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About Sickkids
About SickKids

Julien Muffat, PhD

Research Institute
Neurosciences & Mental Health

University of Toronto
Assistant Professor
Department of Molecular Genetics

Chair Positions
Canada Research Chair
Stem Cell Bioengineering and Synthetic Neuroimmunology

Other Positions
Medicine by Design Investigator

Phone: 416-813-7654 ext. 309997

External Email: julien.muffat@sickkids.ca

Brief Biography

Dr. Julien Muffat is a Scientist in the Neurosciences and Mental Health Program at The Hospital for Sick Children. His laboratory studies interactions of the nervous and immune systems, using an in vitro approach capitalizing on the advent of human induced pluripotent stem cells, directed differentiation in 2D and 3D, and genetic engineering. Of particular interest to the lab is the role of the resident innate immune cells of the brain, microglia, in neurological and psychiatric disorders.

Dr. Muffat studied in France for his Licence (B.Sc.) in Biochemistry and Molecular Biology at the Biochemistry and Bioengineering department of the Ecole Normale Superieure de Paris-Saclay. He went on to receive a Mastaire (M.Sc.) in Biology of Aging from the University of Paris for research on the oxidative and aggregative properties of amyloid in the laboratory of Rudolph Tanzi at Harvard Medical School. Dr. Muffat received his PhD. in Molecular and Cellular Neurosciences from the California Institute of Technology, for his studies of the genetics of normal and pathological aging, under the guidance of Seymour Benzer. He completed his post-doctoral training with Rudolf Jaenisch at the Whitehead Institute at MIT, where he established an in vitro method of differentiation of human iPS cells into microglia-like cells, to model CNS disorders. He joined SickKids in 2017.

Research Interests

  • Non-cell autonomous mechanisms of glio- and neuro-degeneration.
  • Normal and pathological interactions of immune system and nervous system.
  • Directed differentiation and acquisition of cellular identity in vitro vs in vivo.
  • Bioengineering of micro-physiological 3D models of the human cortex.

Research activities

The brain harbors a self-contained immune system, finding its origins early in development. These resident immune cells, microglia, along with rare patrolling blood cells, contribute to the development, maturation, homeostasis, and perhaps eventual demise of the nervous system. The laboratory for Synthetic Neuroimmunology aims to clarify, using humanized in vitro models, the role of these cells in health and disease. Mutations and polymorphisms affecting genes expressed solely in microglia are associated with conditions ranging from psychiatric disorders of developmental origin (e.g. Schizophrenia), to age-related neurological disorders (e.g. Alzheimer’s). Using primary benchmarks and single cell profiling, combined with tissue engineering, we aim to better replicate cellular identity in our cultures, as a prerequisite for identification of disease-associated phenotypes. Functional variations affecting microglial homeostatic behavior and reactivity, at different stages of development and different ages, eventually lead to neuronal dysfunction, loss of connectivity, or death. We use the CRISPR/Cas9 toolkit to engineer putative disease-associated variants in pluripotent stem cells. Directed differentiation into cells of interest (neurons, glia) allows us to test the effects of these variants in monotypic cultures, and in co-cultures designed to replicate the 3D cortical architecture of the human brain. Glial cells such as microglia and astrocytes are capable of sensing and reacting to various stimuli, such as immune/inflammatory modulators. As such, they are uniquely suited to integrate peripheral inputs (pathogens, microbiota, cytokines), as well CNS-centric stimuli (synaptic plasticity, electrophysiological activity, metabolic demands, cell death) over time, ultimately affecting the health of our neural networks, for better or worse. While their roles in development are under evolutionary constrains, their actions in disease or during aging may be maladaptive. Our ultimate goal is to identify and control inflammatory processes that may precede, sometimes by decades, the largely irreversible degenerative processes seen in patients.


  • 2017 – Medicine by Design Investigator
  • 2016 – NINDS scholarship (3D models of CNS disease)
  • 2014 – NARSAD Young Investigator Award, Brain & Behavior Research Foundation
  • 2007 – Graduate Research Fellowship (Della Martin Charitable Foundation)
  • 2003 – Graduate Research Fellowship (Glenn Foundation for Aging Research)
  • 2000 – International Action Award (ENS, France)
  • 1999 – Study Abroad Fellowship (Paris, France)


Liu XS, Wu H, Krzisch M, Wu X, Graef J, Muffat J, Hnisz D, Li CH, Yuan B, Xu C, Li Y, Vershkov D, Cacace A, Young RA, Jaenisch R. “Rescue of Fragile X Syndrome Neurons by DNA Methylation Editing of the FMR1 Gene.” CELL, 2018

Muffat J*, Li Y*, Omer A*, Durbin A, Bosch I, Bakiasi G, Gehrke L, Jaenisch R. “Modeling invasion of the fetal human brain by Zika: microglia as a possible Trojan horse”. BIORXIV, 2017

*Muffat J, *Li Y, and Jaenisch R.  “CNS disease models with human pluripotent stem cells in the CRISPR age.” CURRENT OPINION IN CELL BIOLOGY, 2016

*Li Y, *Muffat J, Omer A, Bosch I, Lancaster M, Sur M, Gehrke L, Knoblich J, and Jaenisch R (2016) “Induction of expansion and folding in human cerebral organoids.” CELL STEM CELL, 2016

