A method for selecting the optimal warping path of dynamic time warping in gait analysis.

This study aims to demonstrate that when performing dynamic time warping (DTW) on gait data, multiple optimal warping paths (OWPs) with a minimum sum of local costs can occur and to propose an additional OWP selection method to address this problem. A 3-dimensional motion analysis experiment was conducted on 55 adult participants, including both males and females, to acquire gait data. This study analyzed 990 instances of DTW on gait data to examine the occurrence of multiple OWPs with the minimum sum of local costs. We subsequently applied an additional selection method to the multiple OWPs to determine the feasibility of identifying a single OWP. Multiple OWPs through DTW were observed 82 times, accounting for 8.28%. Notably, on the ankle joint of males, the rate was the highest at 11.11%. Cases with two multiple OWPs were the most prevalent at 56.10%, and cases with ten or more multiple OWPs accounted for 19.51%. The additional selection method proposed in this study was applied to the 82 instances in which multiple OWPs occurred. The results demonstrated the ability to identify a unique OWP in all cases. These results hold significance in identifying the shortcomings of conventional OWP selection methods previously employed and proposing solutions. It enhances the reliability, validity, and accuracy of studies utilizing DTW.

Normalization and possibility of classification analysis using the optimal warping paths of dynamic time warping in gait analysis.

The purpose of this study was to verify classification performance and the difference analysis between gender using optimal warping paths of dynamic time warping (DTW) and to examine the usefulness of root mean square error (RMSE) represented by the perpendicular distance from the optimal warping path to the diagonal. A 3-dimensional motion analysis experiment was performed with 24 healthy adults (male=12, female=12) in their 20s of age without gait-related diseases or injuries for the past 6 months to collect gait data. This study performed a DTW 132 times in total (male=62, female=62) for the flexion angle of the right leg's hip, knee, and ankle joints. Then, the global cost and the RMSE of the optimal warping paths were calculated and normalized. The difference analysis was performed by independent t-test. Machine learning was performed to test the classification performance using the neural network, support vector machine, and logistic regression model among the supervised models. Results analyzed using global cost and RMSE for hip, knee, and ankle joints showed a statistically significant difference between genders in global cost and RMSE for hip and knee joints but not for ankle joints using RMSE. Considering both area under the receiver operating characteristic curve and F1-score, the logistic regression model has been evaluated as the most suitable for gender classification using the global cost or RMSE. This study demonstrated that optimal warping paths could be used for statistical difference analysis and classification analysis.

Household-specific physical activity levels and energy intakes according to the presence of metabolic syndrome in Korean young adults: Korean National Health and nutrition examination survey 2016-2018.

BACKGROUND: Participation in exercise, and dietary and nutritional intakes have an impact on the risk and prevalence of metabolic syndrome (MetS), but these effects may differ according to whether a person lives alone or in a multi-person household. We analyzed differences in physical activity (PA) levels and energy intake according to household-type and MetS presence among young adults, to investigate the relationships among these factors. METHODS: Data of 3974 young adults (aged > 19 years and < 40 years) were obtained from the Korean National Health and Nutrition Examination Survey (2016-2018). We analyzed PA levels (occupational and recreational PA, and transport) and energy intake (total, carbohydrate, protein, and fat). RESULTS: Logistic regression data showed that low PA levels and higher energy intake were associated with MetS incidence and its components in young adults, after adjusting for body mass index, smoking, household-type, and sex. Overall, there was no significant difference in PA level between the MetS and non-MetS group. The total energy intake was higher in the MetS than in the non-MetS group (p <  0.05). These results were similar to those found in multi-person households. In single-person households, the MetS group had significantly lower PA levels (p <  0.01) and total energy intake (p <  0.05) than the non-MetS group. CONCLUSIONS: We found significant association among low PA levels, high energy intake, and MetS components in young Korean adults, but with patterns differing according to household type. Energy intake was higher in young adults with than those without MetS, who lived in multi-person households, while young adults with MetS who lived alone had lower PA levels and lower energy intake than those without MetS. These findings highlight the need for different approaches of implementing PA and nutrition strategies according to the type of household in order to prevent MetS.

