scholarly journals Rules of tissue packing involving different cell types: human muscle organization

2016 ◽  
Author(s):  
Daniel Sanchez-Gutierrez ◽  
Aurora Saez ◽  
Carmen Paradas ◽  
Luis M. Escudero
Keyword(s):  
Motor Neurons ◽  
Skeletal Muscles ◽  
Spatial Organization ◽  
Biceps Brachii ◽  
Relative Size ◽  
Neuromuscular Diseases ◽  
Cell Types ◽  
Quadriceps Muscle ◽  
Relative Distribution ◽  
Mathematical Concepts

Natural packed tissues are assembled as tessellations of polygonal cells that do not leave empty spaces between them. They include the epithelial sheets and the skeletal muscles. Epithelia are formed by equivalent cells that change shape and organization through development. The skeletal muscles appear as a mosaic composed by two different types of cells: the slow and fast fibres that are determined by the identities of the motor neurons that innervate them. Their relative distribution is important for the muscle function and can be altered in some neuromuscular diseases. Little is known about how the spatial organization of fast and slow fibres is established and maintained. In this work we use computerized image analysis and mathematical concepts to capture the organizational pattern in two different healthy muscles: biceps brachii and quadriceps. Here we show that each type of muscle portrays a characteristic topological pattern that allows distinguishing between them. The biceps brachii muscle presents a particular arrange based on the different size of slow and fast fibres, contrary to the quadriceps muscle where an unbiased distribution exists. Our results indicate that the relative size of each cellular type imposes an intrinsic organization into the tissue. These findings establish a new framework for the analysis of packed tissues where two or more cell types exist.

scholarly journals Interleukin-17 and Th17 Lymphocytes Directly Impair Motoneuron Survival of Wildtype and FUS-ALS Mutant Human iPSCs

2021 ◽  
Vol 22 (15) ◽  
pp. 8042
Author(s):  
Mengmeng Jin ◽  
Katja Akgün ◽  
Tjalf Ziemssen ◽  
Markus Kipp ◽  
Rene Günther ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Th17 Cells ◽  
Immune Cell ◽  
Cell Types ◽  
Positive Control ◽  
Interleukin 17 ◽  
Fused In Sarcoma ◽  
Th17 Lymphocytes ◽  
Human Ipscs ◽  
Als Patients

Amyotrophic lateral sclerosis (ALS) is a progressive disease leading to the degeneration of motor neurons (MNs). Neuroinflammation is involved in the pathogenesis of ALS; however, interactions of specific immune cell types and MNs are not well studied. We recently found a shift toward T helper (Th)1/Th17 cell-mediated, pro-inflammatory immune responses in the peripheral immune system of ALS patients, which positively correlated with disease severity and progression. Whether Th17 cells or their central mediator, Interleukin-17 (IL-17), directly affects human motor neuron survival is currently unknown. Here, we evaluated the contribution of Th17 cells and IL-17 on MN degeneration using the co-culture of iPSC-derived MNs of fused in sarcoma (FUS)-ALS patients and isogenic controls with Th17 lymphocytes derived from ALS patients, healthy controls, and multiple sclerosis (MS) patients (positive control). Only Th17 cells from MS patients induced severe MN degeneration in FUS-ALS as well as in wildtype MNs. Their main effector, IL-17A, yielded in a dose-dependent decline of the viability and neurite length of MNs. Surprisingly, IL-17F did not influence MNs. Importantly, neutralizing IL-17A and anti-IL-17 receptor A treatment reverted all effects of IL-17A. Our results offer compelling evidence that Th17 cells and IL-17A do directly contribute to MN degeneration.

scholarly journals The atlas of RNase H antisense oligonucleotide distribution and activity in the CNS of rodents and non-human primates following central administration

2020 ◽  
Author(s):  
Paymaan Jafar-nejad ◽  
Berit Powers ◽  
Armand Soriano ◽  
Hien Zhao ◽  
Daniel A Norris ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Muscular Atrophy ◽  
Neurological Diseases ◽  
Cell Types ◽  
Rnase H ◽  
Central Administration ◽  
Spinal Motor Neurons ◽  
New Class ◽  
Wide Range ◽  
Therapeutic Development

