Human neural stem cell (hNSC) therapy for stroke is showing promise as it moves from the bench into early clinical trials to treat the long term disabilities resulting from stroke. This provides hope for the millions of Americans living with the chronic, debilitating effects of stroke. Major questions remain, however, about how stem cells injected into the brain drive stroke recovery. A clue to stem cell mechanism of action is the recent discovery of the positive correlation between stroke recovery and a brain MRI signal ? T2-FLAIR signal? in stroke patients treated with stem cells. We have successfully reproduced this stem cell-induced FLAIR signal in stroke-injured rats, and shown that its associated with inflammation. This led to our central hypothesis: stem cell transplantation drives recovery by inducing a regenerative inflammatory response. The objective of this grant is to use a rat model of subcortical stroke to investigate the immunomodulatory effects of hNSC transplanted at the chronic stage of stroke, at the regional, cellular and molecular levels using a multimodal approach.
In Aim1 we use MRI and PET imaging to identify which brain regions show inflammatory changes after hNSC transplantation, and which inflammatory regions best correlate with recovery. This will also test the utility of these clinically relevant imaging modalities as biomarkers for stroke recovery.
In Aim 2 we identify the immune changes induced by hNSC treatment using multiple tools to characterize the types and molecular signatures of the immune cells present, and their spatial interactions.
In Aim 3 we determine which hNSC-secreted factors modulate the immune response by testing several candidates, in vitro and in vivo, using CRISPR tools to modulate expression of key candidate factors. We will study the impact of manipulating the levels of these proteins on stroke recovery and immunomodulation. Upon conclusion of the study, we will have made significant advancements in understanding how hNSC-induced immunomodulation affects brain repair. This contribution is significant because it will: a) identify potential biomarkers, both pre- and post-treatment, for hNSC-induced recovery; b) begin to delineate the molecular pathways involved in brain repair; and c) ultimately lead to identification of novel therapies for stroke.

Public Health Relevance

Stem cells therapy offers hope to the millions of stroke patients in the US who live with its debilitative effects. With its devastating long-term consequences to patients and their families, and the tremendous societal costs in the billions of dollars each year, the implications of a successful treatment for stroke are enormous. Because stem cells target brain repair and thus can have a therapeutic effect months or even years post-injury, their use as a stroke treatment has the potential to impact a vastly larger proportion of the patient population than current therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS058784-09
Application #
9662635
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Lavaute, Timothy M
Project Start
2008-08-01
Project End
2024-01-31
Budget Start
2019-05-01
Budget End
2020-01-31
Support Year
9
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Stanford University
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
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