Human Neural Stem Cell Transplantation-Mediated Alteration of Microglial/Macrophage Phenotypes after Traumatic Brain Injury

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-g receptor b. 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.

Proliferation and differentiation of human fetal brain neural stem cells in vitro

“…13 This transplantation reduced microglial activation and diminished inflammatory mediators. 13 These results pose further interesting applications of hNSC culture for transplantation and mediation of glial responses. The role of glial progenitors and transplantation is critically important due to their proven role in rescuing myelination phenotype in mice.…”

One Step at a Time, Stem Cell Therapy for Traumatic Brain Injury Needs Two More Breakthroughs

“…30,[76][77][78] In other TBI and stroke models, cells have been delivered via intravenous (IV), intra-arterial carotid (IAC) or intraparenchymal (IP) injections. However, IV administration causes loss of the majority (~95%) of the cells during lung passage, 55,[79][80][81] whereas IAC injection carries the risk of causing embolic brain infarction and fails to deliver sufficient cells across the vascular wall barrier to the brain parenchyma, which is the major barrier for putative clinical use of this route.…”

“…1,[23][24][25] Several preclinical studies have evaluated the efficacy of rodent neural precursor cells in TBI rodent models. 22,[26][27][28][29][30] The culturing NSCs in vitro started as an attempt to grow multipotent embryonic cortical tissue (the word neural stem cells was not yet coined) and successfully accomplished in 1989 at the University of Miami. 31 This work evolved when Martin Raff, a Canadian born Boston neurologist decided to move to England and chose to leave the United States (US) than fight in Vietnam War and to pursue immunology.…”

“…1,75 Transplantation of viable fetal neural progenitor cells (as early as 24h post TBI) attenuated host neuronal degeneration (as assessed on day 6 post transplantation), also guided host microglia/macrophages towards an anti-inflammation phenotype indicating that a potentially beneficial effect of progenitor cell transplantation on adjacent host cells. 30,[76][77][78] In other TBI and stroke models, cells have been delivered via intravenous (IV), intra-arterial carotid (IAC) or intraparenchymal (IP) injections. However, IV administration causes loss of the majority (~95%) of the cells during lung passage, 55,[79][80][81] whereas IAC injection carries the risk of causing embolic brain infarction and fails to deliver sufficient cells across the vascular wall barrier to the brain parenchyma, which is the major barrier for putative clinical use of this route.…”

Traumatic Brain Injury: Current Treatment Strategies and Future Endeavors

“…116 Gao et al reported that grafted human NSCs promoted the switch of microglia/macrophages into an anti-inflammation phenotype which may contribute to stem cell-mediated neuroprotective effects after severe TBI in mice. 117 Although there is no clinical trial concerning NSC transplantation for TBI recovery, the clinical study in traumatic cervical spinal cord injury has shown the safe outcomes. 118 Transplantation of embryonic stem cells (ESCs) in TBI has also been studied.…”