Abstract Antisense oligonucleotides (ASOs) have emerged as a new class of drugs to treat a wide range of diseases, including neurological indications. Spinraza, an ASO that modulates splicing of SMN2 RNA, has shown profound disease modifying effects in Spinal Muscular Atrophy (SMA) patients, energizing efforts to develop ASOs for other neurological diseases. While SMA specifically affects spinal motor neurons, other neurological diseases affect different central nervous system (CNS) regions, neuronal and non-neuronal cells. Therefore, it is important to characterize ASO distribution and activity in all major CNS structures and cell types to have a better understanding of which neurological diseases are amenable to ASO therapy. Here we present for the first time the atlas of ASO distribution and activity in the CNS of mice, rats, and non-human primates (NHP), species commonly used in preclinical therapeutic development. Following central administration of an ASO to rodents, we observe widespread distribution and target RNA reduction throughout the CNS in neurons, oligodendrocytes, astrocytes and microglia. This is also the case in NHP, despite a larger CNS volume and more complex neuroarchitecture. Our results demonstrate that ASO drugs are well suited for treating a wide range of neurological diseases for which no effective treatments are available.

scholarly journals Molecular Alterations in Sporadic and SOD1-ALS Immortalized Lymphocytes: Towards a Personalized Therapy

2021 ◽  
Vol 22 (6) ◽  
pp. 3007
Author(s):  
Isabel Lastres-Becker ◽  
Gracia Porras ◽  
Marina Arribas-Blázquez ◽  
Inés Maestro ◽  
Daniel Borrego-Hernández ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Therapeutic Interventions ◽  
Autophagic Flux ◽  
Metabolic Disturbances ◽  
Molecular Alterations ◽  
Healthy Donors ◽  
Inflammatory Profile ◽  
Als Patients

Amyotrophic lateral sclerosis (ALS) is a fatal neurological condition where motor neurons (MNs) degenerate. Most of the ALS cases are sporadic (sALS), whereas 10% are hereditarily transmitted (fALS), among which mutations are found in the gene that codes for the enzyme superoxide dismutase 1 (SOD1). A central question in ALS field is whether causative mutations display selective alterations not found in sALS patients, or they converge on shared molecular pathways. To identify specific and common mechanisms for designing appropriate therapeutic interventions, we focused on the SOD1-mutated (SOD1-ALS) versus sALS patients. Since ALS pathology involves different cell types other than MNs, we generated lymphoblastoid cell lines (LCLs) from sALS and SOD1-ALS patients and healthy donors and investigated whether they show changes in oxidative stress, mitochondrial dysfunction, metabolic disturbances, the antioxidant NRF2 pathway, inflammatory profile, and autophagic flux. Both oxidative phosphorylation and glycolysis appear to be upregulated in lymphoblasts from sALS and SOD1-ALS. Our results indicate significant differences in NRF2/ARE pathway between sALS and SOD1-ALS lymphoblasts. Furthermore, levels of inflammatory cytokines and autophagic flux discriminate between sALS and SOD1-ALS lymphoblasts. Overall, different molecular mechanisms are involved in sALS and SOD1-ALS patients and thus, personalized medicine should be developed for each case.

scholarly journals Establishment of a Human Induced Pluripotent Stem Cell-Derived Neuromuscular Co-Culture Under Optogenetic Control

2020 ◽  
Author(s):  
Elliot W. Swartz ◽  
Greg Shintani ◽  
Jijun Wan ◽  
Joseph S. Maffei ◽  
Sarah H. Wang ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Induced Pluripotent Stem Cell ◽  
Cell Types ◽  
Calcium Flux ◽  
Electrode Arrays ◽  
Spinal Motor Neurons ◽  
Culture Model ◽  
Skeletal Myotubes ◽  
Induced Pluripotent