Neural stem cells derived from human midbrain organoids as a stable source for treating Parkinson's disease: Midbrain organoid-NSCs (Og-NSC) as a stable source for PD treatment.

Successful clinical translation of stem cell-based therapy largely relies on the scalable and reproducible preparation of donor cells with potent therapeutic capacities. In this study, midbrain organoids were yielded from human pluripotent stem cells (hPSCs) to prepare cells for Parkinson's disease (PD) therapy. Neural stem/precursor cells (NSCs) isolated from midbrain organoids (Og-NSCs) expanded stably and differentiated into midbrain-type dopamine(mDA) neurons, and an unprecedentedly high proportion expressed midbrain-specific factors, with relatively low cell line and batch-to-batch variations. Single cell transcriptome analysis followed by in vitro assays indicated that the majority of cells in the Og-NSC cultures are ventral midbrain (VM)-patterned with low levels of cellular senescence/aging and mitochondrial stress, compared to those derived from 2D-culture environments. Notably, in contrast to current methods yielding mDA neurons without astrocyte differentiation, mDA neurons that differentiated from Og-NSCs were interspersed with astrocytes as in the physiologic brain environment. Thus, the Og-NSC-derived mDA neurons exhibited improved synaptic maturity, functionality, resistance to toxic insults, and faithful expressions of the midbrain-specific factors, in vitro and in vivo long after transplantation. Consequently, Og-NSC transplantation yielded potent therapeutic outcomes that are reproducible in PD model animals. Collectively, our observations demonstrate that the organoid-based method may satisfy the demands needed in the clinical setting of PD cell therapy.

Whole-exome sequencing in 168 Korean patients with inherited retinal degeneration.

BACKGROUND: To date, no genetic analysis of inherited retinal disease (IRD) using whole-exome sequencing (WES) has been conducted in a large-scale Korean cohort. The aim of this study was to characterise the genetic profile of IRD patients in Korea using WES. METHODS: We performed comprehensive molecular testing in 168 unrelated Korean IRD patients using WES. The potential pathogenicity of candidate variants was assessed using the American College of Medical Genetics and Genomics and the Association for Molecular Pathology variant interpretation guidelines, in silico prediction tools, published literature, and compatibility with known phenotypes or inheritance patterns. RESULTS: Causative variants were detected in 86/168 (51.2%) IRD patients, including 58/107 (54.2%) with retinitis pigmentosa, 7/15 (46.7%) with cone and cone-rod dystrophy, 2/3 (66.6%) with Usher syndrome, 1/2 (50.0%) with congenital stationary night blindness, 2/2 (100.0%) with Leber congenital amaurosis, 1/1 (100.0%) with Bietti crystalline dystrophy, 1/1 (100.0%) with Joubert syndrome, 9/10 (90.0%) with Stargardt macular dystrophy, 1/10 (10.0%) with vitelliform macular dystrophy, 1/11 (9.1%) with other forms of macular dystrophy, and 3/4 (75.0%) with choroideraemia. USH2A, ABCA4, and EYS were the most common causative genes associated with IRD. For retinitis pigmentosa, variants of USH2A and EYS were the most common causative gene mutations. CONCLUSIONS: This study demonstrated the distribution of causative genetic mutations in Korean IRD patients. The data will serve as a reference for future genetic screening and development of treatment modalities for Korean IRD patients.

Analysis of gait pattern between genders in Korean old people and the effect of dimensionless numbers.

