Mechanisms underlying inflammation in neurodegeneration.

http://icnapedia.org/ezproxy.online.journal/20670828.pdf

The Science of Stroke: Mechanisms in Search of Treatments

https://www.cell.com/cell/pdf/S0092-8674(09)00717-X.pdf

Parkinson’s Disease Patient-Derived Induced Pluripotent Stem Cells Free of Viral Reprogramming Factors

Spinal muscular atrophy is one of the most common inherited forms of neurological disease leading to infant mortality. Patients have selective loss of lower motor neurons resulting in muscle weakness, paralysis and often death. Although patient fibroblasts have been used extensively to study spinal muscular atrophy, motor neurons have a unique anatomy and physiology which may underlie their vulnerability to the disease process. Here we report the generation of induced pluripotent stem cells from skin fibroblast samples taken from a child with spinal muscular atrophy. These cells expanded robustly in culture, maintained the disease genotype and generated motor neurons that showed selective deficits compared to those derived from the child’s unaffected mother. This is the first study to show that human induced pluripotent stem cells can be used to model the specific pathology seen in a genetically inherited disease. As such, it represents a promising resource to study disease mechanisms, screen new drug compounds and develop new therapies. The inherited disease spinal muscular atrophy (SMA), one of the most common neurological disorders causing death in childhood, is caused by mutations in both copies of the SMN1 gene. Little is known about SMA pathogenesis, partly because it is unique to humans who have two versions of this gene — SMN1 and SMN2; rodents and other lab model candidates have just one. Now a new technique has been developed that creates a tool for studying SMA disease pathology at the cellular level. Skin fibroblasts from a child with SMA (and for comparison from his unaffected mother) were used to generate induced pluripotent stem (iPS) cell lines. They form neural progenitor cultures that can produce differentiated neural tissue and motor neurons that maintain the disease phenotype. The cultures also responded to drugs known to elevate the mutated protein associated with the disease. Similar iPS technology may be of value in the study of other genetic disorders such as Huntington's disease. This paper generates an iPS cell line from patients with spinal muscular atrophy, an autosomal recessive genetic disorder that is one of the most common inherited forms of neurological disease in children.

/pdf/induced-pluripotent-stem-cells-from-a-spinal-muscular-2brms3v9u9.pdf

Induced pluripotent stem cells from a spinal muscular atrophy patient

Human induced pluripotent stem (iPS) cells hold great promise for cardiovascular research and therapeutic applications, but the ability of human iPS cells to differentiate into functional cardiomyocytes has not yet been demonstrated. The aim of this study was to characterize the cardiac differentiation potential of human iPS cells generated using OCT4, SOX2, NANOG, and LIN28 transgenes compared to human embryonic stem (ES) cells. The iPS and ES cells were differentiated using the embryoid body (EB) method. The time course of developing contracting EBs was comparable for the iPS and ES cell lines, although the absolute percentages of contracting EBs differed. RT-PCR analyses of iPS and ES cell-derived cardiomyocytes demonstrated similar cardiac gene expression patterns. The pluripotency genes OCT4 and NANOG were downregulated with cardiac differentiation, but the downregulation was blunted in the iPS cell lines due to residual transgene expression. Proliferation of iPS and ES cell derived-cardiomyocytes based on BrdU labeling was similar, and immunocytochemistry of isolated cardiomyocytes revealed indistinguishable sarcomeric organizations. Electrophysiology studies indicated that iPS cells have a capacity like ES cells for differentiation into nodal-, atrial-, and ventricular-like phenotypes based on action potential characteristics. Both iPS and ES cell-derived cardiomyocytes exhibited responsiveness to β-adrenergic stimulation manifest by an increase in spontaneous rate and a decrease in action potential duration. We conclude that human iPS cells can differentiate into functional cardiomyocytes, and thus iPS cells are a viable option as an autologous cell source for cardiac repair and a powerful tool for cardiovascular research.

Functional Cardiomyocytes Derived From Human Induced Pluripotent Stem Cells

The generation of pluripotent stem cells from an individual patient would enable the large-scale production of the cell types affected by that patient's disease. These cells could in turn be used for disease modeling, drug discovery, and eventually autologous cell replacement therapies. Although recent studies have demonstrated the reprogramming of human fibroblasts to a pluripotent state, it remains unclear whether these induced pluripotent stem (iPS) cells can be produced directly from elderly patients with chronic disease. We have generated iPS cells from an 82-year-old woman diagnosed with a familial form of amyotrophic lateral sclerosis (ALS). These patient-specific iPS cells possess properties of embryonic stem cells and were successfully directed to differentiate into motor neurons, the cell type destroyed in ALS.

https://science.sciencemag.org/content/sci/321/5893/1218.full.pdf

Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons.

