Advances in iPSC Technology in Neural Disease Modeling, Drug Screening, and Therapy.

Neurodegenerative disorders (NDs) including Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis (ALS), and Huntington's disease are all incurable and can only be managed with drugs for the associated symptoms. Animal models of human illnesses help to advance our understanding of the pathogenic processes of diseases. Understanding the pathogenesis as well as drug screening using appropriate disease models of neurodegenerative diseases (NDs) are vital for identifying novel therapies. Human-derived induced pluripotent stem cell (iPSC) models can be an efficient model to create disease in a dish and thereby can proceed with drug screening and identifying appropriate drugs. This technology has many benefits, including efficient reprogramming and regeneration potential, multidirectional differentiation, and the lack of ethical concerns, which open up new avenues for studying neurological illnesses in greater depth. The review mainly focuses on the use of iPSC technology in neuronal disease modeling, drug screening, and cell therapy.

The role of smart polymeric biomaterials in bone regeneration: a review.

Addressing critical bone defects necessitates innovative solutions beyond traditional methods, which are constrained by issues such as immune rejection and donor scarcity. Smart polymeric biomaterials that respond to external stimuli have emerged as a promising alternative, fostering endogenous bone regeneration. Light-responsive polymers, employed in 3D-printed scaffolds and photothermal therapies, enhance antibacterial efficiency and bone repair. Thermo-responsive biomaterials show promise in controlled bioactive agent release, stimulating osteocyte differentiation and bone regeneration. Further, the integration of conductive elements into polymers improves electrical signal transmission, influencing cellular behavior positively. Innovations include advanced 3D-printed poly (l-lactic acid) scaffolds, polyurethane foam scaffolds promoting cell differentiation, and responsive polymeric biomaterials for osteogenic and antibacterial drug delivery. Other developments focus on enzyme-responsive and redox-responsive polymers, which offer potential for bone regeneration and combat infection. Biomaterials responsive to mechanical, magnetic, and acoustic stimuli also show potential in bone regeneration, including mechanically-responsive polymers, magnetic-responsive biomaterials with superparamagnetic iron oxide nanoparticles, and acoustic-responsive biomaterials. In conclusion, smart biopolymers are reshaping scaffold design and bone regeneration strategies. However, understanding their advantages and limitations is vital, indicating the need for continued exploratory research.

Lithium attenuates blood-brain barrier damage and brain edema following intracerebral hemorrhage via an endothelial Wnt/ß-catenin signaling-dependent mechanism in mice.

BACKGROUND: Vasogenic cerebral edema resulting from blood-brain barrier (BBB) damage aggravates the devastating consequences of intracerebral hemorrhage (ICH). Although augmentation of endothelial Wnt/ß-catenin signaling substantially alleviates BBB breakdown in animals, no agents based on this mechanism are clinically available. Lithium is a medication used to treat bipolar mood disorders and can upregulate Wnt/ß-catenin signaling. METHODS: We evaluated the protective effect of lithium on the BBB in a mouse model of collagenase IV-induced ICH. Furthermore, we assessed the effect and dependency of lithium on Wnt/ß-catenin signaling in mice with endothelial deletion of the Wnt7 coactivator Gpr124. RESULTS: Lithium treatment (3 mmol/kg) significantly decreased the hematoma volume (11.15 ± 3.89 mm3 vs. 19.97 ± 3.20 mm3 in vehicle controls, p = 0.0016) and improved the neurological outcomes of mice following ICH. Importantly, lithium significantly increased the BBB integrity, as evidenced by reductions in the levels of brain edema (p = 0.0312), Evans blue leakage (p = 0.0261), and blood IgG extravasation (p = 0.0009) into brain tissue around the hematoma. Mechanistically, lithium upregulated the activity of endothelial Wnt/ß-catenin signaling in mice and increased the levels of tight junction proteins (occludin, claudin-5 and ZO-1). Furthermore, the protective effect of lithium on cerebral damage and BBB integrity was abolished in endothelial Gpr124 knockout mice, suggesting that its protective effect on BBB function was mainly dependent on Gpr124-mediated endothelial Wnt/ß-catenin signaling. CONCLUSION: Our findings indicate that lithium may serve as a therapeutic candidate for treating BBB breakdown and brain edema following ICH.

The tissue origin of human mesenchymal stem cells dictates their therapeutic efficacy on glucose and lipid metabolic disorders in type II diabetic mice.