*Muffat J, *Li Y, Yuan B, Mitalipova M, Omer A, Corcoran S, Bakiasi G, Tsai LH, Aubourg P, Ransohoff RM, and Jaenisch R. “Efficient derivation of microglia-like cells from human pluripotent stem cells.” NATURE MEDICINE, 2016

Choi SH, Kim YH, Hebisch M, Sliwinski C, Lee S, D'Avanzo C, Chen H, Hooli B, Asselin C, Muffat J, Klee JB, Zhang C, Wainger BJ, Peitz M, Kovacs DM, Woolf CJ, Wagner SL, Tanzi RE, Kim DY. “A three-dimensional human neural cell culture model of Alzheimer's disease.” NATURE, 2014

Chudnovsky Y, Kim D, Zheng S, Whyte WA, Bansal M, Bray MA, Gopal S, Theisen MA, Bilodeau S, Thiru P, Muffat J, Yilmaz OH, Mitalipova M, Woolard K, Lee J, Nishimura R, Sakata N, Fine HA, Carpenter AE, Silver SJ, Verhaak RG, Califano A, Young RA, Ligon KL, Mellinghoff IK, Root DE, Sabatini DM, Hahn WC, Chheda MG. “ZFHX4 Interacts with the NuRD Core Member CHD4 and Regulates the Glioblastoma Tumor-Initiating Cell State.” CELL REPORTS, 2013

Chung CY, Khurana V, Auluck PK, Tardiff DF, Mazzulli JR, Soldner F, Baru V, Lou Y, Freyzon Y, Cho S, Mungenast AE, Muffat J, Mitalipova M, Pluth MD, Jui NT, Schüle B, Lippard SJ, Tsai LH, Krainc D, Buchwald SL, Jaenisch R, Lindquist S. “Identification and rescue of α-synuclein toxicity in Parkinson patient-derived neurons.” SCIENCE. 2013

Li Y, Wang H, Muffat J, Cheng AW, Orlando DA, Loven J, Kwok S, Feldman DA, Bateup HS, Gao Q, Hockemeyer D, Mitalipova M, Lewis CA, Vander Heiden MG, Sur M, Young RA, and Jaenisch R. “Global transcriptional and translational repression in human-embryonic-stem-cell-derived Rett Syndrome neurons.” CELL STEM CELL, 2013

Saha K, Mei K, Reisterer CM, Pyzocha N, Yang J, Muffat J, Davies MC, Alexander MR, Langer R, Anderson DG, Jaenisch R. “Surface engineered substrates for improved human pluripotent stem cell culture under fully defined conditions” PNAS, 2011

Lengner CJ, Gimelbrant AA, Erwin JA, Cheng AW, Guenther MG, Welstead GW, Alagappan R, Frampton GM, Xu P, Muffat J, Santagata S, Powers D, Barrett CB, Young RA, Lee JT, Jaenisch R, Mitalipova M.  “Derivation of pre-X inactivation human embryonic stem cells under physiological oxygen concentrations”. CELL, 2010

Hanna J, Cheng AW, Saha K, Kim J, Lengner CJ, Soldner F, Cassady JP, Muffat J, Carey BW, Jaenisch R. “Human embryonic stem cells with biological and epigenetic characteristics similar to those of mouse ESCs”. PNAS, 2010

Muffat J, Walker DW. “Apolipoprotein D: an overview of its role in aging and age-related diseases” CELL CYCLE, 2010

Hull-Thompson J*, Muffat J*, Sanchez D, Walker DW, Benzer S, Ganfornina MD, Jasper H. “Control of metabolic homeostasis by stress signaling is mediated by the lipocalin NLaz”. PLOS GENETICS, 2009

Muffat J, Walker DW and Benzer S. "Human ApoD, an apolipoprotein up-regulated in neurodegenerative diseases, extends lifespan and increases stress resistance in Drosophila." PNAS, 2008

Walker DW*, Muffat J*, Rundel C, Benzer S. "Overexpression of a Drosophila homolog of apolipoprotein D leads to increased stress resistance and extended lifespan." CURRENT BIOLOGY, 2006

Walker DW, Hajek P, Muffat J, Knoepfle D, Cornelison S, Attardi G, Benzer S. "Hypersensitivity to oxygen and shortened lifespan in a Drosophila mitochondrial complex II mutant." PNAS, 2006

Goldstein LE, Muffat JA*, Cherny RA, Moir RD, Ericsson MH, Huang X, Mavros C, Coccia JA, Faget KY, Fitch KA, Masters CL, Tanzi RE, Chylack LT Jr, Bush AI. "Cytosolic beta-amyloid deposition and supranuclear cataracts in lenses from people with Alzheimer's disease." LANCET, 2003

Goldstein LE, Leopold MC, Huang X, Atwood CS, Saunders AJ, Hartshorn M, Lim JT, Faget KY, Muffat JA, Scarpa RC, Chylack LT Jr, Bowden EF, Tanzi RE, Bush AI. "3-Hydroxykynurenine and 3-hydroxyanthranilic acid generate hydrogen peroxide and promote alpha-crystallin cross-linking by metal ion reduction." BIOCHEMISTRY, 2000