A Museum of Stem Cells Points to Muse Cells as Robust Transplantable Cells for Stroke: Review.

Stem cell-based therapy stands as a robust experimental treatment for ischemic stroke. Stem cells derived from fetal, embryonic, and adult tissues serve as potential sources for transplantable cells in the setting of ischemic stroke. However, the search continues for finding an optimal cell line for clinical use. Muse cells, a distinct subset of mesenchymal stem cells found sporadically in the connective tissue of nearly every organ, may be a suitable candidate due to its safety and accessibility. These cells have been investigated for therapeutic usage in chronic kidney disease, liver disease, acute myocardial infarction, and stroke. Muse cells display the ability to engraft and differentiate into the host neural network unlike many other cell lines which only display bystander immunomodulating effects. Taking advantage of this unique engraftment and differentiation mechanism behind Muse cells' therapeutic effects on the central nervous system, as well as other organ systems, will undoubtedly advance the cells' utility for cell-based regenerative medicine in stroke.

Inflammatory gut as a pathologic and therapeutic target in Parkinson's disease.

Parkinson's disease (PD) remains a significant unmet clinical need. Gut dysbiosis stands as a PD pathologic source and therapeutic target. Here, we assessed the role of the gut-brain axis in PD pathology and treatment. Adult transgenic (Tg) α-synuclein-overexpressing mice served as subjects and were randomly assigned to either transplantation of vehicle or human umbilical cord blood-derived stem cells and plasma. Behavioral and immunohistochemical assays evaluated the functional outcomes following transplantation. Tg mice displayed typical motor and gut motility deficits, elevated α-synuclein levels, and dopaminergic depletion, accompanied by gut dysbiosis characterized by upregulation of microbiota and cytokines associated with inflammation in the gut and the brain. In contrast, transplanted Tg mice displayed amelioration of motor deficits, improved sparing of nigral dopaminergic neurons, and downregulation of α-synuclein and inflammatory-relevant microbiota and cytokines in both gut and brain. Parallel in vitro studies revealed that cultured dopaminergic SH-SY5Y cells exposed to homogenates of Tg mouse-derived dysbiotic gut exhibited significantly reduced cell viability and elevated inflammatory signals compared to wild-type mouse-derived gut homogenates. Moreover, treatment with human umbilical cord blood-derived stem cells and plasma improved cell viability and decreased inflammation in dysbiotic gut-exposed SH-SY5Y cells. Intravenous transplantation of human umbilical cord blood-derived stem/progenitor cells and plasma reduced inflammatory microbiota and cytokine, and dampened α-synuclein overload in the gut and the brain of adult α-synuclein-overexpressing Tg mice. Our findings advance the gut-brain axis as a key pathological origin, as well as a robust therapeutic target for PD.

Multipronged Attack of Stem Cell Therapy in Treating the Neurological and Neuropsychiatric Symptoms of Epilepsy.

Epilepsy stands as a life-threatening disease that is characterized by unprovoked seizures. However, an important characteristic of epilepsy that needs to be examined is the neuropsychiatric aspect. Epileptic patients endure aggression, depression, and other psychiatric illnesses. Therapies for epilepsy can be divided into two categories: antiepileptic medications and surgical resection. Antiepileptic drugs are used to attenuate heightened neuronal firing and to lessen seizure frequency. Alternatively, surgery can also be conducted to physically cut out the area of the brain that is assumed to be the root cause for the anomalous firing that triggers seizures. While both treatments serve as viable approaches that aim to regulate seizures and ameliorate the neurological detriments spurred by epilepsy, they do not serve to directly counteract epilepsy's neuropsychiatric traits. To address this concern, a potential new treatment involves the use of stem cells. Stem cell therapy has been employed in experimental models of neurological maladies, such as Parkinson's disease, and neuropsychiatric illnesses like depression. Cell-based treatments for epilepsy utilizing stem cells such as neural stem cells (NSCs), mesenchymal stem cells (MSCs), and interneuron grafts have been explored in preclinical and clinical settings, highlighting both the acute and chronic stages of epilepsy. However, it is difficult to create an animal model to capitalize on all the components of epilepsy due to the challenges in delineating the neuropsychiatric aspect. Therefore, further preclinical investigation into the safety and efficacy of stem cell therapy in addressing both the neurological and the neuropsychiatric components of epilepsy is warranted in order to optimize cell dosage, delivery, and timing of cell transplantation.

Major histocompatibility complex Class II-based therapy for stroke.