The purpose of this study was to comparatively analyze normal gait on the plains by gender for old people reference data for the normal gait pattern for the old people. Participants were selected according to the Korean standard body type provided by the Ministry of Health and Welfare and used a three-dimensional motion analysis system. Cortex, Orthotrak, and Excel were used as the software for analyzing the extracted data, and IBM SPSS Statistics ver. 24.0 was used for statistical analysis. When data standardization was performed using the dimensionless numbers conversion, the step length and stride length of the lower extremities, which had differences between genders before dimensionless numbers conversion, showed no difference after dimensionless numbers conversion. Cadence, step time, and single support time of the left lower extremity, which had no difference between genders before dimensionless numbers conversion, were found to have significant differences after dimensionless numbers conversion. In addition, as a result of analyzing the coefficient of variation value to find out the degree of change in data due to dimensionless numbers conversion, there were increase and decrease in the coefficient of variation value ranging from -8.11% to 6.67% before and after dimensionless numbers conversion, which means dimensionless numbers conversion can affect the statistical test.

Beneficial Effect of Chloroquine and Amodiaquine on Type 1 Diabetic Tubulopathy by Attenuating Mitochondrial Nox4 and Endoplasmic Reticulum Stress.

BACKGROUND: Oxidative stress induced by chronic hyperglycemia is recognized as a significant mechanistic contributor to the development of diabetic kidney disease (DKD). Nonphagocytic nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) is a major source of reactive oxygen species (ROS) in many cell types and in the kidney tissue of diabetic animals. We designed this study to explore the therapeutic potential of chloroquine (CQ) and amodiaquine (AQ) for inhibiting mitochondrial Nox4 and diabetic tubular injury. METHODS: Human renal proximal tubular epithelial cells (hRPTCs) were cultured in high-glucose media (30 mM D-glucose), and diabetes was induced with streptozotocin (STZ, 50 mg/kg i.p. for 5 days) in male C57BL/6J mice. CQ and AQ were administered to the mice via intraperitoneal injection for 14 weeks. RESULTS: CQ and AQ inhibited mitochondrial Nox4 and increased mitochondrial mass in hRPTCs under high-glucose conditions. Reduced mitochondrial ROS production after treatment with the drugs resulted in decreased endoplasmic reticulum (ER) stress, suppressed inflammatory protein expression and reduced cell apoptosis in hRPTCs under high-glucose conditions. Notably, CQ and AQ treatment diminished Nox4 activation and ER stress in the kidneys of STZ-induced diabetic mice. In addition, we observed attenuated inflammatory protein expression and albuminuria in STZ-induced diabetic mice after CQ and AQ treatment. CONCLUSION: We substantiated the protective actions of CQ and AQ in diabetic tubulopathy associated with reduced mitochondrial Nox4 activation and ER stress alleviation. Further studies exploring the roles of mitochondrial Nox4 in the pathogenesis of DKD could suggest new therapeutic targets for patients with DKD.

Author Correction: Genetic Characteristics of Korean Patients with Autosomal Dominant Polycystic Kidney Disease by Targeted Exome Sequencing.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

NFATc1+CD31+CD45- circulating multipotent stem cells derived from human endocardium and their therapeutic potential.

Many studies have shown the existence of cardiac stem cells in the myocardium and epicardial progenitor cells in the epicardium. However, the characteristics of stem cells in the endocardium has not been fully elucidated. In this study, we investigated the origin of newly identified cells in the blood and their therapeutic potential. The new population of cells, identified from human peripheral blood, was quite different from previously reported stem cells. These newly identified cells, which we named Circulating Multipotent Stem (CiMS) cells, were multipotent, and therefore differentiated into multiple lineages in vitro and in vivo. In order to determine the origin of these cells, we collected peripheral blood from a group of patients who underwent bone marrow, liver, heart, or kidney transplantation. We identified the endocardium as the origin of these cells because the Short Tandem Repeat profile of CiMS cells from the recipient had changed from the recipient's profile to the donor's profile after heart transplantation. CiMS cells significantly increased after stimuli to the endocardium, such as catheter ablation for arrhythmia or acute myocardial infarction. CiMS cells circulate in human peripheral blood and are easily obtainable, suggesting that these cells could be a promising tool for cell therapy.

Genetic Characteristics of Korean Patients with Autosomal Dominant Polycystic Kidney Disease by Targeted Exome Sequencing.

