The Regents of the University of California (Irvine)
Hal X. Nguyen, Ph.D.

The central nervous system (CNS) is normally isolated and separated from the immune system by the blood brain/spinal barrier (BBB/BSB). However, disruption of the BBB/BSB as a result of traumatic injury permits the entrance of immune cells and other components of the immune system that may affect injury and regeneration. Critically, the immune response has garnered increasing attention because of its potential impact on the outcome of stem cell transplantation. The benefit of stem cell transplantation and the prevention of scar formation after traumatic CNS injury may be affected and enhanced by the outcome of my research because most stem cell transplantation studies today are often faced with obstacles involving stem cell survival and astrocytic differentiation in the host microenvironment. Even in some studies in which animals lacking a fully functional immune system or animals treated with immunosuppressive drugs targeting predominantly the T-cell response are used, the presence of other types of immune cells is staggering and may affect stem cell fate and survival. In these studies, immune cells that infiltrate the brain (TBI) or spinal cord (SCI) post trauma consist of predominantly polymorphonuclear leukocytes (PMNs, neutrophils) and macrophages/microglial. Likewise, partially suppressing a patient immune system for stem cell transplantation will likely result in some suppression of the T-cell response without affecting the response by other immune cells such as PMNs. As the first predominant immune cells to infiltrate the CNS within several hours after injury, PMNs release numerous cytokines that can affect scar formation and stem cell fate/survival. In this proposal, I provide novel evidence that PMNs promote astrocytic proliferation in culture and may mediate astrocytic fate of engrafted human neural stem cells (hNSCs) in immunodeficient (NOD-scid) mice after SCI. Together, these data suggest that PMNs affect scar formation and mediate engrafted hNSC differentiation after SCI. However, a role for PMNs to affect hNSC fate/survival is not known and has not been previously investigated. My proposed investigations will empirically test the role for PMNs affecting hNSC astrocytic fate in culture and astrocytic proliferation/scar formation in vivo after SCI. As a researcher investigating how the immune system interacts with the engrafted hNSCs to affect SCI and recover. I am hopeful that through the manipulations of the immune system, safe and effective treatments and stem cell transplantation therapy can be generated to benefit patients with SCI. Outcome from my proposed studies may provide novel evidence and a better understanding of PMN contribution to scar formation and the fate/survival of engrafted stem cells after SCI. It is my long-term goal to help or take part in the improvement of stem cell transplantation and the generation of effective stem cell therapy through immunological intervention for patients with paralysis.