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Research description

The lethal motor neuron diseases (MNDs) amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are defined by the loss of somatic motor neurons that innervate muscles in arms, legs, trunk and face, leading to muscle wasting. However, not all motor neurons are equally vulnerable; certain groups of motor neurons are spared, including those in the oculomotor nucleus, controlling eye movement and motor neurons in the Onuf's nucleus, controlling pelvic muscles. The reasons for the differential vulnerability to degeneration among motor neuron groups are unknown.

Research in the Hedlund lab is aimed at elucidating mechanisms of neuronal vulnerability and resistance with the goal of identifying new molecular targets for the treatment of motor neuron diseases.

Towards this goal, we utilize laser capture microdissection coupled with RNA sequencing to dissect molecular pathways in distinct motor neuron populations in animal models of MNDs. We also perform cross-disease analyses of degenerative and regenerative axonal responses at neuromuscular junctions - the specialized synapses between motor neurons and muscle.

Motor neuron cultures derived from embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) harboring disease-inducing mutations are coupled with microfluidics to model MNDs and study neuronal vulnerability and protection in vitro. Finally, we modulate candidate gene expression in vivo in transgenic MND mouse models to induce motor neuron protection and axonal regeneration.

More information can be found on the lab web site.

Recent publications:

Differential neuronal vulnerability identifies IGF-2 as a protective factor in ALS.
Allodi I, Comley L, Nichterwitz S, Nizzardo M, Simone C, Benitez J, et al
Sci Rep 2016 05;6():25960

 

Dopamine Receptor Antagonists Enhance Proliferation and Neurogenesis of Midbrain Lmx1a-expressing Progenitors.
Hedlund E, Belnoue L, Theofilopoulos S, Salto C, Bye C, Parish C, et al
Sci Rep 2016 06;6():26448

Cross-disease comparison of amyotrophic lateral sclerosis and spinal muscular atrophy reveals conservation of selective vulnerability but differential neuromuscular junction pathology.
Comley L, Nijssen J, Frost-Nylen J, Hedlund E
J. Comp. Neurol. 2016 May;524(7):1424-42

Motor neurons with differential vulnerability to degeneration show distinct protein signatures in health and ALS.
Comley L, Allodi I, Nichterwitz S, Nizzardo M, Simone C, Corti S, et al
Neuroscience 2015 Apr;291():216-29

Presymptomatic activation of the PDGF-CC pathway accelerates onset of ALS neurodegeneration.
Lewandowski S, Nilsson I, Fredriksson L, Lönnerberg P, Muhl L, Zeitelhofer M, et al
Acta Neuropathol. 2016 Mar;131(3):453-64

Selection Based on FOXA2 Expression Is Not Sufficient to Enrich for Dopamine Neurons From Human Pluripotent Stem Cells.
Aguila J, Blak A, van Arensbergen J, Sousa A, Vázquez N, Aduriz A, et al
Stem Cells Transl Med 2014 Sep;3(9):1032-42

Directed midbrain and spinal cord neurogenesis from pluripotent stem cells to model development and disease in a dish.
Allodi I, Hedlund E
Front Neurosci 2014 ;8():109

Cellular therapy to target neuroinflammation in amyotrophic lateral sclerosis.
Rizzo F, Riboldi G, Salani S, Nizzardo M, Simone C, Corti S, et al
Cell. Mol. Life Sci. 2014 Mar;71(6):999-1015

Specific and integrated roles of Lmx1a, Lmx1b and Phox2a in ventral midbrain development.
Deng Q, Andersson E, Hedlund E, Alekseenko Z, Coppola E, Panman L, et al
Development 2011 Aug;138(16):3399-408

Transcription factor-induced lineage selection of stem-cell-derived neural progenitor cells.
Panman L, Andersson E, Alekseenko Z, Hedlund E, Kee N, Mong J, et al
Cell Stem Cell 2011 Jun;8(6):663-75

Global gene expression profiling of somatic motor neuron populations with different vulnerability identify molecules and pathways of degeneration and protection.
Hedlund E, Karlsson M, Osborn T, Ludwig W, Isacson O
Brain 2010 Aug;133(Pt 8):2313-30

Publications

Characterization of molecular mechanisms underlying the axonal Charcot-Marie-Tooth neuropathy caused by MORC2 mutations
Sancho P, Bartesaghi L, Miossec O, García-garcía F, Ramírez-jiménez L, Siddell A, et al
Human molecular genetics 2019;():-

Axon-Seq Decodes the Motor Axon Transcriptome and Its Modulation in Response to ALS
Nijssen J, Aguila J, Hoogstraaten R, Kee N, Hedlund E
Stem cell reports 2018;11(6):1565-1578

CRISPR-Trap: a clean approach for the generation of gene knockouts and gene replacements in human cells
Reber S, Mechtersheimer J, Nasif S, Benitez Ja, Colombo M, Domanski M, et al
Molecular biology of the cell 2018;29(2):75-83

Fatal demyelinating disease is induced by monocyte-derived macrophages in the absence of TGF-β signaling
Lund H, Pieber M, Parsa R, Grommisch D, Ewing E, Kular L, et al
Nature immunology 2018;19(5):1-7

