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Machine learning (ML) models are poised to transform surgical pathology practice. The most successful use attention mechanisms to examine whole slides, identify which areas of tissue are diagnostic, and use them to guide diagnosis. Tissue contaminants, such as floaters, represent unexpected tissue. Although human pathologists are extensively trained to consider and detect tissue contaminants, we examined their impact on ML models. We trained 4 whole-slide models. Three operate in placenta for the following functions: (1) detection of decidual arteriopathy, (2) estimation of gestational age, and (3) classification of macroscopic placental lesions. We also developed a model to detect prostate cancer in needle biopsies. We designed experiments wherein patches of contaminant tissue are randomly sampled from known slides and digitally added to patient slides and measured model performance. We measured the proportion of attention given to contaminants and examined the impact of contaminants in the t-distributed stochastic neighbor embedding feature space. Every model showed performance degradation in response to one or more tissue contaminants. Decidual arteriopathy detection--balanced accuracy decreased from 0.74 to 0.69 ± 0.01 with addition of 1 patch of prostate tissue for every 100 patches of placenta (1% contaminant). Bladder, added at 10% contaminant, raised the mean absolute error in estimating gestational age from 1.626 weeks to 2.371 ± 0.003 weeks. Blood, incorporated into placental sections, induced false-negative diagnoses of intervillous thrombi. Addition of bladder to prostate cancer needle biopsies induced false positives, a selection of high-attention patches, representing 0.033 mm2, and resulted in a 97% false-positive rate when added to needle biopsies. Contaminant patches received attention at or above the rate of the average patch of patient tissue. Tissue contaminants induce errors in modern ML models. The high level of attention given to contaminants indicates a failure to encode biological phenomena. Practitioners should move to quantify and ameliorate this problem.
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Placenta , Neoplasias da Próstata , Gravidez , Masculino , Humanos , Feminino , Recém-Nascido , Placenta/patologia , Aprendizado de Máquina , Biópsia por Agulha , Próstata/patologia , Neoplasias da Próstata/patologiaRESUMO
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.
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Células-Tronco Pluripotentes , Acidente Vascular Cerebral , Adulto , Alprostadil , Diferenciação Celular , Humanos , Museus , Medicina Regenerativa , Acidente Vascular Cerebral/terapiaRESUMO
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.
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Stroke stands as one of the most common causes of death among adults worldwide. Currently, tissue plasminogen activator serves as the only approved drug by the Food and Drug Administration for the treatment of acute ischemic stroke. Stem cell therapy serves as a viable treatment option and has been deemed as a safe and effective treatment for stroke patients. Adult human bone marrow-derived NCS-01 cells serve as a potential treatment for stroke given their ability to reduce stroke-induced pathological deficits by increasing cell viability and mitochondrial activity. Recently, we demonstrated the use of adult bone marrow-derived NCS-01 cells both on both in vitro and in vivo models. Using NCS-01 cells in rat stroke models subjected to middle cerebral artery occlusion, an effective dosage of 7.5 × 106 cells/ml, administered through the intracarotid artery within 3 days poststroke, was shown to display significant improvements in motor and neurological behaviors, reductions in infarct area, and peri-infarct cell loss. NCS-01 cells, in comparison with other lines of stem cells (Li cells), are shown to produce greater therapeutic effects, most likely due to the observed filopodia formation that allows the stem cells to extend and target the ischemic cells. Given these findings, NCS-01 stem cells serve as a potential treatment for stroke through the demonstration of profound efficacy and further research that favors their filopodia-mediated mechanism of action.
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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.
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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.
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Doença de Alzheimer/psicologia , Eixo Encéfalo-Intestino , Transtornos Cognitivos/etiologia , Disbiose/etiologia , Microbioma Gastrointestinal , Acidente Vascular Cerebral/complicações , Transtornos Cognitivos/microbiologia , Transtornos Cognitivos/psicologia , Disbiose/microbiologia , Disbiose/psicologia , Humanos , Acidente Vascular Cerebral/psicologiaRESUMO
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.