This review discusses the potential of major histocompatibility complex (MHC) Class II constructs as stroke therapeutics. We focus on the delivery of MHC Class II construct, DRmQ, as a safe and effective treatment for ischemic stroke. DRmQ was observed to attenuate behavioral deficits and decrease microglia activation and proinflammatory cytokines, illustrating its ability to mitigate the secondary cell death following stroke. Similar anti-neuroinflammation treatments, such as transplantation of mesenchymal stem cells and mitochondrial transfers, are briefly discussed to provide further support that sequestration of inflammation stands as a robust therapeutic target for stroke.

Gut dysbiosis in stroke and its implications on Alzheimer's disease-like cognitive dysfunction.

Various neurological disorders, such as stroke and Alzheimer's disease (AD), involve neuroinflammatory responses. The advent of the gut-brain axis enhances our understanding of neurological disease progression and secondary cell death. Gut microbiomes, especially those associated with inflammation, may reflect the dysbiosis of both the brain and the gut, opening the possibility to utilize inflammatory microbiomes as biomarkers and therapeutic targets. The gut-brain axis may serve as a contributing factor to disease pathology and offer innovative approaches in cell-based regenerative medicine for the treatment of neurological diseases. In reviewing the pathogenesis of stroke and AD, we also discuss the effects of gut microbiota on cognitive decline and brain pathology. Although the underlying mechanism of primary cell death from either disease is clearly distinct, both may be linked to gut-microbial dysfunction as a consequential aberration that is unique to each disease. Targeting peripheral cell death pathways that exacerbate disease symptoms, such as those arising from the gut, coupled with conventional central therapeutic approach, may improve stroke and AD outcomes.

Pituitary Adenylate Cyclase-Activating Polypeptide: A Potent Therapeutic Agent in Oxidative Stress.

Stroke is a life-threatening condition that is characterized by secondary cell death processes that occur after the initial disruption of blood flow to the brain. The inability of endogenous repair mechanisms to sufficiently support functional recovery in stroke patients and the inadequate treatment options available are cause for concern. The pathology behind oxidative stress in stroke is of particular interest due to its detrimental effects on the brain. The oxidative stress caused by ischemic stroke overwhelms the neutralization capacity of the body's endogenous antioxidant system, which leads to an overproduction of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and eventually results in cell death. The overproduction of ROS compromises the functional and structural integrity of brain tissue. Therefore, it is essential to investigate the mechanisms involved in oxidative stress to help obtain adequate treatment options for stroke. Here, we focus on the latest preclinical research that details the mechanisms behind secondary cell death processes that cause many central nervous system (CNS) disorders, as well as research that relates to how the neuroprotective molecular mechanisms of pituitary adenylate cyclase-activating polypeptides (PACAPs) could make these molecules an ideal candidate for the treatment of stroke.

IL-2/IL-2R Antibody Complex Enhances Treg-Induced Neuroprotection by Dampening TNF-α Inflammation in an In Vitro Stroke Model.

The present in vitro study showed that IL-2/IL-2R antibody complex facilitates Treg-induced neuroprotection in the oxygen glucose deprivation/reoxygenation (OGD/R) model of stroke. First, we examined the role of IL-2/IL-2R-treated Tregs in OGD/R-exposed rat primary cortical cells (PCCs), which represent the cell type of the ischemic gray matter in the stroke brain. Here, OGD/R induced cell death, which was attenuated by Tregs and more robustly by IL-2/IL-2R-treated Tregs, but not by IL-2/IL-2R treatment alone. Second, we next assessed IL-2/IL-2R effects in OGD/R-exposed human oligodendrocyte progenitor cells (OPCs), which correspond to the white matter injury after stroke. Results revealed that a similar pattern neuroprotection as seen in the gray matter, in that OGD/R triggered cell death, which was ameliorated by Tregs and more effectively by IL-2/IL-2R-treated Tregs, but IL-2/IL-2R treatment alone was not therapeutic. Third, as we begin to understand the mechanism underlying IL-2/IL-2R engagement of Tregs, we investigated the inflammatory response in OGD/R-exposed human neural progenitor cells (NPCs), which recapitulate both ischemic gray and white matter damage in stroke. Similar to PCCs and OPCs, OGD/R produced cell death and was blocked by Tregs and more efficiently by IL-2/IL-2R-treated Tregs, whereas IL-2/IL-2R treatment alone did not alter the ischemic insult. Moreover, the inflammatory marker, TNF-α, was upregulated after OGD/R, dampened by both Tregs and more efficiently by IL-2/IL-2R-treated Tregs but more pronounced in the latter, and not affected by IL-2/IL-2R treatment alone, suggesting IL-2/IL-2R-Treg-mediated modulation of inflammatory response in stroke. Altogether, these observations support the use of IL-2/IL-2R treatment in enhancing the anti-inflammatory effects of Tregs in stroke.

