Reduced cortical thickness in subjects at clinical high risk for psychosis and clinical attributes.

OBJECTIVES: Although neuroanatomical abnormalities in subjects at clinical high risk for psychosis have been considered a putative biomarker of psychosis, relevance of cortical thickness alterations remains contested due to discrepant findings. Inconsistencies persist in Asian clinical high risk studies, despite their advantageous settings well-controlled for confounds. Attributes of cortical thickness alterations in clinical high risk subjects warrant further examination. METHODS: We examined cortical thickness at the whole-brain level in 74 clinical high risk subjects and 34 demographically matched healthy controls recruited from Seoul Youth Clinic, South Korea. Clinical symptoms were assessed using the Scale of Prodromal Symptoms, and their associations with cortical thickness were explored using partial correlation analysis. RESULTS: Compared to healthy control, clinical high risk exhibited significant cortical thinning in bilateral prefrontal cortex and inferior parietal lobule clusters. Reduced thickness in the left prefrontal cortex cluster was associated with more severe Scale of Prodromal Symptoms general symptoms scores and the right inferior parietal lobule cluster with Scale of Prodromal Symptoms disorganization symptoms. CONCLUSIONS: Thickness deficits found in the present clinical high risk sample demonstrated a degree of consistency with those reported in the previous Seoul Youth Clinic study. While inconsistencies reported between the present and previous Seoul Youth Clinic samples may reflect markedly decreased rate of converters, consistencies may be relevant to clinical attributes beyond transition, such as the prevalence of comorbidities. Particular recruitment strategies employed for sample selections should also be considered for findings in Asian clinical high risk samples. Our results suggest potential utility of cortical thickness alterations in clinical high risk subjects beyond the frame of transition.

Effect of smoking on the association of HHEX (rs5015480) with diabetes among Korean women and heavy smoking men.

BACKGROUND: Several genome-wide association studies (GWAS) for serum fasting glucose levels have reported HHEX as possibly causal. The objective of this study was to examine the joint effect of smoking on the association of diabetes with the HHEX rs5015480 polymorphism among Korean subjects. METHODS: This replication study included a total of 4240 individuals, and multivariate linear regression and multiple logistic regression models were used. We examined the combined effect of smoking on the relationship between HHEX rs5015480 and diabetes. RESULTS: The rs5015480 SNP in the HHEX gene was related to the mean FBS level (effect per allele, 1.572 mg/dL, p = 0.0122). Females with the CC genotype had a 2.68 times higher (range, 1.05-6.82 times) risk of diabetes than those with the TT/TC genotype. Although the association was stronger in female subjects (OR, 4.46; 95% CI, 1.15-17.3, p = 0.0304) among healthy individuals (N = 2461), the association between HHEX and diabetes was much stronger in male heavy smokers (OR, 4.03; 95% CI, 1.19-13.6, p = 0.0247) than in nonsmokers (p = 0.9709) and ex-smokers (p = 0.2399). The interaction of smoking was also statistically significant (P for interaction =0.0182). CONCLUSIONS: This study clearly demonstrates that a genetic variant in HHEX influences fasting glucose levels in Korean women and male heavy smokers.

Engineering vascularized and innervated bone biomaterials for improved skeletal tissue regeneration.

Blood vessels and nerve fibers are distributed throughout the entirety of skeletal tissue, and play important roles during bone development and fracture healing by supplying oxygen, nutrients, and cells. However, despite the successful development of bone mimetic materials that can replace damaged bone from a structural point of view, most of the available bone biomaterials often do not induce sufficient formation of blood vessels and nerves. In part, this is due to the difficulty of integrating and regulating multiple tissue types within artificial materials, which causes a gap between native skeletal tissue. Therefore, understanding the anatomy and underlying interaction mechanisms of blood vessels and nerve fibers in skeletal tissue is important to develop biomaterials that can recapitulate its complex microenvironment. In this perspective, we highlight the structure and osteogenic functions of the vascular and nervous system in bone, in a coupled manner. In addition, we discuss important design criteria for engineering vascularized, innervated, and neurovascularized bone implant materials, as well as recent advances in the development of such biomaterials. We expect that bone implant materials with neurovascularized networks can more accurately mimic native skeletal tissue and improve the regeneration of bone tissue.