BACKGROUND: The therapeutic efficacy of mesenchymal stem cells (MSCs) of different tissue origins on metabolic disorders can be varied in many ways but remains poorly defined. Here we report a comprehensive comparison of human MSCs derived from umbilical cord Wharton's jelly (UC-MSCs), dental pulp (PU-MSCs), and adipose tissue (AD-MSCs) on the treatment of glucose and lipid metabolic disorders in type II diabetic mice. METHODS: Fourteen-to-fifteen-week-old male C57BL/6 db/db mice were intravenously administered with human UC-MSCs, PU-MSCs, and AD-MSCs at various doses or vehicle control once every 2 weeks for 6 weeks. Metformin (MET) was given orally to animals in a separate group once a day at weeks 4 to 6 as a positive control. Body weight, blood glucose, and insulin levels were measured every week. Glucose tolerance tests (GTT) and insulin tolerance tests (ITT) were performed every 2 weeks. All the animals were sacrificed at week 6 and the blood and liver tissues were collected for biochemical and histological examinations. RESULTS: UC-MSCs showed the strongest efficacy in reducing fasting glucose levels, increasing fasting insulin levels, and improving GTT and ITT in a dose-dependent manner, whereas PU-MSCs showed an intermediate efficacy and AD-MSCs showed the least efficacy on these parameters. Moreover, UC-MSCs also reduced the serum low-density lipoprotein cholesterol (LDL-C) levels with the most prominent potency and AD-MSCs had only very weak effect on LDL-C. In contrast, AD-MSCs substantially reduced the lipid content and histological lesion of liver and accompanying biomarkers of liver injury such as serum aspartate transaminase (AST) and alanine aminotransferase (ALT) levels, whereas UC-MSCs and PU-MSCs displayed no or modest effects on these parameters, respectively. CONCLUSIONS: Taken together, our results demonstrated that MSCs of different tissue origins can confer substantially different therapeutic efficacy in ameliorating glucose and lipid metabolic disorders in type II diabetes. MSCs with different therapeutic characteristics could be selected according to the purpose of the treatment in the future clinical practice.

Updates on Clinical and Genetic Heterogeneity of ASPM in 12 Autosomal Recessive Primary Microcephaly Families in Pakistani Population.

Microcephaly (MCPH) is a genetically heterogeneous disorder characterized by non-progressive intellectual disability, small head circumference, and small brain size compared with the age- and sex-matched population. MCPH manifests as an isolated condition or part of another clinical syndrome; so far, 25 genes have been linked with MCPH. Many of these genes are reported in Pakistani population, but due to a high rate of consanguinity, a significant proportion of MCPH cohort is yet to be explored. MCPH5 is the most frequently reported type, accounting for up to 68.75% alone in a genetically constrained population like Pakistan. In the current study, whole exome sequencing (WES) was performed on probands from 10 families sampled from South Waziristan and two families from rural areas of the Pakistani Punjab. Candidate variants were validated through Sanger sequencing in all available family members. Variant filtering and in silico analysis identified three known mutations in ASPM, a MCPH5-associated gene. The founder mutation p.Trp1326* was segregating in 10 families, which further confirmed the evidence that it is the most prominent mutation in Pashtun ethnicity living in Pakistan and Afghanistan. Furthermore, the previously known mutations p.Arg3244* and p.Arg1019* were inherited in two families with Punjab ethnic profile. Collectively, this study added 12 more families to the mutational paradigm of ASPM and expanded the Pakistani MCPH cohort.

Lithium alleviates blood-brain barrier breakdown after cerebral ischemia and reperfusion by upregulating endothelial Wnt/ß-catenin signaling in mice.

Although upregulation of endothelial Wnt/ß-catenin signaling may be used to treat blood-brain barrier (BBB) breakdown caused by cerebral ischemia/reperfusion injury, no agents based on this mechanism are available clinically. Lithium, a medication used for treating bipolar mood disorders, upregulates Wnt/ß-catenin signaling, but whether lithium alleviates BBB breakdown after ischemic stroke by upregulating endothelial Wnt/ß-catenin signaling is unclear. Here, we evaluated the BBB-protective effect of lithium in adult mice with 1-h middle cerebral artery occlusion and 48-h reperfusion (MCAO/R) by determining neurological outcomes, BBB function and related molecular components. Furthermore, we assessed the effect and dependence of lithium on Wnt/ß-catenin signaling in brain microvascular endothelial cells in cell culture and in mice with conditional endothelial knockout of Wnt7 co-receptor Gpr124. Our data show that lithium treatment (3 mmol/kg) significantly decreased infarct volume (34.1 ± 1.8% versus 58.3 ± 2.8% in vehicle controls, P < 0.0001) and improved neurological outcomes of mice following MCAO/R. Importantly, lithium significantly increased BBB integrity shown by reduction of Evans blue leakage (by 45.7%, P = 0.0064) and blood IgG extravasation (by 65.8%, P < 0.0001) into infarcted brain tissue. Mechanistically, lithium upregulated the activity of endothelial Wnt/ß-catenin signaling in vivo and in vitro, increased the protein levels of tight junctions (Claudin-5 and ZO-1), and reduced MMP-9 expression. Furthermore, the protective effect of lithium on cerebral damage and BBB integrity was abolished in endothelial Gpr124 knockout mice, indicating the protection of lithium on BBB was mainly dependent on the Gpr124-mediated endothelial Wnt/ß-catenin signaling. Taken together, our findings indicate that lithium may serve as a therapeutic candidate for treating the BBB breakdown in the early stage of ischemic stroke following reperfusion therapy.