Inflammation-relevant microbiome signature of the stroke brain, gut, spleen, and thymus and the impact of exercise.

Stroke remains a significant unmet need in the clinic with few therapeutic options. We, and others, have implicated the role of inflammatory microbiota in stroke secondary cell death. Elucidating this inflammation microbiome as a biomarker may improve stroke diagnosis and treatment. Here, adult Sprague-Dawley rats performed 30 minutes of exercise on a motorized treadmill for 3 consecutive days prior to transient middle cerebral artery occlusion (MCAO). Stroke animals that underwent exercise showed 1) robust behavioral improvements, 2) significantly smaller infarct sizes and increased peri-infarct cell survival and 3) decreasing trends of inflammatory microbiota BAC303, EREC482, and LAB158 coupled with significantly reduced levels of inflammatory markers ionized calcium binding adaptor molecule 1, tumor necrosis factor alpha, and mouse monoclonal MHC Class II RT1B in the brain, gut, spleen, and thymus compared to non-exercised stroke rats. These results suggest that a specific set of inflammatory microbiota exists in central and peripheral organs and can serve as a disease biomarker and a therapeutic target for stroke.

Mesenchymal Stem Cell-Induced Anti-Neuroinflammation Against Traumatic Brain Injury.

Traumatic brain injury (TBI) is a pervasive and damaging form of acquired brain injury (ABI). Acute, subacute, and chronic cell death processes, as a result of TBI, contribute to the disease progression and exacerbate outcomes. Extended neuroinflammation can worsen secondary degradation of brain function and structure. Mesenchymal stem cell transplantation has surfaced as a viable approach as a TBI therapeutic due to its immunomodulatory and regenerative features. This article examines the role of inflammation and cell death in ABI as well as the effectiveness of bone marrow-derived mesenchymal stem/stromal cell (BM-MSC) transplants as a treatment for TBI. Furthermore, we analyze new studies featuring transplanted BM-MSCs as a neurorestorative and anti-inflammatory therapy for TBI patients. Although clinical trials support BM-MSC transplants as a viable TBI treatment due to their promising regenerative characteristics, further investigation is imperative to uncover innovative brain repair pathways associated with cell-based therapy as stand-alone or as combination treatments.

Combination of Stem Cells and Rehabilitation Therapies for Ischemic Stroke.

Stem cell transplantation with rehabilitation therapy presents an effective stroke treatment. Here, we discuss current breakthroughs in stem cell research along with rehabilitation strategies that may have a synergistic outcome when combined together after stroke. Indeed, stem cell transplantation offers a promising new approach and may add to current rehabilitation therapies. By reviewing the pathophysiology of stroke and the mechanisms by which stem cells and rehabilitation attenuate this inflammatory process, we hypothesize that a combined therapy will provide better functional outcomes for patients. Using current preclinical data, we explore the prominent types of stem cells, the existing theories for stem cell repair, rehabilitation treatments inside the brain, rehabilitation modalities outside the brain, and evidence pertaining to the benefits of combined therapy. In this review article, we assess the advantages and disadvantages of using stem cell transplantation with rehabilitation to mitigate the devastating effects of stroke.

Fighting the War Against COVID-19 via Cell-Based Regenerative Medicine: Lessons Learned from 1918 Spanish Flu and Other Previous Pandemics.

The human population is in the midst of battling a rapidly-spreading virus- Severe Acute Respiratory Syndrome Coronavirus 2, responsible for Coronavirus disease 2019 or COVID-19. Despite the resurgences in positive cases after reopening businesses in May, the country is seeing a shift in mindset surrounding the pandemic as people have been eagerly trickling out from federally-mandated quarantine into restaurants, bars, and gyms across America. History can teach us about the past, and today's pandemic is no exception. Without a vaccine available, three lessons from the 1918 Spanish flu pandemic may arm us in our fight against COVID-19. First, those who survived the first wave developed immunity to the second wave, highlighting the potential of passive immunity-based treatments like convalescent plasma and cell-based therapy. Second, the long-term consequences of COVID-19 are unknown. Slow-progressive cases of the Spanish flu have been linked to bacterial pneumonia and neurological disorders later in life, emphasizing the need to reduce COVID-19 transmission. Third, the Spanish flu killed approximately 17 to 50 million people, and the lack of human response, overcrowding, and poor hygiene were key in promoting the spread and high mortality. Human behavior is the most important strategy for preventing the virus spread and we must adhere to proper precautions. This review will cover our current understanding of the pathology and treatment for COVID-19 and highlight similarities between past pandemics. By revisiting history, we hope to emphasize the importance of human behavior and innovative therapies as we wait for the development of a vaccine. Graphical Abstract.

