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The limited therapeutic strategies available for stroke leave many patients disabled for life. This study assessed the potential of programmed death-ligand 1 (PD-L1) and hepatocyte growth factor (HGF)-engineered mesenchymal stem cell-derived exosomes (EXO-PD-L1-HGF) in enhancing neurological recovery post-stroke. EXO-PD-L1-HGF, which efficiently endocytosed into target cells, significantly diminishes the H 2 O 2 -induced neurotoxicity and increased the antiapoptotic proteins in vitro. EXO-PD-L1-HGF attenuates inflammation by inhibiting T-cell proliferation and increasing the number of CD8 + CD122 + IL-10 + regulatory T cells. Intravenous injection of EXO-PD-L1-HGF could target stromal cell-derived factor-1α (SDF-1α + ) cells over the peri-infarcted area of the ischemic brain through CXCR4 upregulation and accumulation in neuroglial cells post-stroke. EXO-PD-L1-HGF facilitates endogenous nestin + neural progenitor cell (NPC)-induced neurogenesis via STAT3-FOXO3 signaling cascade, which plays a pivotal role in cell survival and neuroprotection, thereby mitigating infarct size and enhancing neurological recovery in a murine stroke model. Moreover, increasing populations of the immune-regulatory CD19 + IL-10 + and CD8 + CD122 + IL-10 + cells, together with reducing populations of proinflammatory cells, created an anti-inflammatory microenvironment in the ischemic brain. Thus, innovative approaches employing EXO-PD-L1-HGF intervention, which targets SDF-1α + expression, modulates the immune system, and enhances the activation of resident nestin + NPCs, might significantly alter the brain microenvironment and create a niche conducive to inducing neuroplastic regeneration post-stroke., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Although tissue plasminogen activator (t-PA) and endovascular thrombectomy are well-established treatments for acute ischemic stroke, over half of patients with stroke remain disabled for a long time. Thus, a significant unmet need exists to develop an effective strategy for treating acute stroke. We developed a combination of programmed cell death-ligand 1 (PD-L1) and AKT-modified umbilical cord mesenchymal stem cells (UMSC-PD-L1-AKT) implanted through intravenous (IV) and intracarotid (IA) routes to enhance therapeutic efficacy in a murine stroke model for overcoming the hypoxic environment of the ischemic brain, to prolong stem cell survival, and to attenuate systemic inflammation to protect neuroglial cells from ischemic injury. Higher cellular proliferation and survival upon exposure to toxic agents were observed in UMSC-PD-L1-AKT cells than in UMSCs in vitro. Moreover, increased attenuation of CFSE + cell proliferation and increased survival of primary cortical cells were verified by the interaction with UMSC-PD-L1-AKT. Consistently, dual-route administration (IV + IA) of UMSC-PD-L1-AKT resulted in a significant reduction in infarction volume and improvement of neurological dysfunction in a stroke model. Furthermore, enhancing CD8 + CD122 + IL-10 + T-regulatory (Treg) cells and reducing CD11b + CD80 + microglial/macrophages and CD3 + CD8 + TNF-α + and CD3 + CD8 + IFN-α + cytotoxic T cells induced an anti-inflammatory microenvironment to protect neuroglial cells in the ischemic brain. Collectively, therapeutic intervention using UMSC-PD-L1-AKT could provide a niche for inducing neuroplastic regeneration in brains after stroke., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Purpose: Although findings from published studies suggest post-stroke aphasia is associated with an increased risk of dementia, few studies have evaluated its association in a nationally representative cohort with long-term follow-up. No studies have reported data by type of stroke. Therefore, we examined the association between post-stroke aphasia and the risk of developing dementia., Methods: Using claims data from Taiwan's universal health insurance program, a cohort of patients ≥18 years old with an initial hospitalization for stroke in 2002-2005 were identified and followed up until December 31, 2016. Patients with newly diagnosed aphasia during stroke hospitalization or within 6 months of discharge were defined as the aphasia group. Cox proportional hazards models were used to estimate hazard ratios (HRs) for developing overall, vascular, and non-vascular dementia in patients with and without post-stroke aphasia., Results: During a median follow-up period of 7.9 and 8.6 years for the aphasia (n=17063) and non-aphasia groups (n=105940), respectively, overall dementia incidence was similar, whereas vascular dementia incidence was higher in the aphasia group (7.52 vs. 5.52 per 1000 person-years). The adjusted HRs (95% confidence intervals) were 1.11 (1.06-1.17), 1.42 (1.31-1.53), and 0.94 (0.88-1.01) for overall, vascular, and non-vascular dementia, respectively. The association between aphasia and the risk of vascular dementia did not differ by stroke type (P for interaction=0.43). The analysis of 16856 propensity score-matched pairs revealed similar results., Conclusion: Patients with post-stroke aphasia have an increased risk of developing vascular dementia irrespective of the type of stroke., Competing Interests: Declaration of Competing Interest None to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: We aimed to evaluate the predictive value of sex hormone levels on 3-month functional outcomes after acute ischemic stroke (AIS) in males., Materials and Methods: A total of 110 male AIS patients were included in this prospective study. Serum levels of testosterone and estradiol were measured at admission. The National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin Scale (mRS) were measured at admission and after 3 months. A mRS score ≥3 was considered as a poor functional outcome., Results: The median age of the 110 subjects was 62.0 [23.3] years (range 35-93 years). Univariate logistic regression revealed that bioavailable testosterone, free testosterone, age, NIHSS at admission, mRS at admission, and prior ischemic stroke were associated with a poor functional outcome (mRS score ≥3) at 3 months. In multivariate analysis, only age, NIHSS at admission, and mRS at admission were independent predictors., Conclusions: After controlling the covariates, bioavailable and free testosterone levels are not associated with the 3-month mRS in male patients with AIS. Age, NIHSS at admission, and mRS at admission are robust predictors for the functional outcomes.

