Human iPSC-Derived Mononuclear Phagocytes Improve Cognition and Neural Health across Multiple Mouse Models of Aging and Alzheimer's Disease.

Young blood or plasma improves cognitive function in aged animals but has limited availability. The current study generates a subtype of young blood cells from easily expandable induced pluripotent stem cells and evaluates their effects on age- and Alzheimer's disease (AD)-associated cognitive and neural decline. In aging mice, intravenous delivery of induced mononuclear phagocytes (iMPs) improves performance in hippocampus-dependent cognitive tasks, increases neural health, and reduces neuroinflammation.

An organ-chip model of sporadic ALS using iPSC-derived spinal cord motor neurons and an integrated blood-brain-like barrier.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder in which motor neurons (MNs) of the brain and spinal cord degenerate, leading to paralysis. Generating MNs from patient-specific induced pluripotent stem cells (iPSCs) may help elucidate early stages of disease. Here, we combined MNs from patients with early-onset disease with brain microvascular endothelial-like cells in a microfluidic device we termed spinal cord chips (SC-chips) and added media flow, which enhanced neuronal maturation and improved cellular health.

Comprehensive Proteomics Metadata and Integrative Web Portals Facilitate Sharing and Integration of LINCS Multiomics Data.

The Library of Integrated Network-based Cellular Signatures (LINCS), an NIH Common Fund program, has cataloged and analyzed cellular function and molecular activity profiles in response to >80,000 perturbing agents that are potentially disruptive to cells. Because of the importance of proteins and their modifications to the response of specific cellular perturbations, four of the six LINCS centers have included significant proteomics efforts in the characterization of the resulting phenotype. This manuscript aims to describe this effort and the data harmonization and integration of the LINCS proteomics data discussed in recent LINCS papers.

Systemic HER3 ligand-mimicking nanobioparticles enter the brain and reduce intracranial tumour growth.

Crossing the blood-brain barrier (BBB) and reaching intracranial tumours is a clinical challenge for current targeted interventions including antibody-based therapies, contributing to poor patient outcomes. Increased cell surface density of human epidermal growth factor receptor 3 (HER3) is associated with a growing number of metastatic tumour types and is observed on tumour cells that acquire resistance to a growing number of clinical targeted therapies. Here we describe the evaluation of HER3-homing nanobiological particles (nanobioparticles (NBPs)) on such tumours in preclinical models and our discovery that systemic NBPs could be found in the brain even in the absence of such tumours.

Neurotrophic factors for Parkinson's disease: Current status, progress, and remaining questions. Conclusions from a 2023 workshop.

In 2023, a workshop was organized by the UK charity Cure Parkinson's with The Michael J Fox Foundation for Parkinson's Research and Parkinson's UK to review the field of growth factors (GFs) for Parkinson's disease (PD). This was a follow up to a previous meeting held in 2019. This 2023 workshop reviewed new relevant data that has emerged in the intervening 4 years around the development of new GFs and better models for studying them including the merit of combining treatments as well as therapies that can be modulated.

Single-Cell Proteomics Reveals Specific Cellular Subtypes in Cardiomyocytes Derived From Human iPSCs and Adult Hearts.

Single-cell proteomics was performed on human induced pluripotent stem cells (iPSCs), iPSC-derived cardiomyocytes, and adult cardiomyocytes. More than 700 proteins could be simultaneously measured in each cell revealing unique subpopulations. A subset of iPSCs expressed higher levels of Lin28a and Tra-1-60 towards the outer edge of cell colonies.

Longitudinal Quantitative MRI Provides Responsive Outcome Measures for Early and Late Muscle Changes in ALS.

Introduction/aims: Studies have demonstrated the potential of muscle MRIs to measure disease progression in ALS. However, the responsiveness and utility of quantitative muscle MRIs in an ALS clinical trial remain unknown. This study aimed to determine the responsiveness of quantitative muscle MRIs to measure disease progression in ALS.

Cell therapy for neurological disorders.

Cell therapies for neurological disorders are entering the clinic and present unique challenges and opportunities compared with conventional medicines. They have the potential to replace damaged nervous tissue and integrate into the brain or spinal cord to produce functional effects for the lifetime of the patient, which could revolutionize the way clinicians treat debilitating neurological disorders. The major challenge has been cell sourcing, which historically relied mainly on fetal brain tissue.

Surface tension enables induced pluripotent stem cell culture in commercially available hardware during spaceflight.

Low Earth Orbit (LEO) has emerged as a unique environment for evaluating altered stem cell properties in microgravity. LEO has become increasingly accessible for research and development due to progress in private spaceflight. Axiom Mission 2 (Ax-2) was launched as the second all-private astronaut mission to the International Space Station (ISS).

Disease related changes in ATAC-seq of iPSC-derived motor neuron lines from ALS patients and controls.

Amyotrophic Lateral Sclerosis (ALS), like many other neurodegenerative diseases, is highly heritable, but with only a small fraction of cases explained by monogenic disease alleles. To better understand sporadic ALS, we report epigenomic profiles, as measured by ATAC-seq, of motor neuron cultures derived from a diverse group of 380 ALS patients and 80 healthy controls. We find that chromatin accessibility is heavily influenced by sex, the iPSC cell type of origin, ancestry, and the inherent variance arising from sequencing.

