Alzheimer's disease (AD), the most common form of dementia, is characterized by progressive neurodegeneration leading to severe cognitive decline and eventual death. AD pathophysiology is complex, ...but neurotoxic accumulation of amyloid-β (Aβ) and hyperphosphorylation of Tau are believed to be main drivers of neurodegeneration in AD. The formation and deposition of Aβ plaques occurs in the brain parenchyma as well as in the cerebral vasculature. Thus, proper blood-brain barrier (BBB) and cerebrovascular functioning are crucial for clearance of Aβ from the brain, and neurovascular dysfunction may be a critical component of AD development. Further, neuroinflammation and dysfunction of angiogenesis, neurogenesis, and neurorestorative capabilities play a role in AD pathophysiology. Currently, there is no effective treatment to prevent or restore loss of brain tissue and cognitive decline in patients with AD. Based on multifactorial and complex pathophysiological cascades in multiple Alzheimer's disease stages, effective AD therapies need to focus on targeting early AD pathology and preserving cerebrovascular function. Neural stem cells (NSCs) participate extensively in mammalian brain homeostasis and repair and exhibit pleiotropic intrinsic properties that likely make them attractive candidates for the treatment of AD. In the review, we summarize the current advances in knowledge regarding neurovascular aspects of AD-related neurodegeneration and discuss multiple actions of NSCs from preclinical studies of AD to evaluate their potential for future clinical treatment of AD.
Neural stem cells (NSCs) play vital roles in brain homeostasis and exhibit a broad repertoire of potentially therapeutic actions following neurovascular injury. One such injury is stroke, a worldwide ...leading cause of death and disability. Clinically, extensive injury from ischemic stroke results from ischemia-reperfusion (IR), which is accompanied by inflammation, blood-brain barrier (BBB) damage, neural cell death, and extensive tissue loss. Tissue plasminogen activator (tPA) is still the only US Food and Drug Administration-approved clot-lysing agent. Whereas the thrombolytic role of tPA within the vasculature is beneficial, the effects of tPA (in a non-thrombolytic role) within the brain parenchyma have been reported as harmful. Thus, new therapies are needed to reduce the deleterious side effects of tPA and quickly facilitate vascular repair following stroke. The Stroke Treatment Academic Industry Roundtable (STAIR) recommends that stroke therapies "focus on drugs/devices/treatments with multiple mechanisms of action and that target multiple pathways". Thus, based on multifactorial ischemic cascades in various stroke stages, effective stroke therapies need to focus on targeting and ameliorating early IR injury as well as facilitating angiogenesis, neurogenesis, and neurorestorative mechanisms following stroke. This review will discuss the preclinical perspectives of NSC transplantation as a promising treatment for neurovascular injury and will emphasize both the subacute and chronic phase of ischemic stroke.
Neural Stem Cells for Early Ischemic Stroke Hamblin, Milton H.; Lee, Jean-Pyo
International journal of molecular sciences,
07/2021, Letnik:
22, Številka:
14
Journal Article
Recenzirano
Odprti dostop
Clinical treatments for ischemic stroke are limited. Neural stem cell (NSC) transplantation can be a promising therapy. Clinically, ischemia and subsequent reperfusion lead to extensive neurovascular ...injury that involves inflammation, disruption of the blood-brain barrier, and brain cell death. NSCs exhibit multiple potentially therapeutic actions against neurovascular injury. Currently, tissue plasminogen activator (tPA) is the only FDA-approved clot-dissolving agent. While tPA’s thrombolytic role within the vasculature is beneficial, tPA’s non-thrombolytic deleterious effects aggravates neurovascular injury, restricting the treatment time window (time-sensitive) and tPA eligibility. Thus, new strategies are needed to mitigate tPA’s detrimental effects and quickly mediate vascular repair after stroke. Up to date, clinical trials focus on the impact of stem cell therapy on neuro-restoration by delivering cells during the chronic stroke stage. Also, NSCs secrete factors that stimulate endogenous repair mechanisms for early-stage ischemic stroke. This review will present an integrated view of the preclinical perspectives of NSC transplantation as a promising treatment for neurovascular injury, with an emphasis on early-stage ischemic stroke. Further, this will highlight the impact of early sub-acute NSC delivery on improving short-term and long-term stroke outcomes.