Autosomal dominant polycystic kidney disease (ADPKD) is one of the main causes of end-stage renal disease (ESRD). Genetic information is of the utmost importance in understanding pathogenesis of ADPKD. Therefore, this study aimed to demonstrate the genetic characteristics of ADPKD and their effects on renal function in 749 Korean ADPKD subjects from 524 unrelated families. Genetic studies of PKD1/2 were performed using targeted exome sequencing combined with Sanger sequencing in exon 1 of the PKD1 gene and a multiple ligation probe assay. The mutation detection rate was 80.7% (423/524 families, 331 mutations) and 70.7% was novel. PKD1 protein-truncating (PKD1-PT) genotype was associated with younger age at diagnosis, larger kidney volume, lower renal function compared to PKD1 non-truncating and PKD2 genotypes. The PKD1 genotype showed earlier onset of ESRD compared to PKD2 genotype (64.9 vs. 72.9 years old, P < 0.001). In frailty model controlled for age, gender, and familial clustering effect, PKD2 genotype had 0.2 times lower risk for reaching ESRD than PKD1-PT genotype (p = 0.037). In conclusion, our results suggest that genotyping can contribute to selecting rapid progressors for new emerging therapeutic interventions among Koreans.

LIN28A loss of function is associated with Parkinson's disease pathogenesis.

Parkinson's disease (PD) is neurodegenerative movement disorder characterized by degeneration of midbrain-type dopamine (mDA) neurons in the substantia nigra (SN). The RNA-binding protein Lin28 plays a role in neuronal stem cell development and neuronal differentiation. In this study, we reveal that Lin28 conditional knockout (cKO) mice show degeneration of mDA neurons in the SN, as well as PD-related behavioral deficits. We identify a loss-of-function variant of LIN28A (R192G substitution) in two early-onset PD patients. Using an isogenic human embryonic stem cell (hESC)/human induced pluripotent stem cell (hiPSC)-based disease model, we find that the Lin28 R192G variant leads to developmental defects and PD-related phenotypes in mDA neuronal cells that can be rescued by expression of wild-type Lin28A. Cell transplantation experiments in PD model rats show that correction of the LIN28A variant in the donor patient (pt)-hiPSCs leads to improved behavioral phenotypes. Our data link LIN28A to PD pathogenesis and suggest future personalized medicine targeting this variant in patients.

Targeted next-generation DNA sequencing identifies Notch signaling pathway mutation as a predictor of radiation response.

Purpose: Identifying the association between somatic mutations and the radiation response of tumor is essential for understanding the mechanisms and practicing personalized radiotherapy. The present study aimed to discover specific genes or pathways that are associated with radiation response using targeted next-generation DNA sequencing.Material and methods: Fifty-five patients with various solid tumors whose specimen were sequenced using institutional panel which includes 148 cancer-related genes and received radiotherapy for a measurable tumor were analyzed. Patients with irradiated tumors in complete or partial remission for more than 6 months were defined as responders. Association between mutations including pathogenic single nucleotide variants and insertions/deletions in the 148 genes and 39 molecular pathways and radiation response was investigated.Results: Analyzing 17 responders and 38 non-responders, biologically effective dose (BED), but not concurrent chemotherapy, was associated with radiation response. No single gene correlated with radiation response. Mutations in Notch signaling pathway were associated with radiosensitivity after correction for multiple comparison (adjusted p = .094). When BED and Notch signaling pathway mutation were tested with logistic regression, both variables were associated with radiation response.Conclusions: Our results suggest that somatic mutations in Notch signaling pathway may be related to sensitivity to radiation, although these results should be validated in a larger and more homogeneous cohort.

Application of dynamic time warping algorithm for pattern similarity of gait.

