TY - JOUR
T1 - Systemic neutrophil depletion modulates the migration and fate of transplanted human neural stem cells to rescue functional repair
AU - Nguyen, Hal X.
AU - Hooshmand, Mitra J.
AU - Saiwai, Hirokazu
AU - Maddox, Jake
AU - Salehi, Arjang
AU - Lakatos, Anita
AU - Nishi, Rebecca A.
AU - Salazar, Desiree
AU - Uchida, Nobuko
AU - Anderson, Aileen J.
N1 - Funding Information:
This study was funded by National Institutes of Health (NIH) Grant NS-49885 (to A.J.A.), California Institute for RegenerativeMedicine(CIRM)GrantRB2-01496(toH.X.N.andA.J.A.),ParalysisProjectofAmericaGrantPPA-32574 (to H.X.N.), CIRM Stem Cell Training Award T1-00008 (to H.X.N.), Christopher and Dana Reeve Foundation Grant CRF-AAC 2005 (to A.J.A.), National Center for Research Resources and the National Center for Advancing Translational Sciences (NIH) Grant UL1-TR-001414), The Morton Cure Paralysis Fund MCPF-204464 (to H.X.N.), and Stem-Cells,Inc.WethankthetechnicalstaffattheChristopherandDanaReeveFoundationAnimalInjuryCore:HongliLiu and Jovanny Lucero, as well as Gabriella Funes, Joel Trushinsky, and Dena Yassin.
Publisher Copyright:
© 2017 the authors.
PY - 2017/9/20
Y1 - 2017/9/20
N2 - The interaction of transplanted stem cells with local cellular and molecular cues in the host CNS microenvironment may affect the potential for repair by therapeutic cell populations. In this regard, spinal cord injury (SCI), Alzheimer’s disease, and other neurological injuries and diseases all exhibit dramatic and dynamic changes to the host microenvironment over time. Previously, we reported that delayed transplantation of human CNS-derived neural stem cells (hCNS-SCns) at 9 or 30 d post-SCI (dpi) resulted in extensive donor cell migration, predominantly neuronal and oligodendrocytic donor cell differentiation, and functional locomotor improvements. Here, we report that acute transplantation of hCNS-SCns at 0 dpi resulted in localized astroglial differentiation of donor cells near the lesion epicenter and failure to produce functional improvement in an all-female immunodeficient mouse model. Critically, specific immunodepletion of neutrophils (polymorphonuclear leukocytes) blocked hCNS-SCns astroglial differentiation near the lesion epicenter and rescued the capacity of these cells to restore function. These data represent novel evidence that a host immune cell population can block the potential for functional repair derived from a therapeutic donor cell population, and support targeting the inflammatory microenvironment in combination with cell transplantation after SCI.
AB - The interaction of transplanted stem cells with local cellular and molecular cues in the host CNS microenvironment may affect the potential for repair by therapeutic cell populations. In this regard, spinal cord injury (SCI), Alzheimer’s disease, and other neurological injuries and diseases all exhibit dramatic and dynamic changes to the host microenvironment over time. Previously, we reported that delayed transplantation of human CNS-derived neural stem cells (hCNS-SCns) at 9 or 30 d post-SCI (dpi) resulted in extensive donor cell migration, predominantly neuronal and oligodendrocytic donor cell differentiation, and functional locomotor improvements. Here, we report that acute transplantation of hCNS-SCns at 0 dpi resulted in localized astroglial differentiation of donor cells near the lesion epicenter and failure to produce functional improvement in an all-female immunodeficient mouse model. Critically, specific immunodepletion of neutrophils (polymorphonuclear leukocytes) blocked hCNS-SCns astroglial differentiation near the lesion epicenter and rescued the capacity of these cells to restore function. These data represent novel evidence that a host immune cell population can block the potential for functional repair derived from a therapeutic donor cell population, and support targeting the inflammatory microenvironment in combination with cell transplantation after SCI.
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U2 - 10.1523/JNEUROSCI.2785-16.2017
DO - 10.1523/JNEUROSCI.2785-16.2017
M3 - Article
C2 - 28847814
AN - SCOPUS:85029758052
VL - 37
SP - 9269
EP - 9287
JO - Journal of Neuroscience
JF - Journal of Neuroscience
SN - 0270-6474
IS - 38
ER -
