Concise Review: Stem Cell Therapies for Amyotrophic Lateral Sclerosis: Recent Advances and Prospects for the Future

Amyotrophic lateral sclerosis (ALS) is a lethal disease involving the loss of motor neurons. Although the mechanisms responsible for motor neuron degeneration in ALS remain elusive, the development of stem cell‐based therapies for the treatment of ALS has gained widespread support. Here, we review the types of stem cells being considered for therapeutic applications in ALS, and emphasize recent preclinical advances that provide supportive rationale for clinical translation. We also discuss early trials from around the world translating cellular therapies to ALS patients, and offer important considerations for future clinical trial design. Although clinical translation is still in its infancy, and additional insight into the mechanisms underlying therapeutic efficacy and the establishment of long‐term safety are required, these studies represent an important first step toward the development of effective cellular therapies for the treatment of ALS. S tem C ells 2014;32:1099–1109Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106861/1/stem1628.pd

APPLICATION OF DIGITAL IMAGE PROCESSING TO ESTIMATE SLAUGHTER VALUE OF BULLS

Glavna svrha našeg istraživanja bila je dokazati da se analiza video slike može upotrijebiti za procjenu sastava polovica u žive stoke. Primjena mikrokompjutora, gdje se obrađuje slika video kamere, nije novost u znanosti o životinjama. Cross i sur. (1) pokušali su predvidjeti sastav područja 9., 10. i 11. rebra u goveda služeći se analiziranjem video slike. Misztal (3) je upotrijebio obradu slike za procjenjivanje sastava polovica u žive stoke. Nove mogućnosti izračunavanja dale su mnogo veću točnost u ovoj metodi, te manje troškove i mnogo bržu obradu digitalnih slika životinja, nego u ranijim istraživanjima. Naš bi pokus morao dati potpunu automatiziranu metodu procjenjivanja uzgojne vrijednosti živih životinja, što bi se mogla izračunati na osnovi predviđene vrijednosti rasjecanja polutki, težine hladnih polovica i dijelova vrijednog mesa. Djelomični koeficijenti regresije svakog pojedinog modela bili su 0.96 Se=6.0 za težinu hladnih polovica, 0.94 Se=6.0 za vrijedno meso i 0.92 Se=6.0 za meso u vrijednim dijelovima, te su bili neznatno viši od onih što su ih dobili Jankowski et al (2) (R=0,48 - 0.94) i Misztal (R=0.86 - 0.91). Visoki djelomični koeficijent regresije (R) svakog modela pokazuje da postoji mogućnost primjene ove metode kao kriterija selekcije, što se temelji na pojedinom testu performance, z- predviđanje klaoničke produktivnosti mesne pasmine

Stem cell technology for neurodegenerative diseases

Over the past 20 years, stem cell technologies have become an increasingly attractive option to investigate and treat neurodegenerative diseases. In the current review, we discuss the process of extending basic stem cell research into translational therapies for patients suffering from neurodegenerative diseases. We begin with a discussion of the burden of these diseases on society, emphasizing the need for increased attention toward advancing stem cell therapies. We then explain the various types of stem cells utilized in neurodegenerative disease research, and outline important issues to consider in the transition of stem cell therapy from bench to bedside. Finally, we detail the current progress regarding the applications of stem cell therapies to specific neurodegenerative diseases, focusing on Parkinson disease, Huntington disease, Alzheimer disease, amyotrophic lateral sclerosis, and spinal muscular atrophy. With a greater understanding of the capacity of stem cell technologies, there is growing public hope that stem cell therapies will continue to progress into realistic and efficacious treatments for neurodegenerative diseases. Ann Neurol 2011;70: 353–361.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/86937/1/22487_ftp.pd

Autocrine Production of IGF‐I Increases Stem Cell‐Mediated Neuroprotection

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder resulting in motor neuron (MN) loss. There are currently no effective therapies; however, cellular therapies using neural progenitor cells protect MNs and attenuate disease progression in G93A‐SOD1 ALS rats. Recently, we completed a phase I clinical trial examining intraspinal human spinal stem cell (HSSC) transplantation in ALS patients which demonstrated our approach was safe and feasible, supporting the phase II trial currently in progress. In parallel, efforts focused on understanding the mechanisms underlying the preclinical benefit of HSSCs in vitro and in animal models of ALS led us to investigate how insulin‐like growth factor‐I (IGF‐I) production contributes to cellular therapy neuroprotection. IGF‐I is a potent growth factor with proven efficacy in preclinical ALS studies, and we contend that autocrine IGF‐I production may enhance the salutary effects of HSSCs. By comparing the biological properties of HSSCs to HSSCs expressing sixfold higher levels of IGF‐I, we demonstrate that IGF‐I production augments the production of glial‐derived neurotrophic factor and accelerates neurite outgrowth without adversely affecting HSSC proliferation or terminal differentiation. Furthermore, we demonstrate that increased IGF‐I induces more potent MN protection from excitotoxicity via both indirect and direct mechanisms, as demonstrated using hanging inserts with primary MNs or by culturing with organotypic spinal cord slices, respectively. These findings support our theory that combining autocrine growth factor production with HSSC transplantation may offer a novel means to achieve additive neuroprotection in ALS. Stem Cells 2015;33:1480–1489Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111155/1/stem1933.pd