Sex differences between women and men are often overlooked and underappreciated when studying the cardiovascular system. It has been long assumed that men and women are physiologically similar, and ...this notion has resulted in women being clinically evaluated and treated for cardiovascular pathophysiological complications as men. Currently, there is increased recognition of fundamental sex differences in cardiovascular function, anatomy, cell signaling, and pathophysiology. The National Institutes of Health have enacted guidelines expressly to gain knowledge about ways the sexes differ in both normal function and diseases at the various research levels (molecular, cellular, tissue, and organ system). Greater understanding of these sex differences will be used to steer future directions in the biomedical sciences and translational and clinical research. This review describes sex-based differences in the physiology and pathophysiology of the vasculature, with a special emphasis on sex steroid receptor (estrogen and androgen receptor) signaling and their potential impact on vascular function in health and diseases (e.g., atherosclerosis, hypertension, peripheral artery disease, abdominal aortic aneurysms, cerebral aneurysms, and stroke).
Clinically, significant stroke injury results from ischemia-reperfusion (IR), which induces a deleterious biphasic opening of the blood-brain barrier (BBB). Tissue plasminogen activator (tPA) remains ...the sole pharmacological agent to treat ischemic stroke. However, major limitations of tPA treatment include a narrow effective therapeutic window of 4.5 h in most patients after initial stroke onset and off-target non-thrombolytic effects (e.g., the risk of increased IR injury). We hypothesized that ameliorating BBB damage with exogenous human neural stem cells (hNSCs) would improve stroke outcome to a greater extent than treatment with delayed tPA alone in aged stroke mice.
We employed middle cerebral artery occlusion to produce focal ischemia with subsequent reperfusion (MCAO/R) in aged mice and administered tPA at a delayed time point (6 h post-stroke) via tail vein. We transplanted hNSCs intracranially in the subacute phase of stroke (24 h post-stroke). We assessed the outcomes of hNSC transplantation on pathophysiological markers of stroke 48 h post-stroke (24 h post-transplant).
Delayed tPA treatment resulted in more extensive BBB damage and inflammation relative to MCAO controls. Notably, transplantation of hNSCs ameliorated delayed tPA-induced escalated stroke damage; decreased expression of proinflammatory factors (tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6), decreased the level of matrix metalloprotease-9 (MMP-9), increased the level of brain-derived neurotrophic factor (BDNF), and reduced BBB damage.
Aged stroke mice that received delayed tPA treatment in combination with hNSC transplantation exhibited reduced stroke pathophysiology in comparison to non-transplanted stroke mice with delayed tPA. This suggests that hNSC transplantation may synergize with already existing stroke therapies to benefit a larger stroke patient population.
Present therapies for stroke rest with tissue plasminogen activator (tPA), the sole licensed antithrombotic on the market; however, tPA's effectiveness is limited in that the drug not only must be ...administered less than 3–5 hours after stroke but often exacerbates blood‐brain barrier (BBB) leakage and increases hemorrhagic incidence. A potentially promising therapy for stroke is transplantation of human induced pluripotent stem cell‐derived neural stem cells (hiPSC‐NSCs). To date, the effects of iPSCs on injuries that take place during early stage ischemic stroke have not been well studied. Consequently, we engrafted iPSC‐NSCs into the ipsilesional hippocampus, a natural niche of NSCs, at 24 hours after stroke (prior to secondary BBB opening and when inflammatory signature is abundant). At 48 hours after stroke (24 hours after transplant), hiPSC‐NSCs had migrated to the stroke lesion and quickly improved neurological function. Transplanted mice showed reduced expression of proinflammatory factors (tumor necrosis factor‐α, interleukin 6 IL‐6, IL‐1β, monocyte chemotactic protein 1, macrophage inflammatory protein 1α), microglial activation, and adhesion molecules (intercellular adhesion molecule 1, vascular cell adhesion molecule 1) and attenuated BBB damage. We are the first to report that engrafted hiPSC‐NSCs rapidly improved neurological function (less than 24 hours after transplant). Rapid hiPSC‐NSC therapeutic activity is mainly due to a bystander effect that elicits reduced inflammation and BBB damage.
Significance
Clinically, cerebral vessel occlusion is rarely permanent because of spontaneous or thrombolytic therapy‐mediated reperfusion. These results have clinical implications indicating a much extended therapeutic window for transplantation of human induced pluripotent stem cell‐derived neural stem cells (hiPSC‐NSCs; 24 hours after stroke as opposed to the 5‐hour window with tissue plasminogen activator tPA). In addition, there is potential for a synergistic effect by combining hiPSC‐NSC transplantation with tPA to attenuate stroke's adverse effects.
This study is the first to report that engrafted human induced pluripotent stem cell‐derived neural stem cells (hiPSC‐NSCs) rapidly improved neurological function (less than 24 hours after transplant) in a mouse model of stroke. Rapid hiPSC‐NSC therapeutic activity is mainly due to a bystander effect that elicits reduced inflammation and blood‐brain barrier damage.
