Evaluation of Evidence: Stem Cells as a Treatment Option for Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) is a major public health concern. TBI has two phases: a primary injury due to direct damage from a mechanical force applied to the head and a secondary injury due to cellular and molecular responses to the injury. Despite its significant burden on societies, decades of clinical trials have not yielded any FDA‐approved therapies for TBI. Insignificant endogenous repair and continued neuronal cell loss underlie the disability in TBI survivors. The advent of stem cell culture led to the notion that such cells could potentially replace lost cells. Examination of preclinical and clinical studies suggests that stem cell‐replacement approaches in TBI remain elusive. In contrast, stem cell transplantation appears to mitigate multiple TBI‐induced pathologies by modulating inflammation, angiogenesis and endogenous neurogenesis. Thus, transplantation‐based stem cell therapeutic approaches are a viable treatment option for TBI.

Key Concepts

  • Traumatic brain injury (TBI) is a major health concern with complex underlying pathology mechanisms and no FDA‐approved treatments to date.
  • Stem cells, which can be obtained from different sources, have therapeutic properties that render them beneficial for treating various neurological and neurodegenerative diseases, including TBI.
  • Stem cell‐based therapy has been utilised for the treatment of TBI and has shown to be a therapeutic promise in few preclinical and early phase clinical studies.
  • Neural stem cells have neuro‐restorative properties that are promising for the treatment of various neurological and neurodegenerative disorders.
  • Despite their promising therapeutic abilities, stem cell‐based therapies still face several hurdles that limit their efficacy as a treatment in TBI. More research is needed to perfect this treatment approach.

Keywords: TBI; secondary damage; stem cells; neural stem cells; neurogenesis; replacement stem cell therapy; transplantation stem cell therapy

Figure 1. Loss of tissue, impaired neurogenesis due to tissue disruption of neurogenic niches. (a) Mouse brain with severe traumatic brain injury (b) frontal section of the mouse brain stained with hematoxylin and eosin (H&E) stain. Hematoxylin stains cell nuclei blue, and eosin stains the cytoplasm pink. These sections show the two sites of neurogenesis in a mouse. Neurogenesis occurs in two main regions of the mammalian brain: the subventricular zone of the lateral ventricles (SVZ) (left image) and the subgranular zone (SGZ) of the dentate gyrus (DG) around the hippocampus or what is referred to as hippocampal neurogenesis (right image). Neurogenesis is impaired in this mouse due to disruption of neurogenic niches by the injury to the brain.
Figure 2. Restriction of lineage potential following cellular differentiation. Totipotent cells (like: zygote) have the ability to self‐renew and differentiate into all of the cell types of an organism. ICM of the blastocyst (early‐stage preimplantation embryo) gives rise to pluripotent embryonic stem cells in vitro. Foetal stem cells are multipotent and are not capable of giving rise to all cell lineages. During neurogenesis, progenitor neural cells can give rise to a neuroblast, a glioblast or a migratory neural crest cell. The neuroblast gives rise to several neuron types: bipolar (Bi), pyramidal (Pyr), purkinje (Pur). The glioblast can give rise to astrocytes, oligodendrocytes or microglia.
Figure 3. How evidence is gathered in basic research? Therapy development is complex and is composed of several stages to ensure more efficient and safer treatments reach the patients as quickly as possible. Therapy development begins with preclinical research to determine the efficacy and safety of the procedure of therapy. Preclinical research is first done in cells in culture, and then in animal models. Once efficacy and safety of the therapy are proven in preclinical studies, drug testing moves to clinical testing. Clinical testing involves human subject and requires Phase I, II and III clinical trials. Approval of a drug or therapy by the the Food and Drug Administration (FDA) requires full clinical testing.
Figure 4. How do stem cells work in TBI? Following TBI secondary injury, several cellular changes take place including chronic activation of microglia, decrease in tissue blood perfusion as a result of vascular abnormalities, impaired neurogenesis, cell death and loss of neural cells. Stem cell therapy can ameliorate the impact of the secondary injury by decreasing or inhibiting the aforementioned cellular changes. NSC, neural stem cells; TBI, traumatic brain injury; SCs, stem cells.
Figure 5. Sources of stem cells used in the context of TBI. In TBI, ex vivo or exogenous stem cell‐based therapies involve the transplantation of autologous adult NSCs, MSCs, iPSCs and the neural derivatives of iPSCs, MSCs or ESCs into the site of TBI. The lower panel shows the preclinical and clinical trials that have been performed in the field of stem cell transplantation in TBI.
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Tabet, Maha, Hasan, Hiba, Abdelhady, Samar, Mahavadi, Anil K, Clervius, Hélène, Nasrallah, Leila, Ahmad, Fatimah, Shaito, Nour, Ramakrawala, Rashida, Zibara, Kazem, Gajavelli, Shyam, Kobeissy, Firas H, and Shaito, Abdullah(Feb 2020) Evaluation of Evidence: Stem Cells as a Treatment Option for Traumatic Brain Injury. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0025801]