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Traumatismo por Reperfusão , Acidente Vascular Cerebral , Animais , Glucose/metabolismo , Inflamação/metabolismo , Interleucina-2 , Neuroproteção , Oxigênio , Ratos , Traumatismo por Reperfusão/prevenção & controle , Linfócitos T Reguladores , Fator de Necrose Tumoral alfaRESUMO
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.
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Lesões Encefálicas Traumáticas/terapia , Inflamação/terapia , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/metabolismo , HumanosRESUMO
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.
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Stem cell therapy may present an effective treatment for metastatic brain cancer and glioblastoma. Here we posit the critical role of a leaky blood-brain barrier (BBB) as a key element for the development of brain metastases, specifically melanoma. By reviewing the immunological and inflammatory responses associated with BBB damage secondary to tumoral activity, we identify the involvement of this pathological process in the growth and formation of metastatic brain cancers. Likewise, we evaluate the hypothesis of regenerating impaired endothelial cells of the BBB and alleviating the damaged neurovascular unit to attenuate brain metastasis, using the endothelial progenitor cell (EPC) phenotype of bone marrow-derived mesenchymal stem cells. Specifically, there is a need to evaluate the efficacy for stem cell therapy to repair disruptions in the BBB and reduce inflammation in the brain, thereby causing attenuation of metastatic brain cancers. To establish the viability of stem cell therapy for the prevention and treatment of metastatic brain tumors, it is crucial to demonstrate BBB repair through augmentation of vasculogenesis and angiogenesis. BBB disruption is strongly linked to metastatic melanoma, worsens neuroinflammation during metastasis, and negatively influences the prognosis of metastatic brain cancer. Using stem cell therapy to interrupt inflammation secondary to this leaky BBB represents a paradigm-shifting approach for brain cancer treatment. In this review article, we critically assess the advantages and disadvantages of using stem cell therapy for brain metastases and glioblastoma.
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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.
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COVID-19/terapia , Terapia Baseada em Transplante de Células e Tecidos , COVID-19/patologia , COVID-19/prevenção & controle , COVID-19/virologia , História do Século XX , Humanos , Imunização Passiva , Influenza Pandêmica, 1918-1919/história , Pandemias/história , Medicina Regenerativa/história , SARS-CoV-2/patogenicidade , Soroterapia para COVID-19RESUMO
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.
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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.
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Barreira Hematoencefálica/patologia , Células Endoteliais/metabolismo , Células-Tronco/patologia , Acidente Vascular Cerebral/genética , Animais , Modelos Animais de Doenças , Humanos , Masculino , Ratos , Acidente Vascular Cerebral/metabolismoRESUMO
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.
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Stroke is a devastating condition characterized by widespread cell death after disruption of blood flow to the brain. The poor regenerative capacity of neural cells limits substantial recovery and prolongs disruptive sequelae. Current therapeutic options are limited and do not adequately address the underlying mitochondrial dysfunction caused by the stroke. These same mitochondrial impairments that result from acute cerebral ischemia are also present in retinal ischemia. In both cases, sufficient mitochondrial activity is necessary for cell survival, and while astrocytes are able to transfer mitochondria to damaged tissues to rescue them, they do not have the capacity to completely repair damaged tissues. Therefore, it is essential to investigate this mitochondrial transfer pathway as a target of future therapeutic strategies. In this review, we examine the current literature pertinent to mitochondrial repair in stroke, with an emphasis on stem cells as a source of healthy mitochondria. Stem cells are a compelling cell type to study in this context, as their ability to mitigate stroke-induced damage through non-mitochondrial mechanisms is well established. Thus, we will focus on the latest preclinical research relevant to mitochondria-based mechanisms in the treatment of cerebral and retinal ischemia and consider which stem cells are ideally suited for this purpose.
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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.