Microfluidic Production of Biodegradable Microcapsules for Sustained Release of Hydrophilic Actives.

Biodegradable microcapsules with a large aqueous lumen and ultrathin membrane are microfluidically designed for sustained release of hydrophilic bioactives using water-in-oil-in-water double-emulsion drops as a template. As a shell phase, an organic solution of poly(lactic-co-glycolic acid) is used, which is consolidated to form a biodegradable membrane. The encapsulants stored in the lumen are released over a long period of time as the membranes degrade. The period can be controlled in a range of -three to five months at neutral pH condition by adjusting membrane thickness, providing highly sustained release and potentially enabling the programed release of multiple drugs. At acidic or basic condition, the degradation is accelerated, leading to the release in the period of approximately two months. As the membrane is semipermeable, the microcapsules respond to the osmotic pressure difference across the membrane. The microcapsules are inflated in hypotonic condition and deflated in hypertonic condition. Both conditions cause cracks on the membrane, resulting in the fast release of encapsulants in a day. The microcapsules implanted in mice also show sustained release, despite the period is decreased to a month. It is believed that the microcapsules are promising for the in vivo sustained release of drugs for high and long-term efficacy.

Controlling Smectic Liquid Crystal Defect Patterns by Physical Stamping-Assisted Domain Separation and Their Use as Templates for Quantum Dot Cluster Arrays.

Controlling the organization of self-assembling building blocks over a large area is crucial for lithographic tools based on the bottom-up approach. However, the fabrication of liquid crystal (LC) defect patterns with a particular ordering still remains a challenge because of the limited close-packed morphologies of LC defects. Here, we introduce a multiple-stamping domain separation method for the control of the dimensions and organization of LC defect structures. Prepatterns with various grid shapes on planar polyimide (PI) surfaces were fabricated by pressing a line-shaped stamp into the PI surfaces in two different directions, and then these surfaces were used to prepare LC defect structures confined to these grid domains. The dimensions of the LC defect structures, namely, the equilibrium diameter and the center to center spacing, are controlled by varying the line spacing of the stamps and the film thickness. A variety of arrangements of LC defects, including square, rhombic, hexagonal, and other oblique lattices, can be obtained by simply varying the stamping angle (Ω) between the first and second stamping directions. Furthermore, we demonstrate that the resulting controllable LC defect arrays can be used as templates for generating various patterns of nanoparticle clusters by trapping quantum dots (QDs) within the cores of the LC defects.

Anisotropic microparticles created by phase separation of polymer blends confined in monodisperse emulsion drops.

Anisotropic microparticles are promising as a new class of colloidal or granular materials due to their advanced functionalities which are difficult to achieve with isotropic particles. However, synthesis of the anisotropic microparticles with a highly controlled size and shape still remains challenging, despite their intense demands. Here, we report a microfluidic approach to create uniform anisotropic microparticles using phase separation of polymer blends confined in emulsion drops. Two different polymers are homogeneously dissolved in organic solvent at low concentration, which is microfluidically emulsified to produce oil-in-water emulsion drops. As the organic solvent diffuses out, small domains are formed in the emulsion drops, which are then merged, forming only two distinct domains. After the drops are fully consolidated, uniform anisotropic microparticles with two compartments are created. The shape of the resulting microparticles is determined by combination of a pair of polymers and type of surfactant. Spherical microparticles with eccentric core and incomplete shell are prepared by consolidation of polystyrene (PS) and poly(lactic acid) (PLA), and microparticles with single crater are formed by consolidation of PS and poly(methyl methacrylate) (PMMA); both emulsions are stabilized with poly(vinyl alcohol) (PVA). With surfactants of triblock copolymer, acorn-shaped Janus microparticles are obtained by consolidating emulsion drops containing PS and PLA. This microfluidic production of anisotropic particles can be further extended to any combination of polymers and colloids to provide a variety of structural and chemical anisotropy.

Osmocapsules for direct measurement of osmotic strength.