The purpose of this study was to investigate the effectiveness of dynamic time warping (DTW) in gait research. Participants in this study were consist of 10 males and 10 females. Equipment used for collecting the gait data of participants in this study was three-dimensional (3D) motion analysis system consisted of 8 infrared CCD cameras operated with a sampling frequency of 120 frames/sec. DTW program used in this study was made using the MATLAB and the normal operation of the DTW program was verified by comparison of result manually calculated and output by the DTW program. Flexion angle of the knee joint of both feet obtained by 3D motion analysis system was analyzed by the DTW program and symmetry index (SI) equation. Statistical analysis of the values obtained by DTW was performed by one-sample t-test in confidence interval (CI) 99%, 95%, 90%, 85%, and 80% each using the SPSS. The subjects' left and right legs were compared 20 times, and other steps of the same foot were compared 20 times. In this study, DTW showed different results from SI which is generally used to test the similarity of gait. Compared to that of DTW, the threshold figure for similarity evaluation in SI, 10%, is considered too large/high. When the CI threshold figure of 95% was adopted in statistical analysis, DTW demonstrated a lower rate of judging two sequences as similar even in the case of normal gait. This study suggests that DTW can be used for the similarity test of gait research.

Preischemic treadmill exercise improves short-term memory by inhibiting hypoperfusion-induced disruption of blood-brain barrier after bilateral common carotid arteries occlusion.

Bilateral common carotid arteries occlusion (BCCAO) causes an abrupt reduction of cerebral blood flow, and this method has been used to investigate the effects of chronic cerebral hypoperfusion on vascular dementia and neuronal injuries. Chronic cerebral hypoperfusion leads to functional changes in the hippocampus and then results in a cognitive impairment. We investigated the effect of preischemic treadmill exercise on short-term memory and blood-brain barrier integration following cerebral hypoperfusion caused by BCCAO. The rats in the preischemic treadmill exercise and BCCAO group were made to run on a treadmill for 30 min once a day for 4 weeks. At 4 weeks after performing treadmill exercise, right carotid artery was ligated, and 1 week after, left common carotid artery was ligated. At 20 days after BCCAO, short-term memory was evaluated. Half of the rats were sacrificed 2 days after BCCAO and the other rats were sacrificed at 3 weeks after BCCAO. Immunohistochemistry and western blot were performed. Preischemic treadmill exercise alleviated impairment of short-term memory in the step-down avoidance task. Preischemic treadmill exercise reduced microvascular injury in the hippocampus. Preischemic treadmill exercise prevented the reduction of zonula occludens-1 in the hippocampus and inhibited the activation of matrix metalloproteinase-9. Therefore, pre-conditioning treadmill exercise might be used as a therapeutic strategy for the prevention of stroke in patients.

Expression and secretion of CXCL12 are enhanced in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD), one of the most common human monogenic diseases (frequency of 1/1000-1/400), is characterized by numerous fluid-filled renal cysts (RCs). Inactivation of the PKD1 or PKD2 gene by germline and somatic mutations is necessary for cyst formation in ADPKD. To mechanistically understand cyst formation and growth, we isolated RCs from Korean patients with ADPKD and immortalized them with human telomerase reverse transcriptase (hTERT). Three hTERT-immortalized RC cell lines were characterized as proximal epithelial cells with germline and somatic PKD1 mutations. Thus, we first established hTERT-immortalized proximal cyst cells with somatic PKD1 mutations. Through transcriptome sequencing and Gene Ontology (GO) analysis, we found that upregulated genes were related to cell division and that downregulated genes were related to cell differentiation. We wondered whether the upregulated gene for the chemokine CXCL12 is related to the mTOR signaling pathway in cyst growth in ADPKD. CXCL12 mRNA expression and secretion were increased in RC cell lines. We then examined CXCL12 levels in RC fluids from patients with ADPKD and found increased CXCL12 levels. The CXCL12 receptor CXC chemokine receptor 4 (CXCR4) was upregulated, and the mTOR signaling pathway, which is downstream of the CXCL12/CXCR4 axis, was activated in ADPKD kidney tissue. To confirm activation of the mTOR signaling pathway by CXCL12 via CXCR4, we treated the RC cell lines with recombinant CXCL12 and the CXCR4 antagonist AMD3100; CXCL12 induced the mTOR signaling pathway, but the CXCR4 antagonist AMD3100 blocked the mTOR signaling pathway. Taken together, these results suggest that enhanced CXCL12 in RC fluids activates the mTOR signaling pathway via CXCR4 in ADPKD cyst growth. [BMB Reports 2019; 52(7): 463-468].

