Mesenchymal stem cells (MSCs) are multipotent stem cells, whose paracrine and immunomodulatory potential has made them a promising candidate for central nervous system (CNS) regeneration. Numerous studies have demonstrated that MSCs can promote immunomodulation, anti-apoptosis, and axon re-extension, which restore functional neural circuits. The therapeutic effects of MSCs have consequently been evaluated for application in various CNS diseases including spinal cord injury, cerebral ischemia, and neurodegenerative disease. In this review, we will focus on the research works published in the field of mechanisms and therapeutic effects of MSCs in CNS regeneration.

High expression of cellular self‐activated immunosuppressive molecules and extensive infiltration of suppressive immune cells in the tumor microenvironment are the main factors contributing to glioma's resistance to immunotherapy. Nonetheless, technology to modify the expression of glioma cellular self‐molecules through gene editing requires further development. This project advances cell therapy strategies to reverse the immunosuppressive microenvironment of glioma (TIME). Bone marrow‐derived mesenchymal stem cells (MSCs) are engineered to express bioactive proteins and demonstrate tumor‐homing characteristics upon activation by TGF‐β. These MSCs are designed to secrete the anti‐tumor immune cytokine IL‐12 and the nCD47‐SLAMF7 fusion protein, which regulates T‐cell activity and macrophage phagocytosis. The engineered MSCs are then injected in situ into the glioma site, circumventing the blood‐brain barrier to deliver high local concentrations of bioactive proteins. This approach aims to enhance the M1 polarization of infiltrating macrophages, stimulate macrophage‐mediated tumor cell phagocytosis, activate antigen‐presenting cells, and promote effector CD8⁺ T cell infiltration, effectively controlling glioma. Additionally, the engineered MSCs may serve as a universal treatment for other tumors that express TGF‐β at high levels. This study proposes a novel treatment strategy for the clinical management of glioma patients.

Mesenchymal stem cell (MSC)-based regenerative therapy is regarded as a promising strategy for the treatment of Parkinson’s disease (PD). However, MSC components may exhibit poor intracranial survivability, particularly in the later stages following cell transplantation, limiting their potential curative effect and also clinical applications. Glial cell line-derived neurotrophic factor (GDNF), which encompasses a variety of transforming growth factor beta super family members, has been reported to enhance motor function and exert neuroprotective effects. However, no previous studies have investigated the effects of GDNF on human primary adipose-derived MSCs (hAMSCs), despite its potential for enhancing stem cell survival and promoting therapeutic efficacy in the treatment of PD. In the present study, we proposed a novel approach for enhancing the proliferative capacity and improving the efficacy of hAMSC treatment. Pre-exposure of engineered hAMSCs to GDNF enhanced the proliferation and differentiation of these stem cells in vitro. In addition, in 6-hydroxydopamine-lesioned mice, a common PD model, intracranial injection of hAMSCs-GDNF was associated with greater performance on behavioral tests, larger graft volumes 5 weeks after transplantation, and higher levels of Nestin, glial fibrillary acidic protein, and Tuj-1 differentiation than those treated with hAMSCs-Vector. Following transplantation of hAMSCs-GDNF into the striatum of lesioned models, we observed significant increases in tyrosine hydroxylase- and NeuN-positive staining. These findings highlight the therapeutic potential of hAMSCs-GDNF for patients with PD, as well as an efficient method for promoting therapeutic efficacy of these delivery vehicles.