Monodisperse microcapsules with ultra-thin membranes are microfluidically designed to be highly sensitive to osmotic pressure, thereby providing a tool for the direct measurement of the osmotic strength. To make such osmocapsules, water-in-oil-in-water double-emulsion drops with ultra-thin shells are prepared as templates through emulsification of core-sheath biphasic flow in a capillary microfluidic device. When photocurable monomers are used as the oil phase, the osmocapsules are prepared by in-situ photopolymerization of the monomers, resulting in semipermeable membranes with a relatively large ratio of membrane thickness to capsule radius, approximately 0.02. These osmocapsules are buckled by the outward flux of water when they are subjected to a positive osmotic pressure difference above 125 kPa. By contrast, evaporation-induced consolidation of middle-phase containing polymers enables the production of osmocapsules with a small ratio of membrane thickness to capsule radius of approximately 0.002. Such an ultra-thin membrane with semi-permeability makes the osmocapsules highly sensitive to osmotic pressure; a positive pressure as small as 12.5 kPa induces buckling of the capsules. By employing a set of distinct osmocapsules confining aqueous solutions with different osmotic strengths, the osmotic strength of unknown solutions can be estimated through observation of the capsules that are selectively buckled. This approach provides the efficient measurement of the osmotic strength using only a very small volume of liquid, thereby providing a useful alternative to other measurement methods which use complex setups. In addition, in-vivo measurement of the osmotic strength can be potentially accomplished by implanting these biocompatible osmocapsules into tissue, which is difficult to achieve using conventional methods.

Combination of phytochemicals, including ginsenoside and curcumin, shows a synergistic effect on the recovery of radiation-induced toxicity.

Radiotherapy is commonly used to treat solid cancers located in the pelvis. A considerable number of patients experience proctitis of varying severity, even for a considerable period after radiotherapy. These side effects are often long-lasting or progressively worsen despite multiple therapeutic efforts and are a primary cause of an unexpectedly low quality of life, even after successful cancer treatment. Therefore, this study evaluated the individual and combined efficacy of ginsenoside, curcumin, butyric acid, and sucralfate compounds in treating radiation-induced proctitis. While the candidate compounds did not affect the proliferation and migration of cancer cells, they promoted the recovery of cell activity, including motility. They exhibited anti-inflammatory effects on human dermal fibroblasts or human umbilical vein endothelial cells within in vitro disease models. When each compound was tested, curcumin and ginsenoside were the most effective in cell recovery and promoted the migration of human dermal fibroblasts and cell restoration of human umbilical vein endothelial cells. The combination of ginsenoside and curcumin resulted in cell migration recovery of approximately 54%. In addition, there was a significant improvement in the length of the endothelial tube, with an increase of approximately 25%, suggesting that the ginsenoside-curcumin-containing combination was the most effective against radiation-induced damage. Furthermore, studies evaluating the effects of combined treatments on activated macrophages indicated that the compounds effectively reduced the secretion of inflammatory cytokines, including chemokines, and alleviated radiation-induced inflammation. In conclusion, our study provides valuable insights into using curcumin and ginsenoside as potential compounds for the effective treatment of radiation-induced injuries and highlights the promising therapeutic benefits of combining these two compounds.

Mesenchymal stem cells enhance CCL8 expression by podocytes in lupus-prone MRL.Faslpr mice.

Nephritis is common in systemic lupus erythematosus patients and is associated with hyper-activation of immune and renal cells. Although mesenchymal stem cells (MSCs) ameliorate nephritis by inhibiting T and B cells, whether MSCs directly affect renal cells is unclear. To address this issue, we examined the direct effect of MSCs on renal cells with a focus on chemokines. We found that expression of CCL2, CCL3, CCL4, CCL5, CCL8, CCL19, and CXCL10 increased 1.6-5.6-fold in the kidney of lupus-prone MRL.Faslpr mice with advancing age from 9 to 16 weeks. Although MSCs inhibited the increase in the expression of most chemokines by 52-95%, they further increased CCL8 expression by 290%. Using renal cells, we next investigated how MSCs enhanced CCL8 expression. CCL8 was expressed by podocytes, but not by tubular cells. MSCs enhanced CCL8 expression by podocytes in a contact-dependent manner, which was proved by transwell assay and blocking with anti-VCAM-1 antibody. Finally, we showed that CCL8 itself activated MSCs to produce more immunosuppressive factors (IL-10, IDO, TGF-ß1, and iNOS) and to inhibit more strongly IFN-γ production by T cells. Taken together, our data demonstrate that MSCs activate podocytes to produce CCL8 in a contact-dependent manner and conversely, podocyte-derived CCL8 might potentiate immunosuppressive activity of MSCs in a paracrine fashion. Our study documents a previously unrecognized therapeutic mechanism of MSCs in nephritis.