MRPrimerW2: an enhanced tool for rapid design of valid high-quality primers with multiple search modes for qPCR experiments.

For the best results in quantitative polymerase chain reaction (qPCR) experiments, it is essential to design high-quality primers considering a multitude of constraints and the purpose of experiments. The constraints include many filtering constraints, homology test on a huge number of off-target sequences, the same constraints for batch design of primers, exon spanning, and avoiding single nucleotide polymorphism (SNP) sites. The target sequences are either in database or given as FASTA sequences, and the experiment is for amplifying either each target sequence with each corresponding primer pairs designed under the same constraints or all target sequences with a single pair of primers. Many websites have been proposed, but none of them including our previous MRPrimerW fulfilled all the above features. Here, we describe the MRPrimerW2, the update version of MRPrimerW, which fulfils all the features by maintaining the advantages of MRPrimerW in terms of the kinds and sizes of databases for valid primers and the number of search modes. To achieve it, we exploited GPU computation and a disk-based key-value store using PCIe SSD. The complete set of 3 509 244 680 valid primers of MRPrimerW2 covers 99% of nine important organisms in an exhaustive manner. Free access: http://MRPrimerW2.com.

Activities of ankle muscles during gait analyzed by simulation using the human musculoskeletal model.

The purpose of this study was to analyze the activity of ankle muscles during normal gait by simulation method using the human musculoskeletal model. The equipment used in this study was three-dimensional motion capture system and force platform, and OpenSim was used for simulation. Collected data was scaled to Gait2392 that is the human musculoskeletal simulation model using in the OpenSim. Tibialis anterior (TA) worked as a major muscle during gait, producing a higher force than other muscles. Main muscles contributing to propulsion were gastrocnemius medial head (GMH) and soleus (SOL) with their maximum forces appear to be more than 1.5 times the body weight. GMH and SOL showed cooperation for maintaining propulsion around left foot initial contact in the gait cycle. This study has shown a difference between activation and force pattern. The peak-activation of the TA and extensor digitorum longus (EDL) was similarly shown to be around 0.8 in the initial double stance, but the peak-force produced by these muscles in the same period showed a difference with 0.4 Newton/body weight higher in TA than in EDL. We suggest that when assessing muscle contribution to gait, it would be reasonable to consider the force generated because the human movement was generated by the mechanical net force of muscles.

Molecular Characterization and Putative Pathogenic Pathways of Tuberous Sclerosis Complex-Associated Renal Cell Carcinoma.

Tuberous sclerosis complex-associated renal cell carcinoma (TSC-RCC) has distinct clinical and histopathologic features and is considered a specific subtype of RCC. The genetic alterations of TSC1 or TSC2 are responsible for the development of TSC. In this study, we assessed the mTOR pathway activation and aimed to evaluate molecular characteristics and pathogenic pathways of TSC-RCC. Two cases of TSC-RCC, one from a 31-year-old female and the other from an 8-year-old male, were assessed. The mTOR pathway activation was determined by immunohistochemistry. The mutational spectrum of both TSC-RCCs was evaluated by whole exome sequencing (WES), and pathogenic pathways were analyzed. Differentially expressed genes were analyzed by NanoString Technologies nCounter platform. The mTOR pathway activation and the germline mutations of TSC2 were identified in both TSC-RCC cases. The WES revealed several cancer gene alterations. In Case 1, genetic alterations of CHD8, CRISPLD1, EPB41L4A, GNA11, NOTCH3, PBRM1, PTPRU, RGS12, SETBP1, SMARCA4, STMN1, and ZNRF3 were identified. In Case 2, genetic alterations of IWS1 and TSC2 were identified. Further, putative pathogenic pathways included chromatin remodeling, G protein-coupled receptor, Notch signaling, Wnt/ß-catenin, PP2A and the microtubule dynamics pathway in Case 1, and mRNA processing and the PI3K/AKT/mTOR pathway in Case 2. Additionally, the ALK and CRLF2 mRNA expression was upregulated and CDH1, MAP3K1, RUNX1, SETBP1, and TSC1 mRNA expression was downregulated in both TSC-RCCs. We present mTOR pathway activation and molecular characteristics with pathogenic pathways in TSC-RCCs, which will advance our understanding of the pathogenesis of TSC-RCC.

