Neuroprotection of Stem Cells Against Ischemic Brain Injury: From Bench to Clinic

Abstract

Neurological injuries can have numerous debilitating effects on functional status including sensorimotor deficits, cognitive impairment, and behavioral symptoms. Despite the disease burden, treatment options remain limited. Current pharmacological interventions are targeted at symptom management but are ineffective in reversing ischemic brain damage. Stem cell therapy for ischemic brain injury has shown promising preclinical and clinical results and has attracted attention as a potential therapeutic option. Various stem cell sources (embryonic, mesenchymal/bone marrow, and neural stem cells) have been investigated. This review provides an overview of the advances made in our understanding of the various types of stem cells and progress made in the use of these stem cells for the treatment of ischemic brain injuries. In particular, the use of stem cell therapy in global cerebral ischemia following cardiac arrest and in focal cerebral ischemia after ischemic stroke are discussed. The proposed mechanisms of stem cells' neuroprotective effects in animal models (rat/mice, pig/swine) and other clinical studies, different routes of administration (intravenous/intra-arterial/intracerebroventricular/intranasal/intraperitoneal/intracranial) and stem cell preconditioning are discussed. Much of the promising data on stem cell therapies after ischemic brain injury remains in the experimental stage and several limitations remain unsettled. Future investigation is needed to further assess the safety and efficacy and to overcome the remaining obstacles.

Keywords: Cardiac arrest; Global cerebral ischemia; Ischemic brain injury; Ischemic stroke; Stem cell therapy.

Figure 1.. Overview of stem cell application in ischemic brain injury.

Stem cells belong to four major categories based on their differentiation potential. Cell types including iPSC, ESC, NSC, and MSC were applied in the treatment of ischemic brain injury. Multiple delivery routes were selected for the administration of stem cells. NSC, neural stem cell; MSC, mesenchymal stem cell; ESC, embryonic marrow stem cell; iPSC, induced pluripotent stem cell

Figure 2.. Neuroprotective function of stem cell therapy in ischemic brain injury.

Ischemia leads to activation of microglia, demyelination, and a loss of tight junction integrity in BBB. Most microglial cells transform from resting state (small, round cells with elaborate ramifications) into activated state, shown as bigger, more amoeboid cells with retracted processes. Activated microglia recruits and engulfs the debris. The BBB damage, microglia induced-neuroinflammation, neurodegeneration and necrosis can be observed post ischemic brain injury. Stem cell therapy exerts neuroprotective effects by targeting these pathophysiological mechanisms.