Long-term survival benefits of intrathecal autologous bone marrow-derived mesenchymal stem cells (Neuronata-R®: lenzumestrocel) treatment in ALS: Propensity-score-matched control, surveillance study.

Objective: Neuronata-R® (lenzumestrocel) is an autologous bone marrow-derived mesenchymal stem cell (BM-MSC) product, which was conditionally approved by the Korean Ministry of Food and Drug Safety (KMFDS, Republic of Korea) in 2013 for the treatment of amyotrophic lateral sclerosis (ALS). In the present study, we aimed to investigate the long-term survival benefits of treatment with intrathecal lenzumestrocel. Methods: A total of 157 participants who received lenzumestrocel and whose symptom duration was less than 2 years were included in the analysis (BM-MSC group). The survival data of placebo participants from the Pooled-Resource Open-Access ALS Clinical Trials (PROACT) database were used as the external control, and propensity score matching (PSM) was used to reduce confounding biases in baseline characteristics. Adverse events were recorded during the entire follow-up period after the first treatment. Results: Survival probability was significantly higher in the BM-MSC group compared to the external control group from the PROACT database (log-rank, p < 0.001). Multivariate Cox proportional hazard analysis showed a significantly lower hazard ratio for death in the BM-MSC group and indicated that multiple injections were more effective. Additionally, there were no serious adverse drug reactions found during the safety assessment, lasting a year after the first administration. Conclusion: The results of the present study showed that lenzumestrocel treatment had a long-term survival benefit in real-world ALS patients.

Enhancing the quality of life in elderly women through a programme to improve the condition of salivary hypofunction.

OBJECTIVE: The purposes of this study were to examine the effects of oral exercise intended to improve the function of the oral cavity in the elderly and their quality of life to pave the way for the development of oral-health promotion programmes geared towards the elderly. METHODS: The subjects were 78 female Koreans who resided in Seoul and were aged 65 years and older. During a 3-month period, an oral function promotion programme was conducted twice a week, between 10.00 am and 12.00 pm, applying oral exercise suggested by a Japanese public health centre. A survey was conducted by interviewing the selected women to determine the state of their subjective dry mouth, quality of life related to oral health and jaw functional limitation. Their opening, unstimulated whole saliva and pronunciation speed were measured before and after the oral function exercise programme. RESULTS: The subjects showed a significant improvement in subjective dry mouth symptoms, relevant behaviour, the level of discomfort caused by dry mouth and subjective jaw functional limitation during mastication and swallowing and emotional expression after receiving the oral exercise. After the oral exercise, there was a significant increase in mouth opening, unstimulated whole saliva and speaking speed ('patakala' pronunciation) after oral exercise. There was also significant progress in their quality of life related to oral health. Overall improvement in subjective dry mouth symptoms and relevant behaviour over time after oral exercise had a positive correlation with the level of improvement in discomfort triggered by dry mouth and mastication. The level of improvement in OHIP-14 had a positive correlation with the level of overall improvement in dry mouth symptoms and behaviour, the level of improvement in discomfort by dry mouth and that in mastication and swallowing. CONCLUSION: This study showed the effects of the oral function promotion programme and correlation of oral condition and oral health-related quality of life. It is suggested that this oral function promotion programme has positive effects on both objective and subjective oral conditions. It is strongly recommended that this programme, along with other oral health promotion programmes, be implemented to improve oral function and oral health-related quality of life for the elderly.

Efficacy and safety of Lenzumestrocel (Neuronata-R® inj.) in patients with amyotrophic lateral sclerosis (ALSUMMIT study): study protocol for a multicentre, randomized, double-blind, parallel-group, sham procedure-controlled, phase III trial.

