Cell therapy for central nervous system disorders: Current obstacles to progress

Yasuhara, Takao; Kawauchi, Satoshi; Kin, Kyohei; Morimoto, Jun; Kameda, Masahiro; Sasaki, Tatsuya; Bonsack, Brooke; Kingsbury, Chase; Tajiri, Naoki; Borlongan, Cesario V.; Date, Isao

doi:10.1111/cns.13247

Cited by 55 publications

(45 citation statements)

References 76 publications

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“…Stroke and TBI, two principal forms of ABI, pose a significant health and economic burden globally, and limited treatment options necessitate a novel therapeutic strategy to attenuate disease progression. [88][89][90][91] Primary cell death directly results from stroke or TBI, and the extent of this, brain damage is categorized as either focal or diffuse. Along with the influence of patient age, central and peripheral sources of immune cells prominently contribute to secondary neurodegeneration during both the acute and chronic phases following stroke and TBI.…”

Section: Con Clus Ionmentioning

confidence: 99%

Mesenchymal stem cell therapy alleviates the neuroinflammation associated with acquired brain injury

et al. 2020

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Acquired brain injury (ABI) entails any injury that disrupts neuronal activity and is not degenerative, hereditary, congenital, or induced by birth trauma. Traditional examples of ABI include not only stroke and traumatic brain injury (TBI), but also near drowning, aneurysm, tumor, meningitis and other infections involving the brain, and injuries resulting from lack of oxygen supply to the brain, such as those seen in myocardial infarction. ABI may involve a structural insult, changes to metabolic activity, or disruption to neuronal capabilities.While progressive loss of brain cells and debilitating motor and cognitive deficits play a role in all these disorders, stroke and TBI overlap particularly closely in pathology and impose an immense burden on the American and global populations. AbstractIschemic stroke and traumatic brain injury (TBI) comprise two particularly prevalent and costly examples of acquired brain injury (ABI). Following stroke or TBI, primary cell death and secondary cell death closely model disease progression and worsen outcomes. Mounting evidence indicates that long-term neuroinflammation extensively exacerbates the secondary deterioration of brain structure and function. Due to their immunomodulatory and regenerative properties, mesenchymal stem cell transplants have emerged as a promising approach to treating this facet of stroke and TBI pathology. In this review, we summarize the classification of cell death in ABI and discuss the prominent role of inflammation. We then consider the efficacy of bone marrow-derived mesenchymal stem/stromal cell (BM-MSC) transplantation as a therapy for these injuries. Finally, we examine recent laboratory and clinical studies utilizing transplanted BM-MSCs as antiinflammatory and neurorestorative treatments for stroke and TBI. Clinical trials of BM-MSC transplants for stroke and TBI support their promising protective and regenerative properties. Future research is needed to allow for better comparison among trials and to elaborate on the emerging area of cell-based combination treatments. K E Y W O R D Sbone marrow-derived mesenchymal stem cells, clinical trials, inflammation, ischemic stroke, preclinical studies, traumatic brain injury

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Section: Con Clus Ionmentioning

confidence: 99%

Mesenchymal stem cell therapy alleviates the neuroinflammation associated with acquired brain injury

et al. 2020

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“…The research group of Ibarra reveals that immunization with neural derived peptides possesses neurogenic and regenerative properties which render motor and sensitive recovery in the chronic stage of SCI 10 . Such combined targeting of neurogenesis and regeneration may be similarly applied to TBI, since the pathology of TBI manifests with impaired stem cell potencies, as recognized in the cell therapy campaign noted in the other papers described here 5‐7 …”

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confidence: 92%

“…Yasuhara and colleagues 5 review the field of cell therapy for TBI and a relevant brain disorder, stroke. Here, they identify technical challenges that accompany cell transplantation, such as cell dose, timing, and delivery.…”

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confidence: 99%

“…The articles in this special issue probe the pathology of CNS trauma, including TBI and SIC, and begin to understand potential therapeutic modalities. Along this line, the proposed cell therapy 5‐7 and drug and immunization treatments 8‐10 offer new directions in the management of TBI. These promising therapies warrant serious consideration as we translate them into clinical applications.…”

