Stem cell transplantation-mediated immunomodulation – A key promoter of post-stroke brain recovery?

• Applicant: Pardes Habib, Ph.D.
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Experimental Models for the Understanding of Nervous System Diseases ; Clinical Neurology; Neurosurgery and Neuroradiology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 468395010

Stroke is a prevalent medical emergency and remains one of the leading causes of mortality and adult disability worldwide. According to the World Health Organization (WHO), about 15 million people worldwide suffer a stroke annually, leaving one third of them permanently disabled. The current standard of care for acute ischemic stroke (AIS) is removal of the blood clot either pharmacologically (thrombolysis, e.g., alteplase), or by physical removal of the clot using endovascular therapy (mechanical thrombectomy). However, due to their time-dependency and contraindications, these reperfusion modalities are applicable to less than 15% of AIS patients. Beyond the acute period, there are currently no approved neuroprotective/neurorestorative approaches for the myriad of damaging post-ischemic processes that persist in the brain, leaving millions of people living with chronic disabilities from stroke.Human neural stem cell (hNSC) therapy for stroke is showing promise as it moves from the bench into early clinical trials. A recently published early phase clinical trial led by Dr. Gary K. Steinberg (Stanford Stroke Center, Stanford University School of Medicine) in collaboration with SanBio has provided great hope for the millions of people around the globe living with the debilitating effects of chronic stroke. Here, stem cells injected into the brains of patients 6 months to 5 years after their stroke, when natural recovery has plateaued, were shown to provide a clinically meaningful improvement in most patients. A potential clue to the mechanism of stem cell action is the intriguing discovery in this trial that the extent of motor recovery at 6, 12 and 24 months after transplant positively correlated with the size of a transient T2-FLAIR (fluid-attenuated inversion recovery) MRI signal. The stem cell-induced brain changes that cause this T2-FLAIR signal are not known, but cellular and molecular analysis of this brain region could provide valuable insight into the recovery mechanisms involved. A T2-MRI FLAIR signal is often associated with inflammation leading to the hypothesis that hNSC transplantation induces a regenerative inflammatory response involving both brain-resident and infiltrating immune cells after chronic stroke. The ultimate goal is to elucidate how stem cell-induced immunomodulation promotes recovery; this will unveil molecular mechanisms of stem cell action and brain repair. This proposal takes a major step toward this goal by addressing the fundamental question of what immune cell changes are elicited by the stem cells? By investigating this at the cellular and molecular level we can start to determine how immune cells might modulate brain function.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Participating Institution: Stanford University; Department of Neurosurgery; Gary K. Steinberg Laboratory
• Host: Professor Gary K. Steinberg, Ph.D.