BACKGROUND: A single cycle (two repeated treatments) with intrathecal autologous bone marrow-derived mesenchymal stem cells (BM-MSCs, 26-day interval) showed safety and provided therapeutic benefit lasting 6 months in patients with ALS but did not demonstrate long-term efficacy. This phase III clinical trial (ALSUMMIT) protocol was developed to evaluate the long-term efficacy and safety of the combined protocol of single-cycle intrathecal therapy and three additional booster injections of BM-MSC (Lenzumestrocel) treatment in patients with ALS. METHODS: ALSUMMIT is a multicentre, randomized, double-blind, parallel-group, sham procedure-controlled, phase III trial for ALS. The 115 subjects will be randomized (1:2:2) into three groups: (1) study Group 1 (single-cycle, two repeated injections with 26-day interval), (2) study Group 2 (single-cycle + three additional booster injections at 4, 7, and 10 months), and (3) the control group. Participants who have an intermediate rate of disease progression will be included in this trial to reduce clinical heterogeneity. The primary endpoint will be evaluated by combined assessment of function and survival (CAFS), also known as joint rank scores (JRS), at 6 months (study Group 1 vs. control) and 12 months (study Group 2 vs. control) after the first Lenzumestrocel or placebo administration. Safety assessment will be performed throughout the study period. Additionally, after the 56-week main study, a long-term follow-up observational study will be conducted to evaluate the long-term efficacy and safety up to 36 months. DISCUSSION: Lenzumestrocel is the orphan cell therapy product for ALS conditionally approved by the South Korea Ministry of Food and Drug Safety (MFDS). This ALSUMMIT protocol was developed for the adoption of enrichment enrolment, add-on design, and consideration of ethical issues for the placebo group. TRIAL REGISTRATION: ClinicalTrials.gov NCT04745299 . Registered on Feb 9, 2021. Clinical Research Information Service (CRIS) KCT0005954 . Registered on Mar 4, 2021.

Fabrication and Characterization of Graphene Oxide-Coated Plate for Efficient Culture of Stem Cells.

BACKGROUND: For stem cell applications in regenerative medicine, it is very important to produce high-quality stem cells in large quantities in a short time period. Recently, many studies have shown big potential of graphene oxide as a biocompatible substance to enhance cell growth. We investigated if graphene oxide-coated culture plate can promote production efficiency of stem cells. METHODS: Three types of graphene oxide were used for this study. They are highly concentrated graphene oxide solution, single-layer graphene oxide solution, and ultra-highly concentrated single-layer graphene oxide solution with different single-layer ratios, and coated on cell culture plates using a spray coating method. Physiochemical and biological properties of graphene oxide-coated surface were analyzed by atomic force microscope (AFM), scanning electron microscope (SEM), cell counting kit, a live/dead assay kit, and confocal imaging. RESULTS: Graphene oxide was evenly coated on cell culture plates with a roughness of 6.4 ~ 38.2 nm, as measured by SEM and AFM. Young's Modulus value was up to 115.1 GPa, confirming that graphene oxide was strongly glued to the surface. The ex vivo stem cell expansion efficiency was enhanced as bone marrow-derived stem cell doubling time on the graphene oxide decreased compared to the control (no graphene oxide coating), from 64 to 58 h, and the growth rate increased up to 145%. We also observed faster attachment and higher affinity of stem cells to the graphene oxide compared to control by confocal microscope. CONCLUSION: This study demonstrated that graphene oxide dramatically enhanced the ex vivo expansion efficiency of stem cells. Spray coating enabled an ultra-thin coating of graphene oxide on cell culture plates. The results supported that utilization of graphene oxide on culture plates can be a promising mean for mass production of stem cells for commercial applications.

Phase I Trial of Intra-arterial Administration of Autologous Bone Marrow-Derived Mesenchymal Stem Cells in Patients with Multiple System Atrophy.