Multi-lineage heart-chip models drug cardiotoxicity and enhances maturation of human stem cell-derived cardiovascular cells.

Cardiovascular toxicity causes adverse drug reactions and may lead to drug removal from the pharmaceutical market. Cancer therapies can induce life-threatening cardiovascular side effects such as arrhythmias, muscle cell death, or vascular dysfunction. New technologies have enabled cardiotoxic compounds to be identified earlier in drug development.

Roadmap for C9ORF72 in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis: Report on the C9ORF72 FTD/ALS Summit.

A summit held March 2023 in Scottsdale, Arizona (USA) focused on the intronic hexanucleotide expansion in the C9ORF72 gene and its relevance in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS; C9ORF72-FTD/ALS). The goal of this summit was to connect basic scientists, clinical researchers, drug developers, and individuals affected by C9ORF72-FTD/ALS to evaluate how collaborative efforts across the FTD-ALS disease spectrum might break down existing disease silos. Presentations and discussions covered recent discoveries in C9ORF72-FTD/ALS disease mechanisms, availability of disease biomarkers and recent advances in therapeutic development, and clinical trial design for prevention and treatment for individuals affected by C9ORF72-FTD/ALS and asymptomatic pathological expansion carriers.

Human Neural Progenitors Expressing GDNF Enhance Retinal Protection in a Rodent Model of Retinal Degeneration.

Stem cell therapy for retinal degenerative diseases has been extensively tested in preclinical and clinical studies. However, preclinical studies performed in animal models at the early stage of disease do not optimally translate to patients that present to the clinic at a later stage of disease. As the retina degenerates, inflammation and oxidative stress increase and trophic factor support declines.

Organ-Chips Enhance the Maturation of Human iPSC-Derived Dopamine Neurons.

While cells in the human body function in an environment where the blood supply constantly delivers nutrients and removes waste, cells in conventional tissue culture well platforms are grown with a static pool of media above them and often lack maturity, limiting their utility to study cell biology in health and disease. In contrast, organ-chip microfluidic systems allow the growth of cells under constant flow, more akin to the in vivo situation. Here, we differentiated human induced pluripotent stem cells into dopamine neurons and assessed cellular properties in conventional multi-well cultures and organ-chips.

Translational roadmap for regenerative therapies of eye disease.

The translation of regenerative therapies to neuronal eye diseases requires a roadmap specific to the nature of the target diseases, patient population, methodologies for assessing outcome, and other factors. This commentary focuses on critical issues for translating regenerative eye therapies relevant to retinal neurons to human clinical trials.

Reversal of dual epigenetic repression of non-canonical Wnt-5a normalises diabetic corneal epithelial wound healing and stem cells.

Aims/hypothesis: Diabetes is associated with epigenetic modifications including DNA methylation and miRNA changes. Diabetic complications in the cornea can cause persistent epithelial defects and impaired wound healing due to limbal epithelial stem cell (LESC) dysfunction. In this study, we aimed to uncover epigenetic alterations in diabetic vs non-diabetic human limbal epithelial cells (LEC) enriched in LESC and identify new diabetic markers that can be targeted for therapy to normalise corneal epithelial wound healing and stem cell expression.

Human iPSC-derived neural progenitor cells secreting GDNF provide protection in rodent models of ALS and retinal degeneration.

Human induced pluripotent stem cells (iPSCs) are a renewable cell source that can be differentiated into neural progenitor cells (iNPCs) and transduced with glial cell line-derived neurotrophic factor (iNPC-GDNFs). The goal of the current study is to characterize iNPC-GDNFs and test their therapeutic potential and safety. Single-nuclei RNA-seq show iNPC-GDNFs express NPC markers.

Large-scale differentiation of iPSC-derived motor neurons from ALS and control subjects.

Using induced pluripotent stem cells (iPSCs) to understand the mechanisms of neurological disease holds great promise; however, there is a lack of well-curated lines from a large array of participants. Answer ALS has generated over 1,000 iPSC lines from control and amyotrophic lateral sclerosis (ALS) patients along with clinical and whole-genome sequencing data. The current report summarizes cell marker and gene expression in motor neuron cultures derived from 92 healthy control and 341 ALS participants using a 32-day differentiation protocol.

NeuroLINCS Proteomics: Defining human-derived iPSC proteomes and protein signatures of pluripotency.

The National Institute of Health (NIH) Library of integrated network-based cellular signatures (LINCS) program is premised on the generation of a publicly available data resource of cell-based biochemical responses or "signatures" to genetic or environmental perturbations. NeuroLINCS uses human inducible pluripotent stem cells (hiPSCs), derived from patients and healthy controls, and differentiated into motor neuron cell cultures. This multi-laboratory effort strives to establish i) robust multi-omic workflows for hiPSC and differentiated neuronal cultures, ii) public annotated data sets and iii) relevant and targetable biological pathways of spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS).