Peripheral lymphocytes entering brain ischemic regions orchestrate inflammatory responses, catalyze tissue death, and worsen clinical outcomes of acute ischemic stroke (AIS) in preclinical studies. However, it is not known whether modulating brain inflammation can impact the outcome of patients with AIS. In this open-label, evaluator-blinded, parallel-group clinical pilot trial, we recruited 22 patients matched for clinical and MRI characteristics, with anterior cerebral circulation occlusion and onset of stroke that had exceeded 4.5 h, who then received standard management alone (controls) or standard management plus fingolimod (FTY720, Gilenya, Novartis), 0.5 mg per day orally for 3 consecutive days. Compared with the 11 control patients, the 11 fingolimod recipients had lower circulating lymphocyte counts, milder neurological deficits, and better recovery of neurological functions. This difference was most profound in the first week when reduction of National Institutes of Health Stroke Scale was 4 vs. −1, respectively (P = 0.0001). Neurological rehabilitation was faster in the fingolimod-treated group. Enlargement of lesion size was more restrained between baseline and day 7 than in controls (9 vs. 27 mL, P = 0.0494). Furthermore, rT1%, an indicator of microvascular permeability, was lower in the fingolimod-treated group at 7 d (20.5 vs. 11.0; P = 0.005). No drug-related serious events occurred. We conclude that in patients with acute and anterior cerebral circulation occlusion stroke, oral fingolimod within 72 h of disease onset was safe, limited secondary tissue injury from baseline to 7 d, decreased microvascular permeability, attenuated neurological deficits, and promoted recovery. Significance In patients with acute ischemic stroke (AIS), the abrupt and massive influx of lymphocytes from the periphery to the ischemic region orchestrates focal inflammatory responses, catalyzes tissue death, and worsens clinical outcomes. In this early phase clinical study, we reduced lymphocyte migration to the brain during the first 72 h of AIS via oral administration of three doses of fingolimod. This administration led to a significant reduction of secondary lesion enlargement, microvascular permeability, and better clinical outcomes during the acute phase and 3-mo follow-up visit. This study will provoke new investigations on the efficacy of modulation of brain inflammation in AIS.

Intracerebral hemorrhage (ICH) accounts for about 10% to 15% of all strokes and is associated with high rates of mortality and morbidity.^1,2 Although surgical decompression is widely accepted as potentially lifesaving for many such patients, no proven medical treatment exists.^1,2 Quiz Ref ID Hematomas induce injury by mechanical disruption of the neurons and glia, followed by mechanical deformation causing oligemia, neurotransmitter release, mitochondrial dysfunction, and membrane depolarization.^3-5 Activated microglia release products that induce breakdown of the blood-brain barrier,^1,6 which leads to a massive influx of inflammatory cells from the periphery. Resident glia cells and migrant lymphocytes produce cytokines and chemokines, coupled with cell death products, further activating intrinsic and migrant lymphocytes and guiding the subsequent homing of more lymphocytes from the periphery.^7-12 These inflammatory cascades contribute to the formation of edema that surrounds hematomas, exacerbates the mass effect, amplifies the cell death process via secondary ischemia, and produces inflammatory insults.² Perihematomal edema (PHE) increases in volume by about 75% in the first 24 hours after an ICH, peaks about 5 to 6 days later, and lasts up to 14 days.^13-15 An early voluminous edema, relative to hematomal volume, dramatically catalyzes the initial damage triggered by bleeding and critically endangers the overall outcomes of these patients.¹⁶ Quiz Ref ID Previous attempts to reduce edema by infusion of mannitol, glycerol, or dexamethasone have failed to benefit or control regional cerebral blood flow, neurologic functional outcomes, and mortality.^1,2 Although hypertonic saline solutions have been introduced as a promising alternative to reduce the total amount of cerebral edema,¹⁷ no therapies have been directed toward altering the inflammatory and edemic processes of this disease.

Ever since synovium-derived mesenchymal stem cells (SMSCs) were first identified and successfully isolated in 2001, as a brand new member in MSC families, they have been increasingly regarded as a promising therapeutic cell species for musculoskeletal regeneration, particularly for reconstructions of cartilage, bones, tendons, and muscles. Besides the general multipotency in common among the MSC community, SMSCs excel other sourced MSCs in higher ability of proliferation and superiority in chondrogenesis. This review summarizes the latest advances in SMSC-related studies covering their specific isolation methodologies, biological insights, and practical applications in musculoskeletal therapeutics of which an emphasis is cast on engineered chondrogenesis.