BACKGROUND: This study is aimed at investigating the safety and tolerability of the intra-arterial administration of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) in patients with multiple system atrophy- (MSA-) cerebellar type (MSA-C). METHODS: This was a single-center, open-label phase I clinical trial in patients with MSA-C. A three-stage dose escalation scheme (low-dose, 3.0 × 105 cells/kg; medium-dose, 6.0 × 105 cells/kg; high-dose, 9.0 × 105 cells/kg) was applied to determine the maximum tolerated dose of intra-arterial administration of BM-MSCs based on the no-observed-adverse-effect level derived from the toxicity study. The occurrence of adverse events was evaluated 1 day before and 1, 14, and 28 days after BM-MSC therapy. Additionally, we assessed changes in the Unified MSA Rating Scale (UMSARS) score 3 months after BM-MSC treatment. RESULTS: One serious adverse drug reaction (ADR) of leptomeningeal enhancement following the intra-arterial BM-MSC administration occurred in one patient in the low-dose group. The safety review of the Internal Monitoring Committee interpreted this as radiological evidence of the blood-brain barrier permeability for MSCs. No other ADRs were observed in the medium- or high-dose groups. In particular, no ischemic lesions on diffusion-weighted images were observed in any of the study participants. Additionally, the medium- and high-dose groups tended to show a slower increase in UMSARS scores than the low-dose group during the 3-month follow-up. CONCLUSION: The present study confirmed that a single intra-arterial administration of autologous BM-MSCs is a safe and promising neuroprotective strategy in patients with MSA-C.

Mapping thalamocortical functional connectivity with large-scale brain networks in patients with first-episode psychosis.

Abnormal thalamocortical networks involving specific thalamic nuclei have been implicated in schizophrenia pathophysiology. While comparable topography of anatomical and functional connectivity abnormalities has been reported in patients across illness stages, previous functional studies have been confined to anatomical pathways of thalamocortical networks. To address this issue, we incorporated large-scale brain network dynamics into examining thalamocortical functional connectivity. Forty patients with first-episode psychosis and forty healthy controls underwent T1-weighted and resting-state functional magnetic resonance imaging. Independent component analysis of voxelwise thalamic functional connectivity maps parcellated the cortex into thalamus-related networks, and thalamic subdivisions associated with these networks were delineated. Functional connectivity of (1) networks with the thalamus and (2) thalamic subdivision seeds were examined. In patients, functional connectivity of the salience network with the thalamus was decreased and localized to the ventrolateral (VL) and ventroposterior (VP) thalamus, while that of a network comprising the cerebellum, temporal and parietal regions was increased and localized to the mediodorsal (MD) thalamus. In patients, thalamic subdivision encompassing the VL and VP thalamus demonstrated hypoconnectivity and that encompassing the MD and pulvinar regions demonstrated hyperconnectivity. Our results extend the implications of disrupted thalamocortical networks involving specific thalamic nuclei to dysfunctional large-scale brain network dynamics in schizophrenia pathophysiology.

Optimal waist circumference cutoff values for metabolic syndrome diagnostic criteria in a Korean rural population.

The Korean Society for the Study of Obesity (KSSO) has defined the waist circumference cutoff value of central obesity as 90 cm for men and 85 cm for women. The purpose of this investigation was to determine the corresponding waist circumference values. A total of 3,508 persons in the Korean Rural Genomic Cohort Study were enrolled in this survey. Receiver operating characteristic (ROC) curve analysis was used to find appropriate waist circumference cutoff values in relation to insulin resistance determined by homeostasis model assessment for insulin resistance (HOMA-IR), body mass index (BMI), and components of metabolic syndrome. The optimal waist circumference cutoff values were 87 cm for men and 83 cm for women by ROC analysis to HOMA-IR and 86 cm for men and 83 cm for women by ROC analysis to value with more than two components of metaobolic syndrome. By using a BMI > or =25 kg/m(2), 86 cm for men and 82 cm for women were optimal waist circumference cutoff values. In this study, we suggest that the most reasonable waist circumference cutoff values are 86-87 cm for men and 82-83 cm for women.

Effect of Human Mesenchymal Stem Cells on Xenogeneic T and B Cells Isolated from Lupus-Prone MRL.Fas lpr Mice.