Dual Effects of Human Placenta-Derived Neural Cells on Neuroprotection and the Inhibition of Neuroinflammation in a Rodent Model of Parkinson's Disease.

Parkinson's disease (PD) is the second most common age-related neurodegenerative disease in the elderly and the patients suffer from uncontrolled movement disorders due to loss of dopaminergic (DA) neurons on substantia nigra pars compacta (SNpc). We previously reported that transplantation of human fetal midbrain-derived neural precursor cells restored the functional deficits of a 6-hydroxy dopamine (6-OHDA)-treated rodent model of PD but its low viability and ethical issues still remain to be solved. Albeit immune privilege and neural differentiation potentials suggest mesenchymal stem cells (MSCs) from various tissues including human placenta MSCs (hpMSCs) for an alternative source, our understanding of their therapeutic mechanisms is still limited. To expand our knowledge on the MSC-mediated PD treatment, we here investigated the therapeutic mechanism of hpMSCs and hpMSC-derived neural phenotype cells (hpNPCs) using a PD rat model. Whereas both hpMSCs and hpNPCs protected DA neurons in the SNpc at comparable levels, the hpNPC transplantation into 6-OHDA treated rats exhibited longer lasting recovery in motor deficits than either the saline or the hpMSC treated rats. The injected hpNPCs induced delta-like ligand (DLL)1 and neurotrophic factors, and influenced environments prone to neuroprotection. Compared with hpMSCs, co-cultured hpNPCs more efficiently protected primary neural precursor cells from midbrain against 6-OHDA as well as induced their differentiation into DA neurons. Further experiments with conditioned media from hpNPCs revealed that the secreted factors from hpNPCs modulated immune responses and neural protection. Taken together, both DLL1-mediated contact signals and paracrine factors play critical roles in hpNPC-mediated improvement. First showing here that hpMSCs and their neural derivative hpNPCs were able to restore the PD-associated deficits via dual mechanisms, neuroprotection and immunosuppression, this study expanded our knowledge of therapeutic mechanisms in PD and other age-related diseases.

Cografting astrocytes improves cell therapeutic outcomes in a Parkinson's disease model.

Transplantation of neural progenitor cells (NPCs) is a potential therapy for treating neurodegenerative disorders, but this approach has faced many challenges and limited success, primarily because of inhospitable host brain environments that interfere with enriched neuron engraftment and function. Astrocytes play neurotrophic roles in the developing and adult brain, making them potential candidates for helping with modification of hostile brain environments. In this study, we examined whether astrocytic function could be utilized to overcome the current limitations of cell-based therapies in a murine model of Parkinson's disease (PD) that is characterized by dopamine (DA) neuron degeneration in the midbrain. We show here that cografting astrocytes, especially those derived from the midbrain, remarkably enhanced NPC-based cell therapeutic outcomes along with robust DA neuron engraftment in PD rats for at least 6 months after transplantation. We further show that engineering of donor astrocytes with Nurr1 and Foxa2, transcription factors that were recently reported to polarize harmful immunogenic glia into the neuroprotective form, further promoted the neurotrophic actions of grafted astrocytes in the cell therapeutic approach. Collectively, these findings suggest that cografting astrocytes could be a potential strategy for successful cell therapeutic outcomes in neurodegenerative disorders.