LCM-Seq: A Method for Spatial Transcriptomic Profiling Using Laser Capture Microdissection Coupled with PolyA-Based RNA Sequencing
Nichterwitz S, Benitez Ja, Hoogstraaten R, Deng Q, Hedlund E
Methods in molecular biology (Clifton, N.J.) 2018;1649():95-110

Neurturin is a PGC-1α1-controlled myokine that promotes motor neuron recruitment and neuromuscular junction formation
Mills R, Taylor-weiner H, Correia Jc, Agudelo Lz, Allodi I, Kolonelou C, et al
Molecular metabolism 2018;7():12-22

Single-cell RNA sequencing: Technical advancements and biological applications
Hedlund E, Deng Q
Molecular aspects of medicine 2018;59():36-46

Direct Reprogramming of Resident NG2 Glia into Neurons with Properties of Fast-Spiking Parvalbumin-Containing Interneurons
Pereira M, Birtele M, Shrigley S, Benitez Ja, Hedlund E, Parmar M, et al
Stem cell reports 2017;9(3):742-751

Motor neuron vulnerability and resistance in amyotrophic lateral sclerosis
Nijssen J, Comley Lh, Hedlund E
Acta neuropathologica 2017;133(6):863-885

Cross-disease comparison of amyotrophic lateral sclerosis and spinal muscular atrophy reveals conservation of selective vulnerability but differential neuromuscular junction pathology
Comley Lh, Nijssen J, Frost-nylen J, Hedlund E
The Journal of comparative neurology 2016;524(7):1424-42

Differential neuronal vulnerability identifies IGF-2 as a protective factor in ALS
Allodi I, Comley L, Nichterwitz S, Nizzardo M, Simone C, Benitez Ja, et al
Scientific reports 2016;6():25960-

Dopamine Receptor Antagonists Enhance Proliferation and Neurogenesis of Midbrain Lmx1a-expressing Progenitors
Hedlund E, Belnoue L, Theofilopoulos S, Salto C, Bye C, Parish C, et al
Scientific reports 2016;6():26448-

Laser capture microscopy coupled with Smart-seq2 for precise spatial transcriptomic profiling
Nichterwitz S, Chen G, Aguila Benitez J, Yilmaz M, Storvall H, Cao M, et al
Nature communications 2016;7():12139-

Presymptomatic activation of the PDGF-CC pathway accelerates onset of ALS neurodegeneration
Lewandowski Sa, Nilsson I, Fredriksson L, Lönnerberg P, Muhl L, Zeitelhofer M, et al
Acta neuropathologica 2016;131(3):453-64

Single-cell analyses of X Chromosome inactivation dynamics and pluripotency during differentiation
Chen G, Schell Jp, Benitez Ja, Petropoulos S, Yilmaz M, Reinius B, et al
Genome research 2016;26(10):1342-1354

Motor neurons with differential vulnerability to degeneration show distinct protein signatures in health and ALS
Comley L, Allodi I, Nichterwitz S, Nizzardo M, Simone C, Corti S, et al
Neuroscience 2015;291():216-29

Cellular therapy to target neuroinflammation in amyotrophic lateral sclerosis
Rizzo F, Riboldi G, Salani S, Nizzardo M, Simone C, Corti S, et al
Cellular and molecular life sciences : CMLS 2014;71(6):999-1015

Directed midbrain and spinal cord neurogenesis from pluripotent stem cells to model development and disease in a dish
Allodi I, Hedlund E
Frontiers in neuroscience 2014;8():109-

Selection Based on FOXA2 Expression Is Not Sufficient to Enrich for Dopamine Neurons From Human Pluripotent Stem Cells
Aguila Jc, Blak A, Van Arensbergen J, Sousa A, Vázquez N, Aduriz A, et al
Stem cells translational medicine 2014;3(9):1032-42

Cellular programming and reprogramming: sculpting cell fate for the production of dopamine neurons for cell therapy
Aguila Jc, Hedlund E, Sanchez-pernaute R
Stem cells international 2012;2012():412040-

Specific and integrated roles of Lmx1a, Lmx1b and Phox2a in ventral midbrain development
Deng Ql, Andersson E, Hedlund E, Alekseenko Z, Coppola E, Panman L, et al
DEVELOPMENT 2011;138(16):3399-408

The protective effects of beta-lactam antibiotics in motor neuron disorders
Hedlund E
EXPERIMENTAL NEUROLOGY 2011;231(1):14-8

Transcription Factor-Induced Lineage Selection of Stem-Cell-Derived Neural Progenitor Cells
Panman L, Andersson E, Alekseenko Z, Hedlund E, Kee N, Mong J, et al
CELL STEM CELL 2011;8(6):663-75

Global gene expression profiling of somatic motor neuron populations with different vulnerability identify molecules and pathways of degeneration and protection
Hedlund E, Karlsson M, Osborn T, Ludwig W, Isacson O
BRAIN 2010;:2313-30