The generation of human induced pluripotent stem cells (hiPSCs) represents an exciting advancement with promise for stem cell transplantation therapies as well as for neurological disease modeling. Based on the emerging roles for astrocytes in neurological disorders, we investigated whether hiPSC-derived astrocyte progenitors could be engrafted to the rodent spinal cord and how the characteristics of these cells changed between in vitro culture and after transplantation to the in vivo spinal cord environment. Our results show that human embryonic stem cell- and hiPSC-derived astrocyte progenitors survive long-term after spinal cord engraftment and differentiate to astrocytes in vivo with few cells from other lineages present. Gene profiling of the transplanted cells demonstrates the astrocyte progenitors continue to mature in vivo and upregulate a variety of astrocyte-specific genes. Given this mature astrocyte gene profile, this work highlights hiPSCs as a tool to investigate disease-related astrocyte biology using in vivo disease modeling with significant implications for human neurological diseases currently lacking animal models.

https://stemcellsjournals.onlinelibrary.wiley.com/doi/pdf/10.5966/sctm.2013-0153

Gene Profiling of Human Induced Pluripotent Stem Cell-Derived Astrocyte Progenitors Following Spinal Cord Engraftment

Spinal muscular atrophy (SMA) is the most frequent genetic cause of death in infants and toddlers. All cases of spinal muscular atrophy result from reductions in levels of the survival motor neuron (SMN) protein, and so SMN upregulation is a focus of many preclinical and clinical studies. We examine four issues that may be important in planning for therapeutic success. First, neuromuscular phenotypes in the SMNΔ7 mouse model closely match those in human patients but peripheral disease manifestations differ, suggesting that endpoints other than mouse lifespan may be more useful in predicting clinical outcome. Second, SMN plays important roles in multiple central and peripheral cell types, not just motor neurons, and it remains unclear which of these cell types need to be targeted therapeutically. Third, should SMN-restoration therapy not be effective in all patients, blocking molecular changes downstream of SMN reduction may confer significant benefit, making it important to evaluate therapeutic targets other than SMN. Lastly, for patients whose disease progression is slowed, but who retain significant motor dysfunction, additional approaches used to enhance regeneration of the neuromuscular system may be of value.

Spinal muscular atrophy: from tissue specificity to therapeutic strategies.

The human motor system comprises the same basic functional and anatomic categories that have been described in vertebrate model systems. However, almost all of the genetic and molecular information about the development of the motor system and motor neuron subtypes is based on studies in animal models, since human motor neurons have been available only in postmortem samples. With the establishment of human embryonic stem (hES) cells as a research tool, and the demonstration that they could be directed to differentiate into spinal motor neurons, this inaccessibility has changed. Spinal motor neurons are the target of several diseases. As one key example, the progressive paralysis and ultimate death of patients with amyotrophic lateral sclerosis (ALS) reflect changes in motor neuron excitability, selective degeneration of nerve-muscle contacts and finally cell death of vulnerable motor neurons. However, the mechanisms of selective motor neuron degeneration are not well understood and there are no effective therapies. The derivation of induced pluripotent stem (iPS) cells from ALS patients allows human motor neurons and other disease-relevant cell types with the same genetic make-up as the patient to be generated in large numbers. However, before they can be reliably used for mechanistic studies or to establish ALS-relevant screens, they need to be validated as a tool. In this article, we discuss salient aspects of human development and neurodegeneration and consider how they can inform our design of appropriate cell models. In addition, we review our recent data suggesting that human iPS cell-derived motor neurons constitute a robust basis for disease modeling and we discuss some of the technological challenges that nevertheless remain to be addressed.

Potential of Stem Cell-Derived Motor Neurons for Modeling Amyotrophic Lateral Sclerosis (ALS)

The present invention provides, inter alia, methods and pharmaceutical compositions for treating or ameliorating an effect of proximal spinal muscular atrophy (SMA) and methods for preventing or slowing motor neuron death in a subject having SMA. The methods include administering to a subject in need thereof a modulator of a gene selected from the group consisting of phosphodiesterase 1c (Pde1c), Calbindin 2 (Calb2), Egl nine homolog 3 (Egl3), Metabotropic glutamate receptor 8 (mGluR8), Synaptotagmin 1 (Syt1), CUGBP, Elav-like family member 4 (Celf4), and combinations thereof in an amount effective to treat or ameliorate an effect of SMA. Also provided are methods for preventing or slowing motor neuron death.

Christopher E. Henderson

Papers

Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons.

Gene Profiling of Human Induced Pluripotent Stem Cell-Derived Astrocyte Progenitors Following Spinal Cord Engraftment

Spinal muscular atrophy: from tissue specificity to therapeutic strategies.

Potential of Stem Cell-Derived Motor Neurons for Modeling Amyotrophic Lateral Sclerosis (ALS)

Treatment of proximal spinal muscular atrophy