the Ohio State University Wexner Medical Center, College of Engineering and College of Medicine have developed technology that can “retrain” skin cells to help repair damaged brain tissue. The nonviral tissue nanotransfection (TNT) technique effectively reprograms the skin cells to become vascular cells, which generate new blood vessels to help get blood to the damaged tissue. In tests, stroke-affected mice that received intracranial injections of the cells recovered nearly all of their motor function, and exhibited repair to damaged brain areas.

The researchers suggest that the strategy may someday be used to help patients regain speech, cognition, and motor function, even when administered days after an ischemic stroke. “We can rewrite the genetic code of skin cells so that they can become blood vessel cells,” said Daniel Gallego-Perez, PhD, an assistant professor of biomedical engineering and surgery at Ohio State, who led the research. “When they’re deployed into the brain, they’re able to grow new, healthy vascular tissue to restore normal blood supply and aid in the repair of damaged brain tissue.”

Gallego-Perez and colleagues reported on their technique in Science Advances, in a paper titled, “Nanotransfection-based vasculogenic cell reprogramming drives functional recovery in a mouse model of ischemic stroke.”

A new cell therapy technology offers hope for unprecedented recovery, even days after a stroke. [The Ohio State University Wexner Medical Center]

Stroke is the second leading cause of death worldwide, and those patients who do survive often have irreversible brain damage resulting in paralysis, speech impairment, and loss of motor function. “In the United States, a stroke occurs every 40 seconds, with a death rate of ~20% and a financial burden that is expected to reach ~$100 billion by 2035,” the authors wrote.

No treatments exist to address the lasting and debilitating damage to brain tissue caused by stroke. Recombinant tissue plasminogen activator (rtPA) and endovascular thrombectomy (EVT) are the two FDA-approved treatments for treating ischaemic stroke, and while they can clear clots in the brain to improve outcomes, they are only effective in preventing lasting damage if administered within a few hours of the stroke, before the brain tissue dies. rtPA must be administered within 3–4.5 hours, and EVT within 24 hours, and this limits the use of these treatment approaches to about 20% of patients. This means that 80% of ischemic stroke patients don’t receive the clot-busting therapy in time to prevent permanent deficits to their speech, cognition, and motor function.

And as these existing treatments for stroke also focus on reopening the blocked blood vessels, they can’t help damaged tissue, the team continued. “Hence there is still a need for effective therapies to attenuate tissue damage and aid repair after stroke. Recent studies show that therapies solely aimed at boosting endogenous tissue repair via pharmacologic/trophic factors are often inefficient.”

The newly reported approach created by Ohio State researchers uses TNT to introduce a key set of genes into skin cells, which then drive direct reprogramming of the cells into vascular cells. “Recently, we reported on a simple-to-implement, nanotransfection-based approach to nonviral cell and tissue reprogramming,” they explained. For their mouse studies, the team pre-conditioned the cells by introducing a cocktail containing the developmental transcription factor genes Etv2, Roxc2, and Fli1 (collectively, EFF) and injected the cells back into the stroke-affected brains, where they triggered the formation of new blood vessels to deliver blood supply to the tissue and help to repair damage.

The team’s experiments found that mice given this cell therapy regained 90% of their motor function, with MRI scans showing that damaged areas of the brain were repaired within a few weeks. “MRI and behavioral tests revealed ~70% infarct resolution and up to ~90% motor recovery for mice treated with EFF-nanotransfected fibroblasts … Our results indicate that intracranial delivery of fibroblasts nanotransfected with the EFF cocktail leads to dose-dependent increases in perfusion, reduced stroke volume, and significant recovery of locomotive abilities in stroke-affected mice,” they wrote.

“We found that the mice have a higher recovery because the cells that are being injected into the affected area also release healing signals in the form of vesicles that help in the recovery of damaged brain tissue,” said Natalia Higuita Castro, assistant professor of biomedical engineering and surgery at Ohio State and a co-lead author on the study. As the authors noted, “Our results indicate that EFF-nanotransfected fibroblasts not only exhibited the ability to convert into vascular cells in vitro and in vivo but also released exosomes that could potentially be mediating provasculogenic/angiogenic responses following intracranial delivery into the stroke-affected brain … Together, our results suggest that vasculogenic cell therapies based on nanotransfection-driven (i.e., nonviral) cellular reprogramming represent a promising strategy for the treatment of ischemic stroke.”

The thought was that once brain tissue dies, that was it,” said Shahid Nimjee, MD, PhD, a neurosurgeon at Ohio State Wexner Medical Center, a member of Ohio State’s Neurological Institute, and co-author of the study. “We’re now learning that there could be opportunities to regenerate cells to restore brain function.”

Researchers continue to study this approach, and they’re also exploring other potential uses for this technology to treat brain disorders such as Alzheimer’s and autoimmune diseases.