Optimizing Stem Cell Therapy after Ischemic Brain Injury

Abstract

Stem cells have been used for regenerative and therapeutic purposes in a variety of diseases. In ischemic brain injury, preclinical studies have been promising, but have failed to translate results to clinical trials. We aimed to explore the application of stem cells after ischemic brain injury by focusing on topics such as delivery routes, regeneration efficacy, adverse effects, and <i>in vivo</i> potential optimization. PUBMED and Web of Science were searched for the latest studies examining stem cell therapy applications in ischemic brain injury, particularly after stroke or cardiac arrest, with a focus on studies addressing delivery optimization, stem cell type comparison, or translational aspects. Other studies providing further understanding or potential contributions to ischemic brain injury treatment were also included. Multiple stem cell types have been investigated in ischemic brain injury treatment, with a strong literature base in the treatment of stroke. Studies have suggested that stem cell administration after ischemic brain injury exerts paracrine effects via growth factor release, blood-brain barrier integrity protection, and allows for exosome release for ischemic injury mitigation. To date, limited studies have investigated these therapeutic mechanisms in the setting of cardiac arrest or therapeutic hypothermia. Several delivery modalities are available, each with limitations regarding invasiveness and safety outcomes. Intranasal delivery presents a potentially improved mechanism, and hypoxic conditioning offers a potential stem cell therapy optimization strategy for ischemic brain injury. The use of stem cells to treat ischemic brain injury in clinical trials is in its early phase; however, increasing preclinical evidence suggests that stem cells can contribute to the down-regulation of inflammatory phenotypes and regeneration following injury. The safety and the tolerability profile of stem cells have been confirmed, and their potent therapeutic effects make them powerful therapeutic agents for ischemic brain injury patients.

Identification of Angiogenic Cargo in Extracellular Vesicles Secreted from Human Adipose Tissue-Derived Stem Cells and Induction of Angiogenesis In Vitro and In Vivo

“…Many preclinical and clinical studies have reported therapeutic effects of stem cells in ischaemic brain injury, ischaemic heart failure, and limb ischaemia [ 8 , 9 , 10 , 11 , 12 , 13 ]. Although stem cell therapies have been shown to have numerous advantages over conventional therapies, their feasible translation is hindered by many factors, including the isolation of stem cells (especially stem cells derived from the bone marrow, embryo, and umbilical cord), the inability to control differentiation after administration, immunological rejection, tumour formation, inappropriate stem cell migration, the viability of cells after administration, and the limited understanding of how stem cells work in vivo [ 14 , 15 , 16 , 17 , 18 , 19 ].…”

Combination of Stem Cells and Rehabilitation Therapies for Ischemic Stroke

“…Stem cell treatment demonstrates apparent beneficial effects in preclinical stroke models by reducing infarct size and improving behavioral and histological deficits [ 9 , 10 , 11 ]. Furthermore, preclinical experimentation has established that stem cell therapies are effective days after the ischemic stroke event, allowing for an extension of the therapeutic window for stroke treatment [ 11 , 12 ]. Despite the potential of stem cell therapy established in preclinical stroke models, there exists a frustrating disconnect between results when translated to clinical experimentation [ 9 , 13 ].…”

“…Post-ischemic brain tissue is characterized by a pro-inflammatory environment that prevents stem cells from establishing and inducing neuroregeneration [ 13 ]. Thus, combinate administration with different biomaterials and drugs has been analyzed with the aim of improving stem cell transplantation [ 12 , 13 ]. Biomaterials have gained particular interest due to the great variety of molecular compositions and their roles in recovery [ 12 ].…”

“…Thus, combinate administration with different biomaterials and drugs has been analyzed with the aim of improving stem cell transplantation [ 12 , 13 ]. Biomaterials have gained particular interest due to the great variety of molecular compositions and their roles in recovery [ 12 ]. Biomaterials act as scaffolds that mechanically protect stem cells during their migration to the site of action [ 17 , 18 ].…”

The Implementation of Preconditioned Epidermal Neural Crest Stem Cells to Combat Ischemic Stroke. Comment on Othman, F.A.; Tan, S.C. Preconditioning Strategies to Enhance Neural Stem Cell-Based Therapy for Ischemic Stroke. Brain Sci. 2020, 10, 893

“…They explored the regeneration efficacy of neural stem cells and introduced methods to optimize cell-based therapies. Due to some limitations related to the usage of neural stem cells, application of other pretreated cell types can also be beneficial for the ischemic brain [ 2 ]. Our research group has been studying the regenerative potential of epidermal neural crest stem cells (EPI-NCSCs) derived from hair follicles of rat and human since 2013 [ 3 , 4 ].…”