The current study aimed to investigate whether low testosterone predicted the recurrence and clinical outcomes after acute ischemic stroke (AIS) in males. From June 2015 through August 2017, the study prospectively enrolled 110 male AIS patients. All received detailed evaluations at admission and were followed for at least 1 year. The cumulative incidence, overall survival, length of hospital stay, and the percentage of previous stroke were compared between subjects with testosterone <440 ng/dl and >440 ng/dl. The median age was 62 years (range, 35-93 years). The median serum testosterone at admission was 438 [203] ng/dl (range, 44-816 ng/dl); 55 patients (50%) had testosterone <440 ng/dl and were considered as low testosterone. The median follow-up was 23 months. During the period, 12 recurrences and 10 deaths occurred. The 1-year and 3-year cumulative recurrence rate were 8.3% and 11.9%, respectively; the 1-year and 3-year overall survival were 96.3% and 84.6%, respectively. The cumulative recurrence rates were similar between the two testosterone groups (log-rank test, p = .88). Low testosterone was associated with poor survival with marginal significance (log-rank test, p = .079). Men with low testosterone had a higher percentage of previous stroke (29.1% versus 12.7%, p = .035). The mean lengths of hospital stay were similar between the two testosterone groups (16.6 ± 15.8 days versus 14.0 ± 10.6, p = .31). Total testosterone at admission fails to predict stroke recurrence. However, men with low testosterone at admission are more likely to have previous stroke and may have a higher all-cause mortality rate after AIS.

Inflammatory processes have a detrimental role in the pathophysiology of ischemic stroke. However, little is known about the endogenous anti-inflammatory mechanisms in ischemic brain. Here, we identify CXCL14 as a critical mediator of these mechanisms. CXCL14 levels were upregulated in the ischemic brains of humans and rodents. Moreover, hypoxia inducible factor-1α (HIF-1α) drives hypoxia- or cerebral ischemia (CI)-dependent CXCL14 expression via directly binding to the CXCL14 promoter. Depletion of CXCL14 inhibited the accumulation of immature dendritic cells (iDC) or regulatory T cells (Treg) and increased the infarct volume, whereas the supplementation of CXCL14 had the opposite effects. CXCL14 promoted the adhesion, migration, and homing of circulating CD11c + iDC to the ischemic tissue via the upregulation of the cellular prion protein (PrP C ), PECAM-1, and MMPs. The accumulation of Treg in ischemic areas of the brain was mediated through a cooperative effect of CXCL14 and iDC-secreted IL-2-induced Treg differentiation. Interestingly, CXCL14 largely promoted IL-2-induced Treg differentiation. These findings indicate that CXCL14 is a critical immunomodulator involved in the stroke-induced inflammatory reaction. Passive CXCL14 supplementation provides a tractable path for clinical translation in the improvement of stroke-induced neuroinflammation., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Stroke is a result of cerebral ischemia that triggers a cascade of both physiological and biochemical events. No effective treatment is available for stroke; however, stem cells have the potential to rescue tissue from the effects of stroke. Adipose-derived stem cells (ADSCs) are an abundant source of adult stem cells; therefore, ADSC therapy can be considered as a future strategy for regenerative medicine. However, more research is required to improve the effectiveness of transplanted ADSCs as a treatment for stroke in the mouse stroke model. Ligustilide, isolated from the herb Angelica sinensis, exhibits a protective effect on neurons and inhibits inflammation. We also demonstrated that ligustilide treatment increases the expression levels of homing factors such as SDF-1 and CXCR4. In the present study, we evaluated the therapeutic effects of ADSC transplantation and ligustilide treatment in a mouse thromboembolic stroke model by behavioral tests, including beam walking, locomotor activity, and rotarod analysis. ADSCs pretreated with ligustilide were transplanted into the brains of stroke mice. The results showed that the therapeutic effect of ADSCs pretreated with ligustilide was better than that of ADSCs without ligustilide pretreatment. There was no difference between the recovery of mice treated by ADSC transplantation combined with subcutaneous ligustilide injection and that of mice treated only with ADSCs. The TUNEL assay showed fewer apoptotic cells in the brains of mice transplanted with ADSCs pretreated with ligustilide as well as in those without pretreatment. In summary, pretreatment of ADSCs with ligustilide improves the therapeutic efficacy of ADSC transplantation. The results of this study will help improve stem cell therapies being developed for future clinical applications.

