A patient-derived amyotrophic lateral sclerosis blood-brain barrier model for focused ultrasound-mediated anti-TDP-43 antibody delivery.

Background: Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disorder with minimally effective treatment options. An important hurdle in ALS drug development is the non-invasive therapeutic access to the motor cortex currently limited by the presence of the blood-brain barrier (BBB). Focused ultrasound and microbubble (FUS) treatment is an emerging technology that was successfully used in ALS patients to temporarily open the cortical BBB.

A Simple Differentiation Protocol for Generation of Induced Pluripotent Stem Cell-Derived Basal Forebrain-Like Cholinergic Neurons for Alzheimer's Disease and Frontotemporal Dementia Disease Modeling.

The study of neurodegenerative diseases using pluripotent stem cells requires new methods to assess neurodevelopment and neurodegeneration of specific neuronal subtypes. The cholinergic system, characterized by its use of the neurotransmitter acetylcholine, is one of the first to degenerate in Alzheimer's disease and is also affected in frontotemporal dementia. We developed a differentiation protocol to generate basal forebrain-like cholinergic neurons (BFCNs) from induced pluripotent stem cells (iPSCs) aided by the use of small molecule inhibitors and growth factors.

Viral-free generation and characterization of a human induced pluripotent stem cell line from dermal fibroblasts.

Peripheral dermal fibroblasts (DF) from a healthy 56 year old female were obtained from the Centre for Healthy Brain Ageing (CHeBA) Biobank, University of New South Wales, under the material transfer agreement with the University of Wollongong. DFs were reprogrammed via mRNA-delivered transcription factors into induced pluripotent stem cells (iPSCs). The generated iPSCs were confirmed to be pluripotent, capable of three germ layer differentiation and are thus a useful resource for creating iPSC-derived healthy human cells of any lineage.

Generation and characterization of human induced pluripotent stem cell lines from a familial Alzheimer's disease PSEN1 A246E patient and a non-demented family member bearing wild-type PSEN1.

The induced pluripotent stem cell (iPSC) lines UOWi002-A and UOWi003-A were reprogrammed from dermal fibroblasts via mRNA transfection. Dermal fibroblasts from a 56 year old female caucasian familial Alzheimer's disease patient carrying A246E mutation in the PSEN1 gene (familial AD3, autopsy confirmed Alzheimer's disease) and a 75 year old female non-demented control from the same family bearing the wild-type PSEN1 A246 genotype were obtained from the Coriell Institute (AG06848 and AG06846, respectively). The generated iPSCs were characterized and pluripotency was confirmed.

p53 Modulates the Fate of Cardiac Progenitor Cells Ex Vivo and in the Diabetic Heart In Vivo.

p53 is an important modulator of stem cell fate, but its role in cardiac progenitor cells (CPCs) is unknown. Here, we tested the effects of a single extra-copy of p53 on the function of CPCs in the presence of oxidative stress mediated by doxorubicin in vitro and type-1 diabetes in vivo. CPCs were obtained from super-p53 transgenic mice (p53-tg), in which the additional allele is regulated in a manner similar to the endogenous protein.

Inhibition of notch1-dependent cardiomyogenesis leads to a dilated myopathy in the neonatal heart.

Rationale: Physiological hypertrophy in the developing heart has been considered the product of an increase in volume of preexisting fetal cardiomyocytes in the absence of myocyte formation.

Objective: In this study, we tested whether the mouse heart at birth has a pool of cardiac stem cells (CSCs) that differentiate into myocytes contributing to the postnatal expansion of the parenchymal cell compartment.

Methods And Results: We have found that the newborn heart contains a population of c-kit-positive CSCs that are lineage negative, self-renewing, and multipotent.

Clonality of mouse and human cardiomyogenesis in vivo.

An analysis of the clonality of cardiac progenitor cells (CPCs) and myocyte turnover in vivo requires genetic tagging of the undifferentiated cells so that the clonal marker of individual mother cells is traced in the specialized progeny. CPC niches in the atria and apex of the mouse heart were infected with a lentivirus carrying EGFP, and the destiny of the tagged cells was determined 1-5 months later. A common integration site was identified in isolated CPCs, cardiomyocytes, endothelial cells (ECs), and fibroblasts, documenting CPC self-renewal and multipotentiality and the clonal origin of the differentiated cell populations.

In vitro toxicity induced by methylmercury on sympathetic neurons is reverted by L-cysteine or glutathione.

Methylmercury (MeHg) is related to several deleterious effects on the vertebrate nervous system and part of these effects are through interaction with sulfhydryl (-SH) group found in cellular proteins. We decided to characterize the dose-dependent effect of MeHg on the neurotoxicity and the neurite outgrowth induced effects on chick sympathetic neurons dissociated and purified in culture. In this model, MeHg inhibited neurite outgrowth (1-10 microM) and induced cell death (1-10 microM) after 48 h in culture.