SummaryThe failure of the neuromuscular junction (NMJ) is a key component of degenerative neuromuscular disease, yet how NMJs degenerate in disease is unclear. Human induced pluripotent stem cells (hiPSCs) offer the ability to model disease via differentiation toward affected cell types, however, the re-creation of an in vitro neuromuscular system has proven challenging. Here we present a scalable, all-hiPSC-derived co-culture system composed of independently derived spinal motor neurons (MNs) and skeletal myotubes (sKM). In a model of C9orf72-associated disease, co-cultures form functional NMJs that can be manipulated through optical stimulation, eliciting muscle contraction and measurable calcium flux in innervated sKM. Furthermore, co-cultures grown on multi-electrode arrays (MEAs) permit the pharmacological interrogation of neuromuscular physiology. Utilization of this co-culture model as a tunable, patient-derived system may offer significant insights into NMJ formation, maturation, repair, or pathogenic mechanisms that underlie NMJ dysfunction in disease.

scholarly journals Neev, a novel long non-coding RNA, is expressed in chaetoblasts during regeneration of Eisenia fetida

2019 ◽  
Author(s):  
Surendra Singh Patel ◽  
Sanyami Zunjarrao ◽  
Beena Pillai
Keyword(s):  
Eisenia Fetida ◽  
Spatial Organization ◽  
Cell Types ◽  
Ventral Side ◽  
Chitin Synthase ◽  
Chitin Synthesis ◽  
Mirna Sponge ◽  
Non Coding Rna ◽  
Temporal Expression Pattern ◽  
Long Non Coding Rna

AbstractEisenia fetida, the common vermicomposting earthworm, shows robust regeneration of posterior segments removed by amputation. During the period of regeneration, the newly formed tissue initially contains only undifferentiated cells but subsequently differentiates into a variety of cell types including muscle, nerve and vasculature. Transcriptomics analysis, reported previously, provided a number of candidate non-coding RNAs that were induced during regeneration. We found that one such long non-coding RNA (lncRNA) is expressed in the skin, only at the base of newly formed chaetae. The spatial organization and precise arrangement of the regenerating chaetae and the cells expressing the lncRNA on the ventral side clearly support a model wherein the regenerating tissue contains a zone of growth and cell division at the tip and a zone of differentiation at the site of amputation. The temporal expression pattern of the lncRNA, christened Neev, closely resembled the pattern of chitin synthase genes, implicated in chaetae formation. We found that the lncRNA harbours 49 sites for binding a set of four miRNAs while the Chitin Synthase 8 mRNA comprises 478 sites. The over-representation of shared miRNA sites suggests that lncRNA Neev may act as a miRNA sponge to transiently de-repress chitin synthase 8 during formation of new chaetae in the regenerating segments of Eisenia fetida.Summary statementThe earthworm, Eisenia fetida, regenerates posterior segments following amputation. The transcriptome of the regenerating worm revealed a novel lncRNA, expressed only at the base of regenerating chaetae. We propose that this lncRNA is a miRNA sponge that modulates chitin synthesis.

scholarly journals Single cell transcriptome profiling of the human developing spinal cord reveals a conserved genetic programme with human specific features

2021 ◽  
Author(s):  
Teresa Rayon ◽  
Rory J. Maizels ◽  
Christopher Barrington ◽  
James Briscoe
Keyword(s):  
Gene Expression ◽  
Spinal Cord ◽  
Single Cell ◽  
Motor Neurons ◽  
Neural Tube ◽  
Transcriptome Profiling ◽  
Cell Types ◽  
Human Embryos ◽  
Neuronal Populations ◽  
Cell Transcriptome

AbstractThe spinal cord receives input from peripheral sensory neurons and controls motor output by regulating muscle innervating motor neurons. These functions are carried out by neural circuits comprising molecularly and physiologically distinct neuronal subtypes that are generated in a characteristic spatial-temporal arrangement from progenitors in the embryonic neural tube. The systematic mapping of gene expression in mouse embryos has provided insight into the diversity and complexity of cells in the neural tube. For human embryos, however, less information has been available. To address this, we used single cell mRNA sequencing to profile cervical and thoracic regions in four human embryos of Carnegie Stages (CS) CS12, CS14, CS17 and CS19 from Gestational Weeks (W) 4-7. In total we recovered the transcriptomes of 71,219 cells. Analysis of progenitor and neuronal populations from the neural tube, as well as cells of the peripheral nervous system, in dorsal root ganglia adjacent to the neural tube, identified dozens of distinct cell types and facilitated the reconstruction of the differentiation pathways of specific neuronal subtypes. Comparison with existing mouse datasets revealed the overall similarity of mouse and human neural tube development while highlighting specific features that differed between species. These data provide a catalogue of gene expression and cell type identity in the developing neural tube that will support future studies of sensory and motor control systems and can be explored at https://shiny.crick.ac.uk/scviewer/neuraltube/.

scholarly journals Multifaceted roles of microRNAs: From motor neuron generation in embryos to degeneration in spinal muscular atrophy

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Tai-Heng Chen ◽  
Jun-An Chen
Keyword(s):  
Nervous System ◽  
Neurodegenerative Diseases ◽  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Cell Types ◽  
Spinal Motor Neurons ◽  
Potential Applications ◽  
The Central Nervous System

Two crucial questions in neuroscience are how neurons establish individual identity in the developing nervous system and why only specific neuron subtypes are vulnerable to neurodegenerative diseases. In the central nervous system, spinal motor neurons serve as one of the best-characterized cell types for addressing these two questions. In this review, we dissect these questions by evaluating the emerging role of regulatory microRNAs in motor neuron generation in developing embryos and their potential contributions to neurodegenerative diseases such as spinal muscular atrophy (SMA). Given recent promising results from novel microRNA-based medicines, we discuss the potential applications of microRNAs for clinical assessments of SMA disease progression and treatment.

Alteration of nuclear architecture in male germ cells of chromosomally derived subfertile mice

2001 ◽  
Vol 114 (24) ◽  
pp. 4429-4434
Author(s):  
Silvia Garagna ◽  
Maurizio Zuccotti ◽  
Alan Thornhill ◽  
Raul Fernandez-Donoso ◽  
Soledad Berrios ◽  
...  
Keyword(s):  
Sertoli Cells ◽  
Spatial Organization ◽  
Nuclear Architecture ◽  
Spatial Arrangement ◽  
Cell Types ◽  
Condensed State ◽  
Germ Cell Differentiation ◽  
Y Chromosomes ◽  
Dual Colour ◽  
Pachytene Spermatocytes

The mammalian cell nucleus consists of numerous compartments involved in the regular unfolding of processes such as DNA replication and transcription, RNA maturation, protein synthesis and cell division. Knowledge is increasing of the relationships between high-order levels of chromatin organization and its spatial organization, and of how these relationships contribute to the various functions carried out in the nucleus. We have studied the spatial arrangement of mouse telocentric chromosomes 5, 11, 13, 15, 16 and 17, some of their metacentric Robertsonian derivatives, and X and Y chromosomes by whole chromosome painting in male germ (spermatogonia, pachytene spermatocytes and spermatids) and Sertoli cells of homozygous and heterozygous individuals. Using dual-colour fluorescence in situ hybridization we found that these chromosomes occupy specific nuclear territories in each cell type analysed. When chromosomes are present as Robertsonian metacentrics in the heterozygous state, that is, as Robertsonian metacentrics and their homologous telocentrics, differences in their nuclear positions are detectable: heterozygosity regularly produces a change in the nuclear position of one of the two homologous telocentrics in all the cell types studied. In the Robertsonian heterozygotes, the vast majority of the Sertoli cells show the sex chromosomes in a condensed state, whereas they appear decondensed in the Robertsonian homozygotes. As the Robertsonian heterozygosities we studied produce a chromosomally derived impairment of male germ-cell differentiation, we discuss the possibility that changes in chromosome spatial territories may alter some nuclear machinery (e.g., synapsis, differential gene expression) important for the correct unfolding of the meiotic process and for the proper functioning of Sertoli cells.

