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Elevation of astrocyte-derived extracellular vesicles over the first month post-stroke in humans.

ABSTRACT: We sought to identify alterations in the quantity of plasma brain-derived extracellular vesicles (EV) over the first month post-stroke to shed light on related injury and repair mechanisms. We assessed plasma levels of presumed neuron-derived EVs (NDEs), astrocyte-derived EVs (ADEs), and oligodendrocyte-derived EVs (ODEs) in 58 patients 5, 15, and 30 days post-ischemic stroke and 46 controls matched for cardiovascular risk factors using sandwich immunoassays. Subsets of brain-derived EVs were identified by co-expression of the general EV marker CD9 and markers for neurons (L1CAM, CD171), astrocytes (EAAT1), and oligodendrocytes (MOG) respectively. Clinical MRIs assessed lesion volume and presence of hemorrhagic transformation. ADE levels were elevated 5, 15, and 30 days post-stroke compared to controls (p = 0.002, p = 0.002, and p = 0.005 respectively) with no significant change for NDE or ODE. ADEs were increased 15 days post-stroke in patients with hemorrhagic transformation (p = 0.04) compared to patients with no hemorrhage. We conclude that ADE levels are preferentially increased over the first month post-stroke in humans, possibly to provide trophic support to injured neurons following ischemia. ADEs hold potential as biomarkers of blood-brain barrier breakdown and hemorrhagic transformation, but this requires further study at earlier time points post-stroke.

SUBMITTER: Edwardson MA

PROVIDER: S-EPMC10912590 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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Elevation of astrocyte-derived extracellular vesicles over the first month post-stroke in humans.

Edwardson Matthew A MA Mitsuhashi Masato M Van Epps Dennis D

Scientific reports 20240304 1

We sought to identify alterations in the quantity of plasma brain-derived extracellular vesicles (EV) over the first month post-stroke to shed light on related injury and repair mechanisms. We assessed plasma levels of presumed neuron-derived EVs (NDEs), astrocyte-derived EVs (ADEs), and oligodendrocyte-derived EVs (ODEs) in 58 patients 5, 15, and 30 days post-ischemic stroke and 46 controls matched for cardiovascular risk factors using sandwich immunoassays. Subsets of brain-derived EVs were id ...[more]

PMID: 38438491

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Project description:UnlabelledAlthough the initial concepts of stem cell therapy aimed at replacing lost tissue, more recent evidence has suggested that stem and progenitor cells alike promote postischemic neurological recovery by secreted factors that restore the injured brain's capacity to reshape. Specifically, extracellular vesicles (EVs) derived from stem cells such as exosomes have recently been suggested to mediate restorative stem cell effects. In order to define whether EVs indeed improve postischemic neurological impairment and brain remodeling, we systematically compared the effects of mesenchymal stem cell (MSC)-derived EVs (MSC-EVs) with MSCs that were i.v. delivered to mice on days 1, 3, and 5 (MSC-EVs) or on day 1 (MSCs) after focal cerebral ischemia in C57BL6 mice. For as long as 28 days after stroke, motor coordination deficits, histological brain injury, immune responses in the peripheral blood and brain, and cerebral angiogenesis and neurogenesis were analyzed. Improved neurological impairment and long-term neuroprotection associated with enhanced angioneurogenesis were noticed in stroke mice receiving EVs from two different bone marrow-derived MSC lineages. MSC-EV administration closely resembled responses to MSCs and persisted throughout the observation period. Although cerebral immune cell infiltration was not affected by MSC-EVs, postischemic immunosuppression (i.e., B-cell, natural killer cell, and T-cell lymphopenia) was attenuated in the peripheral blood at 6 days after ischemia, providing an appropriate external milieu for successful brain remodeling. Because MSC-EVs have recently been shown to be apparently safe in humans, the present study provides clinically relevant evidence warranting rapid proof-of-concept studies in stroke patients.SignificanceTransplantation of mesenchymal stem cells (MSCs) offers an interesting adjuvant approach next to thrombolysis for treatment of ischemic stroke. However, MSCs are not integrated into residing neural networks but act indirectly, inducing neuroprotection and promoting neuroregeneration. Although the mechanisms by which MSCs act are still elusive, recent evidence has suggested that extracellular vesicles (EVs) might be responsible for MSC-induced effects under physiological and pathological conditions. The present study has demonstrated that EVs are not inferior to MSCs in a rodent stroke model. EVs induce long-term neuroprotection, promote neuroregeneration and neurological recovery, and modulate peripheral post-stroke immune responses. Also, because EVs are well-tolerated in humans, as previously reported, the administration of EVs under clinical settings might set the path for a novel and innovative therapeutic stroke concept without the putative side effects attached to stem cell transplantation.

Project description:BackgroundHigh blood pressure (BP) is the primary risk factor for recurrent strokes. Despite established clinical guidelines, some stroke survivors exhibit uncontrolled BP over the first 12 months post-stroke. Furthermore, research on BP trajectories in stroke survivors admitted to inpatient rehabilitation hospitals is limited. Exercise is recommended to reduce BP after stroke. However, the effect of high repetition gait training at aerobic intensities (>40% heart rate reserve; HRR) during inpatient rehabilitation on BP is unclear. We aimed to determine the effect of an aerobic gait training intervention on BP trajectory over the first 12 months post-stroke.MethodsThis is a secondary analysis of the Determining Optimal Post-Stroke Exercise (DOSE) trial. Participants with stroke admitted to inpatient rehabilitation hospitals were recruited and randomized to usual care (n = 24), DOSE1 (n = 25; >2,000 steps, 40-60% HRR for >30 min/session, 20 sessions over 4 weeks), or DOSE2 (n = 25; additional DOSE1 session/day) groups. Resting BP [systolic (SBP) and diastolic (DBP)] was measured at baseline (inpatient rehabilitation admission), post-intervention (near inpatient discharge), 6- and 12-month post-stroke. Linear mixed-effects models were used to examine the effects of group and time (weeks post-stroke) on SBP, DBP and hypertension (≥140/90 mmHg; ≥130/80 mmHg, if diabetic), controlling for age, stroke type, and baseline history of hypertension.ResultsNo effect of intervention group on SBP, DBP, or hypertension was observed. BP increased from baseline to 12-month post-stroke for SBP (from [mean ± standard deviation] 121.8 ± 15.0 to 131.8 ± 17.8 mmHg) and for DBP (74.4 ± 9.8 to 78.5 ± 10.1 mmHg). The proportion of hypertensive participants increased from 20.8% (n = 15/72) to 32.8% (n = 19/58). These increases in BP were statistically significant: an effect [estimation (95%CI), value of p] of time was observed on SBP [0.19 (0.12-0.26) mmHg/week, p < 0.001], DBP [0.09 (0.05-0.14) mmHg/week, p < 0.001], and hypertension [OR (95%CI): 1.03 (1.01-1.05), p = 0.010]. A baseline history of hypertension was associated with higher SBP by 13.45 (8.73-18.17) mmHg, higher DBP by 5.57 (2.02-9.12) mmHg, and 42.22 (6.60-270.08) times the odds of being hypertensive at each timepoint, compared to those without.ConclusionBlood pressure increased after inpatient rehabilitation over the first 12 months post-stroke, especially among those with a history of hypertension. The 4-week aerobic gait training intervention did not influence this trajectory.

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Elevation of astrocyte-derived extracellular vesicles over the first month post-stroke in humans.

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Elevation of astrocyte-derived extracellular vesicles over the first month post-stroke in humans.

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