Human neural stem cell transplantation-mediated alteration of microglial/macrophage phenotypes after traumatic brain injury

Junling Gao, Raymond J. Grill, Tiffany J. Dunn, Supinder Bedi, Javier Allende Labastida, Robert A. Hetz, Hasen Xue, Jason R. Thonhoff, Douglas Dewitt, Donald Prough, Charles S. Cox, Ping Wu

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Neural stem cells (NSCs) promote recovery from brain trauma, but neuronal replacement is unlikely the sole underlying mechanism. We hypothesize that grafted NSCs enhance neural repair at least partially through modulating the host immune response after traumatic brain injury (TBI). C57BL/6 mice were intracerebrally injected with primed human NSCs (hNSCs) or vehicle 24 h after a severe controlled cortical impact injury. Six days after transplantation, brain tissues were collected for Western blot and immunohistochemical analyses. Observations included indicators of microglia/macrophage activation, M1 and M2 phenotypes, axonal injury detected by amyloid precursor protein (APP), lesion size, and the fate of grafted hNSCs. Animals receiving hNSC transplantation did not show significant decreases of brain lesion volumes compared to transplantation procedures with vehicle alone, but did show significantly reduced injury-dependent accumulation of APP. Furthermore, intracerebral transplantation of hNSCs reduced microglial activation as shown by a diminished intensity of Iba1 immunostaining and a transition of microglia/macrophages toward the M2 anti-inflammatory phenotype. The latter was represented by an increase in the brain M2/M1 ratio and increases of M2 microglial proteins. These phenotypic switches were accompanied by the increased expression of anti-inflammatory interleukin-4 receptor a and decreased proinflammatory interferon-γ receptor β. Finally, grafted hNSCs mainly differentiated into neurons and were phagocytized by either M1 or M2 microglia/macrophages. Thus, intracerebral transplantation of primed hNSCs efficiently leads host microglia/macrophages toward an anti-inflammatory phenotype that presumably contributes to stem cell-mediated neuroprotective effects after severe TBI in mice.

Original languageEnglish (US)
Pages (from-to)1863-1877
Number of pages15
JournalCell Transplantation
Volume25
Issue number10
DOIs
StatePublished - 2016

Fingerprint

Neural Stem Cells
Macrophages
Stem Cell Transplantation
Stem cells
Brain
Microglia
Phenotype
Transplantation
Anti-Inflammatory Agents
Amyloid beta-Protein Precursor
Proteins
Brain Tissue Transplantation
Wounds and Injuries
Chemical activation
Interleukin-4 Receptors
Interferon Receptors
Interferons
Macrophage Activation
Neuroprotective Agents
Inbred C57BL Mouse

Keywords

  • Immunomodulation
  • Microglia
  • Neural stem cells (NSCs)
  • Transplantation
  • Traumatic brain injury (TBI)

ASJC Scopus subject areas

  • Biomedical Engineering
  • Cell Biology
  • Transplantation

Cite this

Human neural stem cell transplantation-mediated alteration of microglial/macrophage phenotypes after traumatic brain injury. / Gao, Junling; Grill, Raymond J.; Dunn, Tiffany J.; Bedi, Supinder; Labastida, Javier Allende; Hetz, Robert A.; Xue, Hasen; Thonhoff, Jason R.; Dewitt, Douglas; Prough, Donald; Cox, Charles S.; Wu, Ping.

In: Cell Transplantation, Vol. 25, No. 10, 2016, p. 1863-1877.