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Traumatic brain injury

Bailes

Borlongan

2020

CNS Neurosci Ther

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Traumatic brain injury (TBI) stands as a major cause of mortality and morbidity around the world. More than 30% of injury-related deaths in the United States involve TBI. 1,2 TBI entails two phases of injury, namely an initial head trauma via an external force that results in mechanical damage to brain tissue and a secondary biochemical cascades including inflammation, apoptosis, oxidative stress, and other pathophysiological complications that propel further brain degeneration. 3,4 Treatment options for TBI remain limited, indicating an urgent need to examine novel therapeutic modalities designed to protect or to regenerate the injured brain.This special issue compiles recent advances in TBI research focused on cell-based regenerative medicine and pharmacologic therapies. We envision that rigorous translational research will provide the necessary testbed for ushering safe and effective therapeutics from the laboratory to the clinic.Yasuhara and colleagues 5 review the field of cell therapy for TBI and a relevant brain disorder, stroke. Here, they identify technical challenges that accompany cell transplantation, such as cell dose, timing, and delivery. In particular, they outline important preclinical investigations that are warranted to translate induced pluripotent stem cells for clinical applications in TBI and stroke.Next, our laboratory further elucidates the potential benefits, as well as caveats associated with cell therapy for TBI. 6 This review paper tackles neuroinflammation as a major cell death mechanism that closely approximates the secondary cell death in TBI. We also recognize that because neuroinflammation ensues immediately after TBI onset but also persists over time, it presents a large therapeutic window for cell therapy intervention. We provide encouraging laboratory studies detailing the success of cell transplantation in mitigating the inflammation-plagued secondary cell death of TBI.Recognizing that cell therapy may not be a magic bullet, Willing and co-workers 7 offer a combination therapy. Here, they show the potential of combining cell therapy with drugs that target signaling pathways of the neuro-immune-inflammatory axis. The concept posits that since singular targeting of a cell death pathway mostly fails, drugs that engage multiple pathways will likely promote improved sequestration of degenerative processes for TBI.The next two papers indeed advance novel drugs that encompass multiple targeting of cell death pathways. The paper by Dore and teammates demonstrate the potential of engaging the lipid metabolite prostaglandin E2 (PGE 2 ) as therapeutic targets to treat repetitive concussions and other acute brain injuries. 8 PGE 2 binding with the EP2 receptor activates adenylate cyclase and phosphorylates various cellular targets can lead to multiple neuroprotective processes, including anti-inflammation. In a similar fashion, Greig and co-investigators 9 reveal that the small molecular weight drug (-)-phenserine tartrate (PhenT), originally developed for Alzheimer's disease, effectivel...

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“…Central nervous system (CNS) disorders, such as Parkinson's disease, traumatic brain injury (TBI), and stroke, are thought to be good targets for MSC transplantation therapy and several clinical trials have been conducted. 1 Unlike CNS disorders, MSC transplantation has not been strongly focused on and the literature in the field of psychiatric disorders is limited. Depression, which is one of the most common and leading causes of disability around the world, is not well controlled with currently available treatments.…”

Section: Introductionmentioning

confidence: 99%

Encapsulation of Mesenchymal Stem Cells: Dissecting the Underlying Mechanism of Mesenchymal Stem Cell Transplantation Therapy

2020

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Mesenchymal stem cells (MSCs) are widely considered good candidates for cell transplantation therapy. Various central nervous system disorders have been suggested as suitable targets for MSC transplantation therapy. In this context, a great deal of basic and clinical research has been conducted to explore its clinical uses. Although depression is one of the most common diseases in the world, the response rate to the currently available treatment is insufficient and new treatments are much needed. Despite the fact that MSC transplantation therapy has the potential to elicit an antidepressant effect, few studies have been conducted on this topic to date and the underlying mechanism remains poorly understood. To address the development of a new treatment for depression, we evaluated the effect of MSCs using the encapsulation technique and Wistar-Kyoto rats. Encapsulation enables dissection of the complicated underlying mechanism of MSC transplantation therapy. Wistar-Kyoto rats that exhibit treatment-resistant depressive-like behaviors allow us to compare the effect of MSCs with that of conventional antidepressant treatment. In this commentary, we briefly summarize our recent published results and discuss future research prospects.

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Cell therapy for central nervous system disorders: Current obstacles to progress

Cited by 55 publications

References 76 publications

Mesenchymal stem cell therapy alleviates the neuroinflammation associated with acquired brain injury

Mesenchymal stem cell therapy alleviates the neuroinflammation associated with acquired brain injury

Traumatic brain injury

Encapsulation of Mesenchymal Stem Cells: Dissecting the Underlying Mechanism of Mesenchymal Stem Cell Transplantation Therapy

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