Polarization analysis in the crayfish visual system

2001 ◽  
Vol 204 (14) ◽  
pp. 2383-2390 ◽  
Author(s):  
Raymon M. Glantz
Keyword(s):  
Visual System ◽  
Motor Neurons ◽  
Polarized Light ◽  
Cell Types ◽  
Afferent Input ◽  
Polarization Sensitivity ◽  
Polarization Analysis ◽  
Low Contrast ◽  
Motion Responses ◽  
Light Flashes

SUMMARY It is proposed that polarization sensitivity at the most peripheral stages of the crayfish visual system (lamina ganglionaris and medulla externa) is used to enhance contrast and thus may contribute to motion detection in low contrast environments. The four classes of visual interneurons that exhibit polarization sensitivity (lamina monopolar cells, tangential cells, sustaining fibers and dimming fibers) are not sensitive exclusively to polarized light but also respond to unpolarized contrast stimuli. Furthermore, many of these cells and the sustaining fibers in particular exhibit a greater differential e-vector responsiveness to a changing e-vector than to e-vector variations among steady-state stimuli. While all four cell types respond modestly to light flashes at an e-vector of 90° to the preferred orientation, the dynamic response to a changing e-vector is small or absent at this orientation. Because the sustaining fibers exhibit polarization sensitivity, and they provide afferent input to a subset of optomotor neurons, the latter were also tested for polarization sensitivity. The optomotor neurons involved in compensatory reflexes for body pitch were differentially sensitive to the e-vector angle of a flash of light, with maximum responses for e-vectors near the vertical. The motor neurons also exhibited a maximum response near the vertical e-vector to a continuously rotating polarizer. Two scenarios are described in which the sensitivity to a changing e-vector can produce motion responses in the absence of intensity contrast.

The spatial organization of epidermal structures: hairy establishes the geometrical pattern of Drosophila leg bristles by delimiting the domains of achaete expression

Development ◽  
1993 ◽  
Vol 118 (1) ◽  
pp. 9-20 ◽  
Author(s):  
T.V. Orenic ◽  
L.I. Held ◽  
S.W. Paddock ◽  
S.B. Carroll
Keyword(s):  
Drosophila Melanogaster ◽  
Spatial Organization ◽  
Expression Patterns ◽  
Cell Types ◽  
Precursor Cells ◽  
Geometrical Pattern ◽  
Leg Development ◽  
Puparium Formation ◽  
Late Expression ◽  
Bristle Pattern

The spatial organization of Drosophila melanogaster epidermal structures in embryos and adults constitutes a classic model system for understanding how the two dimensional arrangement of particular cell types is generated. For example, the legs of the Drosophila melanogaster adult are covered with bristles, which in most segments are arranged in longitudinal rows. Here we elucidate the key roles of two regulatory genes, hairy and achaete, in setting up this periodic bristle pattern. We show that achaete is expressed during pupal leg development in a dynamic pattern which changes, by approximately 6 hours after puparium formation, into narrow longitudinal stripes of 3–4 cells in width, each of which represents a field of cells (proneural field) from which bristle precursor cells are selected. This pattern of gene expression foreshadows the adult bristle pattern and is established in part through the function of the hairy gene, which also functions in patterning other adult sense organs. In pupal legs, hairy is expressed in four longitudinal stripes, located between every other pair of achaete stripes. We show that in the absence of hairy function achaete expression expands into the interstripe regions that normally express hairy, fusing the two achaete stripes and resulting in extra-wide stripes of achaete expression. This misexpression of achaete, in turn, alters the fields of potential bristle precursor cells which leads to the misalignment of bristle rows in the adult. This function of hairy in patterning achaete expression is distinct from that in the wing in which hairy suppresses late expression of achaete but has no effect on the initial patterning of achaete expression. Thus, the leg bristle pattern is apparently regulated at two levels: a global regulation of the hairy and achaete expression patterns which partitions the leg epidermis into striped zones (this study) and a local regulation (inferred from other studies on the selection of neural precursor cells) that involves refinement steps which may control the alignment and spacing of bristle cells within these zones.

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