Neuronal cell replacement in Parkinson's disease
Hedlund E, Perlmann T
JOURNAL OF INTERNAL MEDICINE 2009;266(4):358-71

ALS Model Glia Can Mediate Toxicity to Motor Neurons Derived from Human Embryonic Stem Cells
Hedlund E, Isacson O
CELL STEM CELL 2008;3(6):575-6

Embryonic stem cell-derived Pitx3-enhanced green fluorescent protein midbrain dopamine neurons survive enrichment by fluorescence-activated cell sorting and function in an animal model of Parkinson's disease
Hedlund E, Pruszak J, Lardaro T, Ludwig W, Vinuela A, Kim Ks, et al
STEM CELLS 2008;26(6):1526-36

Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson's disease
Wernig M, Zhao Jp, Pruszak J, Hedlund E, Fu Dd, Soldner F, et al
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2008;105(15):5856-61

Cell therapy and stem cells in animal models of motor neuron disorders
Hedlund E, Hefferan Mp, Marsala M, Isacson O
EUROPEAN JOURNAL OF NEUROSCIENCE 2007;26(7):1721-37

Selection of embryonic stem cell-derived enhanced green fluorescent protein-positive dopamine neurons using the tyrosine hydroxylase promoter is confounded by reporter gene expression in immature cell populations
Hedlund E, Pruszak J, Ferree A, Vinuela A, Hong Sh, Isacson O, et al
STEM CELLS 2007;25(5):1126-35

A tyrosine hydroxylase-yellow fluorescent protein knock-in reporter system labeling dopaminergic neurons reveals potential regulatory role for the first intron of the rodent tyrosine hydroxylase gene
Kelly Bb, Hedlund E, Kim C, Ishiguro H, Isacson O, Chikaraishi Dm, et al
NEUROSCIENCE 2006;142(2):343-54

Genetic selection of sox1GFP-expressing neural precursors removes residual tumorigenic pluripotent stem cells and attenuates tumor formation after transplantation
Chung S, Shin Bs, Hedlund E, Pruszak J, Ferree A, Kang Uj, et al
JOURNAL OF NEUROCHEMISTRY 2006;97(5):1467-80

L1 CAM expression is increased surrounding the lesion site in rats with complete spinal cord transection as neonates
Kubasak Md, Hedlund E, Roy Rr, Carpenter Em, Edgerton Vr, Phelps Pe
EXPERIMENTAL NEUROLOGY 2005;194(2):363-75

The homeodomain transcription factor Pitx3 facilitates differentiation of mouse embryonic stem cells into AHD2-expressing dopaminergic neurons
Chung S, Hedlund E, Hwang M, Kim Dw, Shin Bs, Hwang Dy, et al
MOLECULAR AND CELLULAR NEUROSCIENCE 2005;28(2):241-52

Identification of a Hoxd10-regulated transcriptional network and combinatorial interactions with Hoxa10 during spinal cord development
Hedlund E, Karsten Sl, Kudo L, Geschwind Dh, Carpenter Em
JOURNAL OF NEUROSCIENCE RESEARCH 2004;75(3):307-19

Region-specific cell grafting into cervical and lumbar spinal cord in rat: a qualitative and quantitative stereological study
Kakinohana O, Cizkova D, Tomori Z, Hedlund E, Marsala S, Isacson O, et al
EXPERIMENTAL NEUROLOGY 2004;190(1):122-32

Differential Pax6 promoter activity and transcript expression during forebrain development
Anderson Tr, Hedlund E, Carpenter Em
MECHANISMS OF DEVELOPMENT 2002;114(1-2):171-5

Cytochrome P450 in the brain; A review
Hedlund E, Gustafsson Ja, Warner M
CURRENT DRUG METABOLISM 2001;2(3):245-63

Neurosteroid hydroxylase CYP7B - Vivid reporter activity in dentate gyrus of gene-targeted mice and abolition of a widespread pathway of steroid and oxysterol hydroxylation
Rose K, Allan A, Gauldie S, Stapleton G, Dobbie L, Dott X, et al
JOURNAL OF BIOLOGICAL CHEMISTRY 2001;276(26):23937-44

Cytochrome P450 in the brain: 2B or not 2B
Hedlund E, Gustafsson Ja, Warner M
TRENDS IN PHARMACOLOGICAL SCIENCES 1998;19(3):82-5

Extrahepatic cytochrome P450: role in in situ toxicity and cell-specific hormone sensitivity
Warner M, Hellmold H, Magnusson M, Rylander T, Hedlund E, Gustafsson Ja
Archives of toxicology. Supplement. = Archiv fur Toxikologie. Supplement 1998;20():455-63

Cytochrome P450 in the breast and brain: Role in tissue-specific activation of xenobiotics
Warner M, Hellmold H, Yoshida S, Liao Dz, Hedlund E, Gustafsson Ja
MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS 1997;376(1-2):79-85

Cytochrome P4502D4 in the brain: Specific neuronal regulation by clozapine and toluene
Hedlund E, Wyss A, Kainu T, Backlund M, Kohler C, Peltohuikko M, et al
MOLECULAR PHARMACOLOGY 1996;50(2):342-50

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