Stem Cell Biology
Although a glial component in neurological disorders is increasingly appreciated, we still lack proper understanding of neuron-glia communications. Our goal is to identify and describe glial defects in neurodevelopmental disorders, and to perform proof-of-concept studies for glial-targeted therapy strategies using advanced stem cell technologies.
Glial Defects in Neurological Disorders
More and more evidence shows that glial cells are essential in proper neuronal functioning in the brain, like axonal conduction and synaptic transmission. The two major glial cell types in the brain are the oligodendrocytes and the astrocytes. The oligodendrocytes are responsible for myelin formation in the central neural system and astrocytes have homeostatic functions including synaptic and metabolic functions. The communication between neurons and glia involves signals like ion fluxes, neurotransmitters, growth factors and calcium. By regulating these signaling factors, glial cells can affect neuronal activity locally as well as on network level. Already during neurodevelopment, astrocytes have instructive influences on for example neuronal migration, distribution of synaptic connections and formation of myelinated axons, while oligodendrocytes regulate proper axonal transport, axonal diameter and microtubule number and stability. Since glial dysfunction is increasingly appreciated in neurological disorders, they might be target in future therapies.
Induced Pluripotent Stem Cell (iPSC) Technology
iPSC technology gives the opportunity to generate early stem cells from somatic cell types (incl. skin, hair, blood), and to generate patient-derived and disease-specific neural cell types of interest. This discovery opened new avenues to model diseases, where the genetic components have yet to be identified, or for which animal models are inappropriate. We use up-to-date and optimized procedures to generate patient iPSCs and iPSC-derived astrocytes, oligodendrocytes and neurons, which are functionally analyzed in collaboration with on-side laboratories with state-of-the-art expertise in advanced microscopy, electrophysiology, proteomics and high content cellular screening. These efforts created the base for the VU/VUmc iPSCenter with the goal to improve current and to develop new treatment options for a variety of brain disorders. iPSC technology hold great promises for high-throughput screening platforms and cell replacement therapies for the future.
1) Towards understanding glial defects in neurodevelopmental disorders
Since glial cells can potentially serve as novel therapeutic targets, it is critical to understand these glial contributions to disease. Current projects involve generation and analysis of iPSCs from patients with the neurodevelopmental disorders Rett Syndrome, Tuberous Sclerosis, Vanishing White Matter Disease, 4H Syndrome, Major Depressive Disorder and Schizophrenia. We use iPSC-derived glial / neuronal co-cultures to identify glial-specific defects.
2) Towards developing new therapies for white matter disorders
We need better treatment for white matter disorders (WMDs). We currently focus on Vanishing White Matter Disease (VWM), a progressive autosomal recessive leukodystrophy which leads to early death. The main clinical features are cerebellar ataxia, spasticity and occasional seizures. We are currently exploring iPSC-derived glia replacement and microenviromental-targeting strategies. Our mission is to translate our experimental studies towards neural replacement therapies for VWM and other childhood WMD.
Leferink P*, Dooves S*, Hillen A*, Watanabe K, Jacobs G, Gasparotto L, Cornelissen-Steijger P, Van der Knaap MS, Heine VM. Human and mouse iPSC-derived astrocyte subtypes reveal vulnerability in Vanishing White Matter. bioRxiv 523233, Jan 2019
Dooves S, Leferink PS, Krabbenborg S, Breeuwsma N, Bots S, Hillen A, Jacobs G, Van der Knaap MS, Heine VM. Cell replacement therapy improves pathological hallmarks in a mouse model of leukodystrophy Vanishing White Matter. Stem Cell Reports. 2019, in press.
Nadadhur AG, Alsaqati M, Gasparotto L, Cornelissen-Steijger P, van Hugte E, Dooves S, Harwood AJ, Heine VM. Neuron-Glia Interactions Increase Neuronal Phenotypes in Tuberous Sclerosis Complex Patient iPSC-Derived Models. Stem Cell Reports. 2019 Jan 8;12(1):42-56.
Hinz L, Hoekstra SD, Watanabe K, Posthuma D, Heine VM. Generation of Isogenic Controls for In Vitro Disease Modelling of X-Chromosomal Disorders. Stem Cell Rev. 2018 Nov 13.
Holmes DB & Heine VM. Simplified 3D protocol capable of generating early cortical neuroepithelium. Biol Open. 2017 Mar 15;6(3):402-406.
Falk A, Heine VM, Harwood AJ, Sullivan PF, Peitz M, Brüstle O, Shen S, Sun YM, Glover JC, Posthuma D, Djurovic S. Modeling psychiatric disorders: from genomic findings to cellular phenotypes. Mol Psychiatry. 2016 Sep;21(9):1321.