Research output: Contribution to journalArticle

Gao, Junling ; Grill, Raymond J. ; Dunn, Tiffany J. ; Bedi, Supinder ; Labastida, Javier Allende ; Hetz, Robert A. ; Xue, Hasen ; Thonhoff, Jason R. ; Dewitt, Douglas ; Prough, Donald ; Cox, Charles S. ; Wu, Ping. / Human neural stem cell transplantation-mediated alteration of microglial/macrophage phenotypes after traumatic brain injury. In: Cell Transplantation. 2016 ; Vol. 25, No. 10. pp. 1863-1877.
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abstract = "Neural stem cells (NSCs) promote recovery from brain trauma, but neuronal replacement is unlikely the sole underlying mechanism. We hypothesize that grafted NSCs enhance neural repair at least partially through modulating the host immune response after traumatic brain injury (TBI). C57BL/6 mice were intracerebrally injected with primed human NSCs (hNSCs) or vehicle 24 h after a severe controlled cortical impact injury. Six days after transplantation, brain tissues were collected for Western blot and immunohistochemical analyses. Observations included indicators of microglia/macrophage activation, M1 and M2 phenotypes, axonal injury detected by amyloid precursor protein (APP), lesion size, and the fate of grafted hNSCs. Animals receiving hNSC transplantation did not show significant decreases of brain lesion volumes compared to transplantation procedures with vehicle alone, but did show significantly reduced injury-dependent accumulation of APP. Furthermore, intracerebral transplantation of hNSCs reduced microglial activation as shown by a diminished intensity of Iba1 immunostaining and a transition of microglia/macrophages toward the M2 anti-inflammatory phenotype. The latter was represented by an increase in the brain M2/M1 ratio and increases of M2 microglial proteins. These phenotypic switches were accompanied by the increased expression of anti-inflammatory interleukin-4 receptor a and decreased proinflammatory interferon-γ receptor β. Finally, grafted hNSCs mainly differentiated into neurons and were phagocytized by either M1 or M2 microglia/macrophages. Thus, intracerebral transplantation of primed hNSCs efficiently leads host microglia/macrophages toward an anti-inflammatory phenotype that presumably contributes to stem cell-mediated neuroprotective effects after severe TBI in mice.",
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T1 - Human neural stem cell transplantation-mediated alteration of microglial/macrophage phenotypes after traumatic brain injury

AU - Gao, Junling

AU - Grill, Raymond J.

AU - Dunn, Tiffany J.

AU - Bedi, Supinder

AU - Labastida, Javier Allende

AU - Hetz, Robert A.

AU - Xue, Hasen

AU - Thonhoff, Jason R.

AU - Dewitt, Douglas

AU - Prough, Donald

AU - Cox, Charles S.

AU - Wu, Ping

PY - 2016

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AB - Neural stem cells (NSCs) promote recovery from brain trauma, but neuronal replacement is unlikely the sole underlying mechanism. We hypothesize that grafted NSCs enhance neural repair at least partially through modulating the host immune response after traumatic brain injury (TBI). C57BL/6 mice were intracerebrally injected with primed human NSCs (hNSCs) or vehicle 24 h after a severe controlled cortical impact injury. Six days after transplantation, brain tissues were collected for Western blot and immunohistochemical analyses. Observations included indicators of microglia/macrophage activation, M1 and M2 phenotypes, axonal injury detected by amyloid precursor protein (APP), lesion size, and the fate of grafted hNSCs. Animals receiving hNSC transplantation did not show significant decreases of brain lesion volumes compared to transplantation procedures with vehicle alone, but did show significantly reduced injury-dependent accumulation of APP. Furthermore, intracerebral transplantation of hNSCs reduced microglial activation as shown by a diminished intensity of Iba1 immunostaining and a transition of microglia/macrophages toward the M2 anti-inflammatory phenotype. The latter was represented by an increase in the brain M2/M1 ratio and increases of M2 microglial proteins. These phenotypic switches were accompanied by the increased expression of anti-inflammatory interleukin-4 receptor a and decreased proinflammatory interferon-γ receptor β. Finally, grafted hNSCs mainly differentiated into neurons and were phagocytized by either M1 or M2 microglia/macrophages. Thus, intracerebral transplantation of primed hNSCs efficiently leads host microglia/macrophages toward an anti-inflammatory phenotype that presumably contributes to stem cell-mediated neuroprotective effects after severe TBI in mice.

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KW - Microglia

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KW - Transplantation

KW - Traumatic brain injury (TBI)

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