Although intravenous administration of mesenchymal stem cells (MSCs) is effective for experimental stroke, low engraftment and the limited functional capacity of transplanted cells are critical hurdles for clinical applications. C–C motif chemokine ligand 2 (CCL2) is associated with neurological repair after stroke and delivery of various cells into the brain via CCL2/CCR2 (CCL2 receptor) interaction. In this study, after CCL2-overexpressing human umbilical cord-derived MSCs (hUC-MSCs) were intravenously transplanted with mannitol in rats with middle cerebral arterial occlusion, we compared the differences between four different treatment groups: mannitol + CCL2-overexpressing hUC-MSCs (CCL2-MSC), mannitol + naïve hUC-MSCs (M-MSC), mannitol only, and control. At four-weeks post-transplantation, the CCL2-MSC group showed significantly better functional recovery and smaller stroke volume relative to the other groups. Additionally, we observed upregulated levels of CCR2 in acute ischemic brain and the increase of migrated stem cells into these areas in the CCL2-MSC group relative to the M-MSC. Moreover, the CCL2-MSC group displayed increased angiogenesis and endogenous neurogenesis, decreased neuro-inflammation but with increased healing-process inflammatory cells relative to other groups. These findings indicated that CCL2-overexpressing hUC-MSCs showed better functional recovery relative to naïve hUC-MSCs according to the increased migration of these cells into brain areas of higher CCR2 expression, thereby promoting subsequent endogenous brain repair.

Introduction: There is no single blood marker for predicting the prognosis in ischemic stroke. A combination of multiple blood markers may enhance the ability to predict long-term outcome following ischemic stroke. Methods: Blood concentrations of neuronal markers (neuron-specific enolase, visinin-like protein 1, heart type fatty acid binding protein (hFABP) and neuroglobin), astroglial markers (S100B and glial fibrillary acidic protein), inflammatory markers (IL-6, TNF-α, and C-reactive protein), blood-brain barrier marker (matrix metalloproteinase 9), and haemostatic markers (D-dimer and PAI-1) were measured within 24 hours after stroke onset. The discrimination and reclassification for favorable and poor outcome were compared after adding individual or a combination of blood markers to the clinical model of stroke outcome. Results: In multivariate analysis, natural log-transformed (_log) IL-6 (odds ratio (OR): 1.75, 95% CI: 1.25 to 2.25, P = 0.001) and _loghFABP (OR: 3.23, 95% CI: 1.44 to 7.27, P = 0.005) were independently associated with poor outcome. The addition of a single blood marker to the clinical model did not improve the discriminating ability of the clinical model of stroke outcome. However, the addition of the combination of _logIL-6 and _loghFABP to the clinical model showed improved discrimination (area under receiver operating characteristic (AUROC) curve: 0.939 versus 0.910, P = 0.03) and reclassification performance (net reclassification improvement index: 0.18, P = 0.005). Conclusions: A combination of circulating IL-6 and hFABP level has an additive clinical value for the prediction of stroke outcome.

Although prompt diagnosis and emergent surgical intervention are important in acute spinal subdural hematoma (SSDH), some cases with spontaneous remission of symptom and hematoma without surgery have been reported. We present a case of acute nontraumatic SSDH presenting with transient left hemiplegia for 4 hours. A magnetic resonance imaging study of cervical spine confirmed SSDH with C3-6 cervical cord compression at the left side. The patient had conservative management without recurrence. Although hemiplegia is an unusual clinical manifestation of SSDH, it should be differentiated from that of cerebrovascular origin promptly. Conservative management may be an alternative therapeutic option for selective cases with transient neurological deficits.

The human umbilical cord is a promising source of mesenchymal stromal cells (MSCs). Intravenous administration of human umbilical cord-derived MSCs (IV-hUMSCs) showed a favorable effect in a rodent stroke model by a paracrine mechanism. However, its underlying therapeutic mechanisms must be determined for clinical application. We investigated the therapeutic effects and mechanisms of our good manufacturing practice (GMP)-manufactured hUMSCs using various cell doses and delivery time points in a rodent model of stroke. IV-hUMSCs at a dose of 1 × 10⁶ cells at 24 h after stroke improved functional deficits and reduced neuronal damage by attenuation of post-ischemic inflammation. Transcriptome and immunohistochemical analyses showed that interleukin-1 receptor antagonist (IL-1ra) was highly upregulated in ED-1-positive inflammatory cells in rats treated with IV-hUMSCs. Treatment with conditioned medium of hUMSCs increased the expression of IL-1ra in a macrophage cell line via activation of cAMP-response element-binding protein (CREB). These results strongly suggest that the attenuation of neuroinflammation mediated by endogenous IL-1ra is an important therapeutic mechanism of IV-hUMSCs for the treatment of stroke.

Alzheimers disease (AD) animal studies have reported that mesenchymal stem cells (MSCs) have therapeutic effects; however, clinical trial results are controversial. Neprilysin (NEP) is the main cleavage enzyme of β-amyloid (Aβ), which plays a major role in the pathology and etiology of AD. We evaluated whether transplantation of MSCs with NEP gene modification enhances the therapeutic effects in an AD animal model and then investigated these pathomechanisms. We manufactured NEP gene-enhanced human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) and intravenously transplanted them in Aβ_1-42-injected AD animal models. We compared the differences in behavioral tests and immunohistochemical assays between four groups: normal, Aβ_1-42 injection, nave hUC-MSCs, and NEP-enhanced hUC-MSCs. Both nave and NEP-enhanced hUC-MSC groups showed significant improvements in memory compared to the Aβ_1-42 injection group. There was no significant difference between nave and NEP-enhanced hUC-MSC groups. There was a significant decrease in Congo red, BACE-1, GFAP, and Iba-1 and a significant increase in BDNF, NeuN, and NEP in both hUC-MSC groups compared to the Aβ_1-42 injection group. Among them, BDNF, NeuN, GFAP, Iba-1, and NEP showed more significant changes in the NEP-enhanced hUC-MSC group than in the nave group. After stem cell injection, stem cells were not found. Extracellular vesicles (EVs) were equally observed in the hippocampus in the nave and NEP-enhanced hUC-MSC groups. However, the EVs of NEP-enhanced hUC-MSCs contained higher amounts of NEP as compared to the EVs of nave hUC-MSCs. Thus, hUC-MSCs affect AD animal models through stem cell-released EVs. Although there was no significant difference in cognitive function between the hUC-MSC groups, NEP-enhanced hUC-MSCs had superior neurogenesis and anti-inflammation properties compared to nave hUC-MSCs due to increased NEP in the hippocampus by enriched NEP-possessing EVs. NEP gene-modified MSCs that release an increased amount of NEP within EVs may be a promising therapeutic option in AD treatment.