Neuromuscular effects of G93A-SOD1 expression in zebrafish

Abstract Background Amyotrophic lateral sclerosis (ALS) is a fatal disorder involving the degeneration and loss of motor neurons. The mechanisms of motor neuron loss in ALS are unknown and there are no effective treatments. Defects in the distal axon and at the neuromuscular junction are early events in the disease course, and zebrafish provide a promising in vivo system to examine cellular mechanisms and treatments for these events in ALS pathogenesis. Results We demonstrate that transient genetic manipulation of zebrafish to express G93A-SOD1, a mutation associated with familial ALS, results in early defects in motor neuron outgrowth and axonal branching. This is consistent with previous reports on motor neuron axonal defects associated with familial ALS genes following knockdown or mutant protein overexpression. We also demonstrate that upregulation of growth factor signaling is capable of rescuing these early defects, validating the potential of the model for therapeutic discovery. We generated stable transgenic zebrafish lines expressing G93A-SOD1 to further characterize the consequences of G93A-SOD1 expression on neuromuscular pathology and disease progression. Behavioral monitoring reveals evidence of motor dysfunction and decreased activity in transgenic ALS zebrafish. Examination of neuromuscular and neuronal pathology throughout the disease course reveals a loss of neuromuscular junctions and alterations in motor neuron innervations patterns with disease progression. Finally, motor neuron cell loss is evident later in the disease. Conclusions This sequence of events reflects the stepwise mechanisms of degeneration in ALS, and provides a novel model for mechanistic discovery and therapeutic development for neuromuscular degeneration in ALS.http://deepblue.lib.umich.edu/bitstream/2027.42/112892/1/13024_2012_Article_367.pd

Family A DNA Polymerase Phylogeny Uncovers Diversity and Replication Gene Organization in the Virioplankton

Shotgun metagenomics, which allows for broad sampling of viral diversity, has uncovered genes that are widely distributed among virioplankton populations and show linkages to important biological features of unknown viruses. Over 25% of known dsDNA phage carry the DNA polymerase I (polA) gene, making it one of the most widely distributed phage genes. Because of its pivotal role in DNA replication, this enzyme is linked to phage lifecycle characteristics. Previous research has suggested that a single amino acid substitution might be predictive of viral lifestyle. In this study Chesapeake Bay virioplankton were sampled by shotgun metagenomic sequencing (using long and short read technologies). More polA sequences were predicted from this single viral metagenome (virome) than from 86 globally distributed virome libraries (ca. 2,100, and 1,200, respectively). The PolA peptides predicted from the Chesapeake Bay virome clustered with 69% of PolA peptides from global viromes; thus, remarkably the Chesapeake Bay virome captured the majority of known PolA peptide diversity in viruses. This deeply sequenced virome also expanded the diversity of PolA sequences, increasing the number of PolA clusters by 44%. Contigs containing polA sequences were also used to examine relationships between phylogenetic clades of PolA and other genes within unknown viral populations. Phylogenic analysis revealed five distinct groups of phages distinguished by the amino acids at their 762 (Escherichia coli IAI39 numbering) positions and replication genes. DNA polymerase I sequences from Tyr762 and Phe762 groups were most often neighbored by ring-shaped superfamily IV helicases and ribonucleotide reductases (RNRs). The Leu762 groups had non-ring shaped helicases from superfamily II and were further distinguished by an additional helicase gene from superfamily I and the lack of any identifiable RNR genes. Moreover, we found that the inclusion of ribonucleotide reductase associated with PolA helped to further differentiate phage diversity, chiefly within lytic podovirus populations. Altogether, these data show that DNA Polymerase I is a useful marker for observing the diversity and composition of the virioplankton and may be a driving factor in the divergence of phage replication components

Human Cortical Neural Stem Cells Expressing Insulin‐Like Growth Factor‐I: A Novel Cellular Therapy for Alzheimer’s Disease

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135291/1/sct3201653379.pd