This special issue of Brain Circulation presents cutting-edge research discoveries in stem cell-based regenerative medicine. Each article highlights recent advances in the fields of neurodegeneration and regenerative medicine. The selected contributions offer the groundwork for translating stem cell therapy to the clinic for treating central nervous system disorders. This issue is dedicated to Dr. Teng Ma, who passed away on May 18, 2019. Dr. Ma devoted a significant portion of his life in advancing biomedical engineering, including the utility of 3-dimensional bioreactor and magnetic resonance imaging, as a key element of the biological and therapeutic applications of stem cells for neurological disorders. Dr. Ma's research vision is celebrated in this compilation of ten articles on stem cell-based regenerative medicine.

Although hyperbaric oxygen therapy (HBOT) is common as a treatment for injuries, this study aimed to research the ability of HBOT in preconditioning to diminish any potential damage. The hypothesis stated that HBOT preconditioning alleviated the death of cells in primary rat neuronal cells (PRNCs) by transferring mitochondria from astrocytes. In this experiment, PRNCs were given an HBOT treatment before a tumor necrosis factor-alpha or lipopolysaccharide injury which resembled cell death associated with stroke and traumatic brain injury (TBI). After being examined, the study found more cell viability in the PRNCs that had received HBOT precondition and a mitochondrial transfer. The mitochondrial transfer was visualized by a series of images showing the transfer after the HBOT treatment. This study demonstrated the ability of HBOT preconditioning as a treatment for inflammation in stroke and TBI, with the transfer of mitochondria from astrocytes to PRNCs reducing cell death. Along with discussion of the study, this review also focuses on different stroke treatments in comparison with HBOT.

Progress in stem cell research demonstrates stem cells' potential for treating neurodegenerative diseases. Stem cells have proliferative/differentiative properties and produce a variety of paracrine factors that can potentially be used to regenerate nervous tissue. Previous studies have shown the positive regenerative effects of endothelial progenitor cells (EPCs), and thus, they may be used as a tool for regeneration. A study by Di Santo et al. explored whether EPC-derived conditioned medium (EPC-CM) promotes the survival of cultured striatal progenitor cells and attempted to find the paracrine factors and signaling pathways involved with EPC-CM's effects. The neuronal progenitor cells that were cultured with EPC-CM had much higher densities of GABA-immunoreactive (GABA-ir) neurons. It was shown that phosphatidylinositol-3-kinase/AKT and mitogen-activated protein kinase/ERK signaling pathways are involved in the proliferation of GABAergic neurons, as inhibition of these pathways decreased GABAergic densities. In addition, the results suggest that paracrine factors from EPC, both proteinaceous and lipidic, significantly elevated the viability and/or differentiation in the cultures. Importantly, it was found that EPC-CM provided neuroprotection against toxins from 3-nitropropionic acid. In sum, EPC-CM engendered proliferation and regeneration of the cultured striatal cells through paracrine factors and imparted neuroprotection. Furthermore, the effects of EPC-CM may generate a cell-free therapeutic strategy to address neurodegeneration.

With restricted therapeutic opportunities, stroke remains a relevant, critical disease necessitating study. Due to the unique aspect of ischemic strokes, finding approaches to maintain the vigor of the cerebral vasculature, such as increased angiogenesis, may protect against stroke. Ischemic strokes are caused by disruptions in blood movement in the brain, resulting in a torrent of harmful cerebrovasculature modifications. In an investigation by Pianta et al., Sprague-Dawley rats have been separated into those that undergo exercise prior to middle cerebral artery occlusion (MCAO) and those that were not exposed to physical activity preceding MCAO. The outcomes and results of the current study gave new insights into the capacity of exercise to help prevent ischemic strokes or mitigate poststroke effects. The data collected from the study suggested that rats that went through a short bout of exercise before MCAO presented superior motor performance, more active cells in the peri-infarct region, and reduced infarct sizes. When compared to the control group, the rats that went through exercise also had heightened angiogenesis and improved neuroprotection. Thus, a brief bout of physical activity preceding a stroke may provide neuroprotection by enhancing the strength of the cerebrovasculature in the brain. This notion that even an instant of physical exercise before a stroke is induced can help dampen the effects of ischemic stroke, which could lead to future techniques in preventing the ischemic stroke so that it never happens at all.

Angiogenesis involves new blood vessels sprouting from preexisting blood vessels. This process may serve to improve brain circulation. Moyamoya disease (MMD) is a cerebrovascular disorder causing intracranial stenosis which significantly reduces the blood supply to the brain. Mainly stroke is the first symptom of the disorder, so treatments that reduce the risk of stroke are used for patients with MMD. To prevent stroke for those with chronic cerebral hypoperfusion, more blood needs to flow to the brain, which was thought to be achieved by enhancing angiogenesis. Indirect bypass surgery, such as encephalo-myo-synangiosis (EMS), is used for revascularization. However, EMS alone sometimes cannot provide enough circulation to avoid ischemic strokes. The current study examined if EMS combined with high-mobility group box-1 (HMGB1) and vascular endothelial growth factor (VEGF) enhanced angiogenesis and increased cerebral circulation. The results indicated that HMGB1 administered with EMS increased angiogenesis through a VEGF-dependent mechanism. In addition, exercising and stem cell transplantation possess possible means to increase angiogenesis. Overall, EMS with gene therapy, maintaining fitness, and stem cell utilization may prevent or help one recover from stroke by enhancing brain angiogenesis. Thus, these treatments may be applicable for patients with MMD. This paper is a review article. Referred literature in this paper has been listed in the references section. The datasets supporting the conclusions of this article are available online by searching various databases, including PubMed.