Progress in progestin-based therapies for neurological disorders.

Hormone therapy, primarily progesterone and progestins, for central nervous system (CNS) disorders represents an emerging field of regenerative medicine. Following a failed clinical trial of progesterone for traumatic brain injury treatment, attention has shifted to the progestin Nestorone for its ability to potently and selectively transactivate progesterone receptors at relatively low doses, resulting in robust neurogenetic, remyelinating, and anti-inflammatory effects. That CNS disorders, including multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), spinal cord injury (SCI), and stroke, develop via demyelinating, cell death, and/or inflammatory pathological pathways advances Nestorone as an auspicious candidate for these disorders. Here, we assess the scientific and clinical progress over decades of research into progesterone, progestins, and Nestorone as neuroprotective agents in MS, ALS, SCI, and stroke. We also offer recommendations for optimizing timing, dosage, and route of the drug regimen, and identifying candidate patient populations, in advancing Nestorone to the clinic.

LncRNAs Stand as Potent Biomarkers and Therapeutic Targets for Stroke.

Stroke is a major public health problem worldwide with a high burden of neurological disability and mortality. Long noncoding RNAs (lncRNAs) have attracted much attention in the past decades because of their newly discovered roles in pathophysiological processes in many diseases. The abundance of lncRNAs in the nervous system indicates that they may be part of a complex regulatory network governing physiology and pathology of the brain. In particular, lncRNAs have been shown to play pivotal roles in the pathogenesis of stroke. In this article, we provide a review of the multifaceted functions of lncRNAs in the pathogenesis of ischemic stroke and intracerebral hemorrhage, highlighting their promising use as stroke diagnostic biomarkers and therapeutics. To this end, we discuss the potential of stem cells in aiding lncRNA applications in stroke.

Stem Cell Repair of the Microvascular Damage in Stroke.

Stroke is a life-threatening disease that leads to mortality, with survivors subjected to long-term disability. Microvascular damage is implicated as a key pathological feature, as well as a therapeutic target for stroke. In this review, we present evidence detailing subacute diaschisis in a focal ischemic stroke rat model with a focus on blood-brain barrier (BBB) integrity and related pathogenic processes in contralateral brain areas. Additionally, we discuss BBB competence in chronic diaschisis in a similar rat stroke model, highlighting the pathological changes in contralateral brain areas that indicate progressive morphological brain disturbances overtime after stroke onset. With diaschisis closely approximating stroke onset and progression, it stands as a treatment of interest for stroke. Indeed, the use of stem cell transplantation for the repair of microvascular damage has been investigated, demonstrating that bone marrow stem cells intravenously transplanted into rats 48 h post-stroke survive and integrate into the microvasculature. Ultrastructural analysis of transplanted stroke brains reveals that microvessels display a near-normal morphology of endothelial cells and their mitochondria. Cell-based therapeutics represent a new mechanism in BBB and microvascular repair for stroke.

An Extra Breath of Fresh Air: Hyperbaric Oxygenation as a Stroke Therapeutic.

Stroke serves as a life-threatening disease and continues to face many challenges in the development of safe and effective therapeutic options. The use of hyperbaric oxygen therapy (HBOT) demonstrates pre-clinical effectiveness for the treatment of acute ischemic stroke and reports reductions in oxidative stress, inflammation, and neural apoptosis. These pathophysiological benefits contribute to improved functional recovery. Current pre-clinical and clinical studies are testing the applications of HBOT for stroke neuroprotection, including its use as a preconditioning regimen. Mild oxidative stress may be able to prime the brain to tolerate full extensive oxidative stress that occurs during a stroke, and HBOT preconditioning has displayed efficacy in establishing such ischemic tolerance. In this review, evidence on the use of HBOT following an ischemic stroke is examined, and the potential for HBOT preconditioning as a neuroprotective strategy. Additionally, HBOT as a stem cell preconditioning is also discussed as a promising strategy, thus maximizing the use of HBOT for ischemic stroke.

Melatonin-A Potent Therapeutic for Stroke and Stroke-Related Dementia.

Secreted by the pineal gland to regulate the circadian rhythm, melatonin is a powerful antioxidant that has been used to combat oxidative stress in the central nervous system. Melatonin-based therapies have been shown to provide neuroprotective effects in the setting of ischemic stroke by mitigating neuroinflammation and accelerating brain tissue restoration. Melatonin treatment includes injection of exogenous melatonin, pineal gland grafting and melatonin-mediated stem cell therapy. This review will discuss the current preclinical and clinical studies investigating melatonin-based therapeutics to treat stroke.

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

Ischemic 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.

Hyperbaric oxygen therapy: A new look on treating stroke and traumatic brain injury.

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.