Systemic lupus erythematosus (SLE) is an autoimmune disease, which is characterized by hyperactivation of T and B cells. Human mesenchymal stem cells (hMSCs) ameliorate the progression of SLE in preclinical studies using lupus-prone MRL.Fas lpr mice. However, whether hMSCs inhibit the functions of xenogeneic mouse T and B cells is not clear. To address this issue, we examined the in vitro effects of hMSCs on T and B cells isolated from MRL.Fas lpr mice. Naïve hMSCs inhibited the functions of T cells but not B cells. hMSCs preconditioned with IFN-γ (i) inhibited the proliferation of and IgM production by B cells, (ii) attracted B cells for cell-cell interactions in a CXCL10-dependent manner, and (iii) inhibited B cells by producing indoleamine 2,3-dioxygenase. In summary, our data demonstrate that hMSCs exert therapeutic activity in mice in three steps: first, naïve hMSCs inhibit the functions of T cells, hMSCs are then activated by IFN-γ, and finally, they inhibit B cells.

Therapeutic Effects of Human Mesenchymal Stem Cells in a Mouse Model of Cerebellar Ataxia with Neuroinflammation.

Cerebellar ataxias (CAs) are neurological diseases characterized by loss of muscle coordination that is a result of damage and inflammation to the cerebellum. Despite considerable efforts in basic and clinical research, most CAs are currently incurable. In this study, we evaluated the therapeutic potential of human mesenchymal stem cells (hMSCs) against CAs associated with neuroinflammation. We observed that hMSC treatment significantly inhibited the symptoms of ataxia in lipopolysaccharide (LPS)-induced inflammatory CA (ICA) mice, which were recently reported as a potential animal model of ICA, through the anti-inflammatory effect of hMSC-derived TNFα-stimulated gene-6 (TSG-6), the protection of Purkinje cells by inhibition of apoptosis, and the modulatory effect for microglial M2 polarization. Thus, our results suggest that hMSC treatment may be an effective therapeutic approach for preventing or improving ataxia symptoms.

Lipopolysaccharide administration for a mouse model of cerebellar ataxia with neuroinflammation.

Most cerebellar ataxias (CAs) are incurable neurological disorders, resulting in a lack of voluntary control by inflamed or damaged cerebellum. Although CA can be either directly or indirectly related to cerebellar inflammation, there is no suitable animal model of CA with neuroinflammation. In this study, we evaluated the utility of an intracerebellar injection of lipopolysaccharide (LPS) to generate an animal model of inflammatory CA. We observed that LPS administration induced the expression of pro-inflammatory molecules following activation of glial cells. In addition, the administration of LPS resulted in apoptotic Purkinje cell death and induced abnormal locomotor activities, such as impaired motor coordination and abnormal hindlimb clasping posture. Our results suggest that intracerebellar LPS administration in experimental animals may be useful for studying the inflammatory component of CA.

Characterization of Mesenchymal Stem Cells Derived from Patients with Cerebellar Ataxia: Downregulation of the Anti-Inflammatory Secretome Profile.

Mesenchymal stem cell (MSC) therapy is a promising alternative approach for the treatment of neurodegenerative diseases, according to its neuroprotective and immunomodulatory potential. Despite numerous clinical trials involving autologous MSCs, their outcomes have often been unsuccessful. Several reports have indicated that MSCs from patients have low capacities in terms of the secretion of neurotrophic or anti-inflammatory factors, which might be associated with cell senescence or disease severity. Therefore, a new strategy to improve their capacities is required for optimal efficacy of autologous MSC therapy. In this study, we compared the secretory potential of MSCs among cerebellar ataxia patients (CA-MSCs) and healthy individuals (H-MSCs). Our results, including secretome analysis findings, revealed that CA-MSCs have lower capacities in terms of proliferation, oxidative stress response, motility, and immunomodulatory functions when compared with H-MSCs. The functional differences were validated in a scratch wound healing assay and neuron-glia co-cultures. In addition, the neuroprotective and immunoregulatory protein follistatin-like 1 (FSTL1) was identified as one of the downregulated proteins in the CA-MSC secretome, with suppressive effects on proinflammatory microglial activation. Our study findings suggest that targeting aspects of the downregulated anti-inflammatory secretome, such as FSTL1, might improve the efficacy of autologous MSC therapy for CA.