Characterization of Neurodevelopmental Abnormalities in iPSC-Derived Striatal Cultures from Patients with Huntington’s Disease

Abstract

Background:Huntington’s disease (HD) is an inherited neurodegenerative disease and is characterized by atrophy of certain regions of the brain in a progressive manner. HD patients experience behavioral changes and uncontrolled movements which can be primarily attributed to the atrophy of striatal neurons. Previous publications describe the models of the HD striatum using induced pluripotent stem cells (iPSCs) derived from HD patients with a juvenile onset (JHD). In this model, the JHD iPSC-derived striatal cultures had altered neurodevelopment and contained a high number of nestin expressing progenitor cells at 42 days of differentiation.Objective:To further characterize the altered neurodevelopmental phenotype and evaluate potential phenotypic reversal.Methods:Differentiation of human iPSCs towards striatal fate and characterization by means of immunocytochemistry and stereological quantification.Results:Here this study demonstrates a distinct delay in the differentiation of the JHD neural progenitor population. However, reduction of the JHD aberrant progenitor populations can be accomplished either by targeting the canonical Notch signaling pathway or by treatment with HTT antisense oligonucleotides (ASOs).Conclusions:In summary, this data is postulated to reflect a potential overall developmental delay in JHD.

Aberrant Development Corrected in Adult-Onset Huntington's Disease iPSC-Derived Neuronal Cultures via WNT Signaling Modulation

“…Temporal dysregulation of other developmental markers has also been observed; juvenile HD iPSCs differentiated toward a striatal fate maintain nestin + NPCs susceptible to death by brain-derived neurotrophic factor withdrawal, suggesting that mitotically persistent populations of cells are vulnerable to factors mimicking the HD environment (Mattis et al, 2014). These nestin + NPCs were reduced by targeting the canonical Notch signaling pathway and lowering HTT by antisense oligonucleotide treatment (Mathkar et al, 2019). Additionally, transcriptomic analysis of HD iPSC isogenic lines showed that differences related to neuronal development and dorsal striatum formation occur at the NSC stage (Ring et al, 2015), further implicating the NSC stage in manifestation of developmental aberrations due to mHTT expression.…”

Expanded huntingtin CAG repeats disrupt the balance between neural progenitor expansion and differentiation in human cerebral organoids

“…Indeed, studies examining neurogenesis using mouse HD stem cells have given conflicting results showing that mutant HTT both impairs neurogenesis [21] and promotes it [13,22]. Efforts to examine the impact of mutant HTT on neurodevelopment and neurogenesis using human pluripotent stem cells (hPSCs) having been similarly unclear [18,19,[23][24][25][26] (reviewed in [27]). Mutant HTT was shown to impact early ectodermal development, reflected in an altered phenotypic signature, in an in vitro model of neurulation [28].…”

“…Mutant HTT was shown to impact early ectodermal development, reflected in an altered phenotypic signature, in an in vitro model of neurulation [28]. Based on transcriptional analyses of hPSCs [26], neural progenitors [23,25], and neurons [24], a number of studies 2/26 have also suggested that mutant HTT impairs neural progenitor differentiation and delays neuronal maturation. However, assessment of cortical neurogenesis showed no effect of mutant HTT on the quantity or timeline of differentiation of deep and upper layer cortical neurons [24].…”

Striatal Circuit Development and Its Alterations in Huntington’s Disease

“…These defects were only observed in the striatum, suggesting a specific altered maturation and enhanced vulnerability of striatal neurons (Molero et al, 2009). In this context, it is noteworthy that in vitro analyses of induced pluripotent stem cells derived from HD patients (Mathkar et al, 2019) or human embryonic stem cells bearing the HD mutation (Ruzo et al, 2018) also display delayed progenitor differentiation as well as an increased volume of progenitors cells with abnormal morphologies. Moreover, in zQ175 mice, the maturation of striatal dendritic spines appears to be accelerated at PND21 without any significant change in either cortical or thalamic striatal synapse numbers (McKinstry et al, 2014).…”