The process of aging underlies many degenerative disorders that arise in the living body, including gradual neuronal loss of the hippocampus that often leads to decline in both memory and cognition. Recent evidence has shown a significant connection between gut microbiota and brain function, as butyrate production by microorganisms is believed to activate the secretion of brain-derived neurotrophic factor (BDNF). To investigate whether modification of intestinal microbiota could impact cognitive decline in the aging brain, Romo-Araiza et al. conducted a study to test how probiotic and prebiotic supplementation impacted spatial and associative memory in middle-aged rats. Their results showed that rats supplemented with the symbiotic (both probiotic and prebiotic) treatment performed significantly better than other groups in the spatial memory test, though not in that of associative memory. Their data also reported that this improvement correlated with increased levels of BDNF, decreased levels of pro-inflammatory cytokines, and better electrophysiological outcomes in the hippocampi of the symbiotic group. Thus, the results indicated that the progression of cognitive impairment is indeed affected by changes in microbiota induced by probiotics and prebiotics. Potential future applications of these findings center around combatting neurodegeneration and inflammation associated not only with aging but also with the damaging posttraumatic effects of ischemic stroke.

A major limitation with cell transplantation in patients is the unimpressive number of cells survived. The death of grafted cells involves apoptosis and immunorejection. In this review, we encapsulate the recent preclinical development that improves the survival of grafted cells and mitigates the immunorejection of human-induced pluripotent stem cells (iPSCs) through co-grating nanoparticles-containing cyclosporine A (NanoCsA) in hemiparkinsonian rats. The study supported the notion that NanoCsA allows for long-lasting CsA discharge and limits immunorejection of human iPSC xenograft in a 6-hydroxydopamine Parkinson's disease rat model.

The potential use of stem cells as a therapeutic treatment for many neurological disorders, such as stroke, has spiked an interest in their properties. Due to limitations of the present-day treatments, regenerative and protective therapies could prove very beneficial if a safe and effective treatment is identified. Using human amniotic fluid stem (hAFS) cells could theoretically provide both neuroprotective and regenerative properties to patients, and knowledge of p53's activity and function could be a key component in understanding the behavior and characteristics of these stem cells to harness their full potential. Many recent studies on p53 have provided new and valuable information that could give rise to new ideas for treatment options. More specifically, p53's activity inside hAFS cells lead them closer to becoming a potential therapeutic stem cell. Other neuroprotective treatments, such as hyperoxia and hypoxia sessions, are showing positive results. In combination, these data are helping to get closer to an effective treatment for neurological disorders.

Mesenchymal stem cells (MSCs) are multipotent adult stem cells which have become popular research targets for their use in cellular therapy for tissue repair. While recent advancements in research have shown the MSCs have immunomodulatory functions which are altered in response to host inflammatory molecules, how these stimuli produce different functional outcomes is not understood. Here, we evaluate research examining how the proinflammatory cytokine interferon-γ (IFN-γ) affects the immunomodulatory functions of MSCs by altering their metabolism. This study indicates that IFN-γ causes an increase in glycolytic activity and uncoupling of glycolysis to tricarboxylic acid cycle and hence, the glycolytic metabolites and intermediates can be funneled toward the production of anti-inflammatory modulators indoleamine-2,3-dioxygenase and PGE2. A complete understanding of how MSCs' cellular metabolism affects their function is necessary for their employment in cellular therapy, as MSCs have been demonstrated to have pro- and anti-inflammatory functions. These findings are a large step forward in the understanding of the regulation of MSCs and toward their eventual use in cellular therapy, specifically for stroke recovery, in which MSCs have been shown to have powerful neuroprotective and neurogenerative effects.

Stroke is one of the world's leading causes of mortality and morbidity. Greater understanding is required of the underlying relationships in ischemic brains in order to prevent stroke or to develop effective treatment. This review highlights new findings about the relationship of blood–brain barrier with astrocytes, pentraxin-3 (PTX3), and other factors expressed during or after ischemic stroke. These are discussed with respect to their ameliorative or deleterious effects. These effects are measured in vivo in animal models as well as in vitro in cell cultures. Evidence was found to suggest that astrocytes play a key role in stroke by expressing PTX3, which, in turn, enhances endothelial tightness, increases tight junction proteins, and inhibits vascular endothelial growth factor. The role of astrocytes and PTX3 is examined in relation to hypoxic stress and conditioning as well as mitochondrial transfer. Astrocytes and PTX3 are placed in the context of brain circulation and related areas.

Moyamoya disease (MMD) represents a rare steno-occlusive disorder affecting the terminal ends of the internal carotid artery and promoting the development of a poor, abnormal vascular network at the brain's base. Primarily affecting East Asian countries over Western populations, MMD can be further divided into symptomatic and asymptomatic subtypes. The current knowledge of the underlying mechanisms and potential management strategies for asymptomatic cases of MMD are largely lacking and thus warrant investigation to elucidate the pathology of this rare disorder. Here, we assess research examining the expression profile of circular RNAs (circRNAs) of neutrophil transcriptome in asymptomatic MMD patients. These findings conclude that 123 differentially expressed circRNAs significantly contributed to metabolism, angiogenesis, and immune response. The hypoxia-inducing factor-1α signaling pathway was also revealed to be crucial in angiogenesis. We also evaluate current therapeutic options demonstrating the potential for MMD patients, such as EC-IC bypass and ischemic pre- and post-conditioning. These approaches combined with recent findings on the circRNA expression profile suggest a crucial role of anti-inflammatory and angiogenic-related mechanisms underlying MMD. Investigating the role of circRNAs and neutrophils in the asymptomatic MMD subtype may provide insight into its elusive pathology and direct future approaches to combat the progression of this rare disease.