Cell-based therapy for traumatic brain injury

Abstract

Traumatic brain injury is a major economic burden to hospitals in terms of emergency department visits, hospitalizations, and utilization of intensive care units. Current guidelines for the management of severe traumatic brain injuries are primarily supportive, with an emphasis on surveillance (i.e. intracranial pressure) and preventive measures to reduce morbidity and mortality. There are no direct effective therapies available. Over the last fifteen years, pre-clinical studies in regenerative medicine utilizing cell-based therapy have generated enthusiasm as a possible treatment option for traumatic brain injury. In these studies, stem cells and progenitor cells were shown to migrate into the injured brain and proliferate, exerting protective effects through possible cell replacement, gene and protein transfer, and release of anti-inflammatory and growth factors. In this work, we reviewed the pathophysiological mechanisms of traumatic brain injury, the biological rationale for using stem cells and progenitor cells, and the results of clinical trials using cell-based therapy for traumatic brain injury. Although the benefits of cell-based therapy have been clearly demonstrated in pre-clinical studies, some questions remain regarding the biological mechanisms of repair and safety, dose, route and timing of cell delivery, which ultimately will determine its optimal clinical use.

Keywords: cell-based therapy; stem cells; traumatic brain injury.

© The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Figures

Fig 1

Neurogenesis and Angiogenesis After Traumatic Brain Injury. Neurogenesis occurs throughout adult human life in two different zones of the brain: the subgranular zone of the hippocampus dentate gyrus, and the subventricular zone (SVZ) of the lateral ventricles - olfactory bulb pathway. The hippocampus and the SVZ generate neural stem cells (NSCs), which are self-renewing and multipotent. NSCs can generate neural progenitor cells (NPCs), which do not maintain the NSCs pool but rather generate neuronal and glial cells. After the initial neuronal loss in the hippocampus after traumatic brain injury (TBI): (a) Neurogenesis increase in the SVZ and in the hippocampus as early as two days, essentially in the ipsilateral side of the injured brain but also in the contralateral side to a lesser extent. Neurogenesis remains usually high for two weeks in the SVZ and one month in the hippocampus, and sometimes last up to one year. NSCs can therefore migrate directly from the SVZ to the site of injury and differentiate into neuronal and glial cells. New neurones can extend axonal projections to the cornu ammonis (CA)-3 region of the hippocampus two weeks after TBI, leading to cognitive improvement. (b) Angiogenesis from pre-existing vessels and vasculogenesis from bone-marrow and adipose-tissue derived endothelial cells are also stimulated after TBI. Increased angiogenesis has been shown three days after injury, with proliferation of endothelial cells by twelve hours. Endothelial cells also stimulate the proliferation and differentiation of NSCs and migration of neuroblasts, in part through the production of soluble growth factors such as the brain derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF). Endothelial cells also promote neuronal differentiation by up- and down- regulating Hes6 and Sox2 expression, respectively. Although effective after minor brain injury, these mechanisms may be insufficient after severe TBI. BDNF, brain derived neurotrophic factor; CA, cornu ammonis; Hes6 and Sox2, transcription factors; NPC, neural progenitor cells; NSC, neural stem cells; SVZ, subventricular zone; TBI, traumatic brain injury; VEGF, vascular endothelial growth factor.

Fig 2

Potential Mechanisms of Action of Stem and Progenitor Cells in Traumatic Brain Injury. The therapeutic effect of stem and progenitor cells in traumatic brain injury (TBI) may be explained by the following mechanisms of action: 1) Differentiation of stem cells into loco-regional cell types and cell replacement although the long term engraftment rates are very low; 2) Stabilization of damage cells via gene and protein transfer by inter-cellular contact or fusion; 3) Increase of regional cell survival or proliferation via the secretion of chemokine and growth factors such as neurotrophic growth factor (NGF), brain derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and fibroblast growth factor (FGF); 4) Reduction of oedema and inflammation caused by TBI, by enhancing, in the injured brain and the systemic circulation, the secretion of anti-inflammatory cytokines such as interleukin (IL)-10, and reducing the secretion of pro-inflammatory cytokines such as interferon-γ by immune cells; 5) Enhancement of angiogenesis and vasculogenesis in the ischaemic brain, by increasing VEGF secretion and the VEGF receptor (VEGFR)-2 expression; 6) And by development of pathways between the subventricular zone (SVZ) and the site of injury expressing high levels of extracellular matrix metalloproteinases and where transplanted stem cells implant initially. These transplanted stem cells act as pathways for the migration of host neurogenic cells. Once the ‘biobridge’ is formed, the grafted stem cells disappear and the host neurogenic cells persist, replacing the initial tasks of transplanted stem cells. BDNF, brain derived neurotrophic factor; FGF, fibroblast growth factor; IL, interleukin; NGF, neurotrophic growth factor; SVZ, subventricular zone; TBI, traumatic brain injury; VEGF, vascular endothelial growth factor; VEGFR-2, vascular endothelial growth factor receptor-2.