Objective: The purpose of the study was to assess the functional outcomes after microsurgical resection of arteriovenous malformations (AVMs) and to compare the results between patients eligible for A Randomized Trial of Unruptured Brain Arteriovenous Malformations in this surgical series to the results reported and the ARUBA study. Methods: We reviewed the records of 169 patients who underwent microsurgical treatment of arteriovenous malformation (AVMs) in our institution between January 2016 and December 2021. These patients’ functional status was assessed using modified Rankin Scale (mRS) scores at the last follow-up and before treatment. The mRS scores at the latest follow-up were classified into good outcomes (mRS < 3) and poor outcomes (mRS ≥ 3). Clinical presentation, patients’ demographics, AVM characteristics, follow-up time, and obliteration rate were analyzed. Subgroup analyses were performed on the whole cohort, comparing Spetzler–Martin Grade I and Grade II, and ARUBA-eligible AVMs. Results: The initial hemorrhagic presentation occurred in 71 (42%) out of 169 patients. The majority of the patients presented with headaches (73%). The AVMs were completely obliterated in 166 (98.2%) patients. The series included 65 Spetzler–Martin Grade I (38.5%), 46 Grade II (27.2%), 32 Grade III (18.9%), 22 Grade IV (13%), and 4 Grade V (2.4%) AVMs. There were 98 unruptured and 79 ARUBA-eligible cases. Also, optimal functional outcome was achieved in 145 (85.8%) patients. The overall mortality rate was 5.3% (9/169). The multivariate analysis illustrated that a poor outcome was significantly associated with presurgical mRS ≥3 (p < 0.013; OR, 0.206; 95% CI 0.059–0.713), increasing age (p < 0.045; odds ratio [OR], 1.022; 95% CI 1.000–0.045), and female gender (p < 0.009; OR, 2.991; 95% CI 1.309–6.832). Conclusions: Our study suggests that better outcomes can be obtained using microsurgical resection in the majority of patients with AVMs. Independent predictors of poor outcomes after surgical resection of AVMs include increasing age at the time of surgery, poor presurgical functional status, and female gender. Supposing that patients are more suitable for microsurgery after presurgical examination, outcomes are normally better in that case than those achieved by multimodal interventions (such as conservative treatment or ARUBA treatment arm). Therefore, we recommend early surgical removal on all surgically accessible AVMs to prevent successive hemorrhages and the consequences of poor neurological outcomes.

The absence of signaling pathways related to intrinsic immune activation in tumor cells and the immunosuppressive microenvironment limit lymphocyte infiltration, constitutes an "immune-desert" tumor displaying insensitivity to various immunotherapies. This study investigates strategies to activate intrinsic immune pathways in glioma cells, reverse immunosuppression, and induce tertiary lymphoid structures (TLS) within the glioma microenvironment (GME) to enhance natural and adaptive immune responses. We successfully induced antigen-presenting cell activation, macrophage/microglia polarization, and TLS formation in GME by intracranial delivery of BafA1@Rexo-SC, which comprises exosomes from irradiated bone marrow-derived stem cells overexpressing CD47 nanobodies and STING, loaded with the autophagy inhibitor BafA1. These exosomes efficiently activated the cGAS-STING pathway, leading to the formation of "lymphoid tissue organizer cells (Lto)" cells, VEGFA release for high endothelial microvessel formation, and chemokine release for T and B cell recruitment. BafA1@Rexo-SC also promoted macrophage phagocytosis of tumor cells and enhanced effector T cell function by blocking CD47, while releasing type I interferon. Our findings suggest novel therapeutic approaches for glioma treatment.

Vascular endothelial growth factor (VEGF) is a pro-angiogenic factor that mediates the differentiation and function of vascular endothelial cells. VEGF has been implicated in modulating various pains. However, the effects of VEGF in Parkinson’s disease (PD)-related pain have not been studied. The goal of this study was to understand the effects of VEGF-expressing mesenchymal stem cells (MSCs) on PD-related pain and the involved mechanisms. We used two types of MSCs: hAMSC-Vector-GFP and hAMSC-VEGF189-GFP in PD mice. Then, the expression of VEGF and the viability have been compared between two types of MSCs. To demonstrate the therapeutic effect of hAMSC-VEGF189-GFP, we transplanted each cell line in a PD mouse model. Head mechanical withdrawal thresholds were examined. hAMSC-VEGF189-GFP was associated with significantly increased VEGF expression and slightly increased viability, compared with hAMSC-Vector-GFP. The transplanted hAMSC-VEGF189-GFP significantly improved mechanical allodynia and inhibited transient receptor potential vanilloid 1 (TRPV1) expression in site. And such pain relief effects could be partially blocked by TRPV1 agonist. However, we did not observe tumor generation or neuron degeneration in hAMSC-VEGF189-GFP-transplanted animals. Taken together, our data suggest that hAMSC-VEGF189-GFP is safely therapeutically appropriate for treating PD-related pain. VEGF inhibits TRPV1 expression, which may contribute to its analgesic properties.