Stroke is the number one cause of disability among Americans each year. Currently there is no therapy to cure stroke patients except the thrombolytic treatments, which have limited use. Our long-term goal is to promote functional recovery from stroke using human neural progenitor cells (hNPCs) as a potential therapy. We and others have shown that neural stem/progenitor in some cases can improve neurological function in rodents. However, transplant viability and functional outcome vary widely across studies. Our overall hypothesis is that hNPCs facilitate long-term functional by enhancing endogenous repair mechanisms through secretion of trophic factors. Including a focus on the trophic factors gives a mechanistic understanding of how transplanted stems cells augment endogenous repair processes. Importantly, we do not believe that the cells enhance recovery integrating into the host brain circuitry.
In Specific Aim 1, we determine the effect of the transplanted cells on several endogenous repair mechanisms as well as the trophic factors expressed by the hNPCs in vivo over time, and then correlate these phenomena with functional recovery. We then test specific factors by manipulating their expression levels in hNPCs before transplantation.
In Specific Aim 2, we determine the host microenvironment that is most conducive to cell-induced repair by varying the timing of transplantation post- stroke, with the goal of finding the optimal time to transplant. We also test the interplay between the host microenvironment and hNPCs by surveying host factors that are affected by hNPCs and also modifying the hNPCs' sensitivity to signals for migration and survival from the host's microenvironment. Together these aims will help identify the optimal time to transplant human neural progenitor cells after stroke and link successful cell therapy with critical molecular and cellular mechanisms that underlie endogenous repair after stroke. Graft survival and biology, and its effect on host repair mechanisms, will be assessed using immunohistochemistry. Functional recovery will be examined using behavioral tests. Our expertise in stroke research and cellular therapies (Kelly, 2004), neural stem cell biology and culture methods (Palmer, 2001), synaptogenesis (Christopherson, 2005), imaging (Micheva, 2007) and genetic manipulation of hNPCs (Suzuki, 2007) provide an excellent opportunity to develop a cross-disciplinary effort to study cell transplants for brain injury at Stanford.

Public Health Relevance

Stroke is the number one cause of disability among Americans each year, and there are limited therapeutic treatments that can be offered. Our long-term goal is to promote functional recovery from stroke using human neural progenitor cells (NPCs) as a potential therapy. In this proposal we seek to understand how the NPCs augment the brain's natural repair processes after stroke so that we can enhance these properties in the future. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS058784-01A2
Application #
7526368
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Owens, David F
Project Start
2008-08-01
Project End
2012-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
1
Fiscal Year
2008
Total Cost
$404,210
Indirect Cost
Name
Stanford University
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Boshuizen, Marieke C S; Steinberg, Gary K (2018) Stem Cell-Based Immunomodulation After Stroke: Effects on Brain Repair Processes. Stroke 49:1563-1570
George, Paul M; Oh, Byeongtaek; Dewi, Ruby et al. (2018) Engineered stem cell mimics to enhance stroke recovery. Biomaterials 178:63-72
Sussman, Eric S; Steinberg, Gary K (2017) A Focused Review of Clinical and Preclinical Studies of Cell-Based Therapies in Stroke. Neurosurgery 64:92-96
George, Paul M; Bliss, Tonya M; Hua, Thuy et al. (2017) Electrical preconditioning of stem cells with a conductive polymer scaffold enhances stroke recovery. Biomaterials 142:31-40
Rennert, Robert C; Schäfer, Richard; Bliss, Tonya et al. (2016) High-Resolution Microfluidic Single-Cell Transcriptional Profiling Reveals Clinically Relevant Subtypes among Human Stem Cell Populations Commonly Utilized in Cell-Based Therapies. Front Neurol 7:41
Azad, Tej D; Veeravagu, Anand; Steinberg, Gary K (2016) Neurorestoration after stroke. Neurosurg Focus 40:E2
Steinberg, Gary K; Kondziolka, Douglas; Wechsler, Lawrence R et al. (2016) Clinical Outcomes of Transplanted Modified Bone Marrow-Derived Mesenchymal Stem Cells in Stroke: A Phase 1/2a Study. Stroke 47:1817-24
Hiu, Takeshi; Farzampour, Zoya; Paz, Jeanne T et al. (2016) Enhanced phasic GABA inhibition during the repair phase of stroke: a novel therapeutic target. Brain 139:468-80
Daadi, Marcel M; Klausner, Jill Q; Bajar, Bryce et al. (2016) Optogenetic Stimulation of Neural Grafts Enhances Neurotransmission and Downregulates the Inflammatory Response in Experimental Stroke Model. Cell Transplant 25:1371-80
George, Paul M; Steinberg, Gary K (2015) Novel Stroke Therapeutics: Unraveling Stroke Pathophysiology and Its Impact on Clinical Treatments. Neuron 87:297-309

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