Ischemic stroke followed by reperfusion (IR) leads to extensive cerebrovascular injury characterized by neuroinflammation and brain cell death. Inhibition of matrix metalloproteinase-3 (MMP-3) ...emerges as a promising therapeutic approach to mitigate IR-induced stroke injury. We employed middle cerebral artery occlusion with subsequent reperfusion (MCAO/R) to model ischemic stroke in adult mice. Specifically, we investigated the impact of MMP-3 knockout (KO) on stroke pathophysiology using RNA sequencing (RNA-seq) of stroke brains harvested 48 h post-MCAO. MMP-3 KO significantly reduced brain infarct size following stroke. Notably, RNA-seq analysis showed that MMP-3 KO altered expression of 333 genes (252 downregulated) in male stroke brains and 3768 genes (889 downregulated) in female stroke brains. Functional pathway analysis revealed that inflammation, integrin cell surface signaling, endothelial- and epithelial-mesenchymal transition (EndMT/EMT), and apoptosis gene signatures were decreased in MMP-3 KO stroke brains. Intriguingly, MMP-3 KO downregulated gene signatures more profoundly in females than in males, as indicated by greater negative enrichment scores. Our study underscores MMP-3 inhibition as a promising therapeutic strategy, impacting multiple cellular pathways following stroke.
Ischemic stroke is a leading cause of death and disability worldwide. Currently, the only pharmacological therapy for ischemic stroke is thrombolysis with tissue plasminogen activator that has a ...narrow therapeutic window and increases the risk of intracerebral hemorrhage. New pharmacological treatments for ischemic stroke are desperately needed, but no neuroprotective drugs have successfully made it through clinical trials. Beneficial effects of peroxisome proliferator-activated receptor alpha (PPARα) activation on vascular integrity and function have been reported, and PPARα agonists have clinically been used for many years to manage cardiovascular disease. Thus, PPARα has gained interest in recent years as a target for neurovascular disease such as ischemic stroke. Accumulating preclinical evidence suggests that PPARα activation modulates several pathophysiological hallmarks of stroke such as oxidative stress, blood-brain barrier (BBB) dysfunction, and neuroinflammation to improve functional recovery. Therefore, this review summarizes the various actions PPARα exerts in neurovascular health and disease and the potential of employing exogenous PPARα agonists for future pharmacological treatment of ischemic stroke.
Neural stem cell (NSC) transplantation offers great potential for treating ischemic stroke. Clinically, ischemia followed by reperfusion results in robust cerebrovascular injury that upregulates ...proinflammatory factors, disrupts neurovascular units, and causes brain cell death. NSCs possess multiple actions that can be exploited for reducing the severity of neurovascular injury. Our previous studies in young adult mice showed that human NSC transplantation during the subacute stage diminishes stroke pathophysiology and improves behavioral outcome.
We employed a well-established and commonly used stroke model, middle cerebral artery occlusion with subsequent reperfusion (MCAO/R). Here, we assessed the outcomes of hNSC transplantation 48 h post-MCAO (24 h post-transplant) in aged mouse brains in response to stroke because aging is a crucial risk factor for cerebral ischemia. Next, we tested whether administration of the integrin α5β1 inhibitor, ATN-161, prior to hNSC transplantation further affects stoke outcome as compared with NSCs alone. RNA sequencing (RNA-seq) was used to assess the impact of hNSC transplantation on differentially expressed genes (DEGs) on a transcriptome-wide level.
Here, we report that hNSC-engrafted brains with or without ATN-161 showed significantly reduced infarct size, and attenuated the induction of proinflammatory factors and matrix metalloproteases. RNA-seq analysis revealed DEGs and molecular pathways by which hNSCs induce a beneficial post-stroke outcome in aged stroke brains. 811 genes were differentially expressed (651 downregulated and 160 upregulated) in hNSC-engrafted stroke brains. Functional pathway analysis identified enriched and depleted pathways in hNSC-engrafted aged mouse stroke brains. Depletion of pathways following hNSC-engraftment included signaling involving neuroinflammation, acute phase response, leukocyte extravasation, and phagosome formation. On the other hand, enrichment of pathways in hNSC-engrafted brains was associated with PPAR signaling, LXR/RXR activation, and inhibition of matrix metalloproteases. Hierarchical cluster analysis of DEGs in hNSC-engrafted brains indicate decreased expression of genes encoding TNF receptors, proinflammatory factors, apoptosis factors, adhesion and leukocyte extravasation, and Toll-like receptors.
Our study is the first to show global transcripts differentially expressed following hNSC transplantation in the subacute phase of stroke in aged mice. The outcome of our transcriptome study would be useful to develop new therapies ameliorating early-stage stroke injury.
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