Unlabelled: Study Type--Prognosis (cohort) Level of Evidence 2b. What's known on the subject? and What does the study add? Although early studies failed to detect an association between urinary calculi (UC) and subsequent cardiovascular risk, there is growing evidence among more recent research supporting this association with some studies more specifically suggesting that stroke is a major concern for UC sufferers. After adjusting for potential confounding factors, UC patients were more likely to have experienced a stroke then those without UC during the five-year follow-up period (hazard ratio = 1.43, 95% Cl = 1.35-1.50, P < 0.001)., Objective: • To examine in a population-based study the relationship between a history of nephrolithiasis and/or ureterolithiasis and the subsequent risk of stroke, as previous studies have shown that stone disease is associated with several cardiovascular risk factors. However, none of the studies that have investigated the relationship between urinary calculi (UC) and stroke were able to detect an association at a significant level., Patients and Methods: • We used data sourced from the Taiwan Longitudinal Health Insurance Database 2000. • In all, 25,181 adult patients newly diagnosed with UC were recruited as a study cohort, along with 125,905 matched enrolees with no history of stone disease as a comparison cohort. • All the subjects were tracked for a 5-year period beginning from their index ambulatory care visits, and those who subsequently had a stroke identified. • Cox proportional hazards regressions were used to compare the risk of stroke between the study and comparison cohorts., Results: • During the 5-year follow-up period, the incidence rate of stroke was 1.78 (95% confidence interval [CI] 1.71-1.86) per 100 person-years in patients with UC and 1.25 (95% CI 1.22-1.27) per 100 person-years in patients without UC. • After adjusting for hypertension, diabetes, hyperlipidaemia, cardiovascular disease, urbanization level, gout, and obesity, patients with UC were more likely to have had a stroke than those without UC during the 5-year follow-up period (hazard ratio 1.43, 95% CI 1.35-1.50, P < 0.001)., Conclusion: • Our results suggest that there is an increased risk of stroke during the first 5 years after a diagnosis of UC., (© 2012 THE AUTHORS. BJU INTERNATIONAL © 2012 BJU INTERNATIONAL.)

Cellular senescence induces changes in cellular physiology, morphology, proliferative capacity, and gene expression. Stem cell senescence might be one of the major issues of limited efficacy of stem cell transplantation. In this study, we demonstrated that implantation of human umbilical cord mesenchymal stem cells (hUCMSCs) cultured in human umbilical cord serum (hUCS) significantly enhanced neuroplasticity and angiogenesis in stroke and ischemic limb models. Immunophenotypic analysis indicated that hUCMSCs cultured in hUCS had more small and rapidly self-renewing cells than those expanded in FCS. The main cause of greater senescence in FCS-cultured cells was increased generation of reactive oxygen species (ROS). Proteome profiling showed significantly more senescence-associated vimentin in FCS-cultured hUCMSCs than in hUCS-cultured hUCMSCs. In contrast, there was significant upregulation of heat shock protein 27 (Hsp27) in the hUCS-cultured hUCMSCs. By gene targeting, we found that overexpression of Hsp27 may downregulate vimentin expression through inhibition of the nuclear translocation of p65 (NF-κB signaling). Thus, an interaction between Hsp27 and vimentin may modulate the degree of senescence in hUCS- and FCS-cultured hUCMSCs. In summary, hUCMSCs exhibiting senescence are detrimental to cell engraftment and differentiation in animal models via activation of NF-κB pathway. Human stem cells incubated in hUCS might reduce the senescent process through upregulation of Hsp27 to increase implantation efficiency.

Understanding stem cell homing, which is governed by environmental signals from the surrounding niche, is important for developing effective stem cell-based repair strategies. The molecular mechanism by which the brain under ischemic stress recruits bone marrow-derived cells (BMDCs) to the vascular niche remains poorly characterized. Here we report that hypoxia-inducible factor-1α (HIF-1α) activation upregulates pituitary adenylate cyclase-activating peptide 38 (PACAP38), which in turn activates PACAP type 1 receptor (PAC1) under hypoxia in vitro and cerebral ischemia in vivo. BMDCs homing to endothelial cells in the ischemic brain are mediated by HIF-1α activation of the PACAP38-PAC1 signaling cascade followed by upregulation of cellular prion protein and α6-integrin to enhance the ability of BMDCs to bind laminin in the vascular niche. Exogenous PACAP38 confers a similar effect in facilitating BMDCs homing into the ischemic brain, resulting in reduction of ischemic brain injury. These findings suggest a novel HIF-1α-activated PACAP38-PAC1 signaling process in initiating BMDCs homing into the ischemic brain for reducing brain injury and enhancing functional recovery after ischemic stroke. S tem C ells 2015;33:1153-1172 [ABSTRACT FROM AUTHOR]