Neurological Disease Modeling Using Pluripotent and Multipotent Stem Cells: A Key Step towards Understanding and Treating Mucopolysaccharidoses

Abstract

Despite extensive research, the links between the accumulation of glycosaminoglycans (GAGs) and the clinical features seen in patients suffering from various forms of mucopolysaccharidoses (MPSs) have yet to be further elucidated. This is particularly true for the neuropathology of these disorders; the neurological symptoms are currently incurable, even in the cases where a disease-specific therapeutic approach does exist. One of the best ways to get insights on the molecular mechanisms driving that pathogenesis is the analysis of patient-derived cells. Yet, not every patient-derived cell recapitulates relevant disease features. For the neuronopathic forms of MPSs, for example, this is particularly evident because of the obvious inability to access live neurons. This scenario changed significantly with the advent of induced pluripotent stem cell (iPSC) technologies. From then on, a series of differentiation protocols to generate neurons from iPSC was developed and extensively used for disease modeling. Currently, human iPSC and iPSC-derived cell models have been generated for several MPSs and numerous lessons were learnt from their analysis. Here we review most of those studies, not only listing the currently available MPS iPSC lines and their derived models, but also summarizing how they were generated and the major information different groups have gathered from their analyses. Finally, and taking into account that iPSC generation is a laborious/expensive protocol that holds significant limitations, we also hypothesize on a tempting alternative to establish MPS patient-derived neuronal cells in a much more expedite way, by taking advantage of the existence of a population of multipotent stem cells in human dental pulp to establish mixed neuronal and glial cultures.

Modeling Lysosomal Storage Disorders in an Innovative Way: Establishment and Characterization of Stem Cell Lines from Human Exfoliated Deciduous Teeth of Mucopolysaccharidosis Type II Patients

“…Only then could a marked GAG accumulation be detected, though for two of the three MPS II cell lines alone. The third patient-derived MPS II neuronal cell line did not differ significantly from the control cell line [ 20 ] (reviewed in [ 22 ]). This is significantly different from our own observation in MPS II SHED cell lines, where GAG storage was quite evident.…”

“… Schematic drawing illustrating the different sources of dental mesenchymal stem cells (DMSCs) in the oral cavity. Abbreviations: GMSCs, gingiva-derived mesenchymal stem cells; DFSCs, dental follicle stem cells; SHEDs, stem cells from exfoliated deciduous teeth; SCAPs, stem cells from the apical papilla; DPSCs, dental pulp stem cells; PDLSCs, periodontal ligament stem cells (reproduced from [ 22 ]). …”

“…Altogether, the need for deeper understanding of the pathophysiological mechanisms that underlie the disorder and for more effective treatments to counteract it justify the need for a cellular in vitro model that accurately recapitulates the disease phenotype in hard-to-reach/hard-to-treat cells, e.g., those derived from the nervous and/or skeletal systems. Regarding neurons in particular, the use of induced pluripotent stem cells (iPSCs) to model neurogenetic disorders is well established, for example, the function of cortical neurons from patient-derived fibroblasts or blood cells is now well documented and numerous studies in MPS II-derived iPSCs have already been published, with remarkable results and insights on the neuropathology of this disorder [ 19 , 20 , 21 ] (reviewed in [ 22 ]). However, there are notable drawbacks to using these de-differentiated, reprogrammed cells as in vitro models for molecular studies, mostly their high cost and time-consuming technology validation.…”

“…However, there are notable drawbacks to using these de-differentiated, reprogrammed cells as in vitro models for molecular studies, mostly their high cost and time-consuming technology validation. That is why we are working with a completely different patient-derived cellular model: an alternative, less invasive and less laborious, source of stem cells, the so-called dental mesenchymal stem cells (DMSCs), which can be isolated from different sources in the oral cavity (reviewed in [ 22 ]).…”

Modelling Lysosomal Storage Disorders in an innovative way: Establishment and Characterization of Stem Cell Lines from Human Exfoliated Deciduous Teeth of Mucopolysaccharidoses Type II Patients

“…Altogether, the need for deeper understanding of the pathophysiological mechanisms that underlie the disorder, and for more effective treatments to counteract it, justify the need for a cellular in vitro model that accurately recapitulates the disease phenotype in hard-to reach/hard to treat cells, such as those derived from the nervous and/or skeletal systems. Regarding neurons, in particular, the use of induced pluripotent stem cells (iPSC) to model neurogenetic disorders is well established, for example the function of cortical neurons from patient derived fibroblasts or blood cells is now well-documented and numerous studies in MPS II-derived iPSCs have already been published, with remarkable results and insights on the neuropathology of this disorder [19][20][21] (reviewed in [22]). However, there are notable drawbacks to using these de-differentiated, reprogrammed cells as in vitro models for molecular studies, mostly their high cost and time-consuming technology validation.…”