TABLE 1.
DS-related phenotypes observed in iPSC-derived cell culture systems and remaining questions that can be addressed with the emerging technology.
| Culture system | Phenotype(s) observed in DS iPSC-derived system(s) | Select remaining question(s) |
|---|---|---|
| Induced pluripotent stem cells (iPSCs) | • Lengthened cell cycle Li et al. (2012)
• Minimal impact on pluripotency or transcriptional signature Park et al. (2008b); Li et al. (2012); Maclean et al. (2012); Meharena et al. (2022) |
What is the consequence of altered cell cycle kinetics on pluripotency and/or fate specification? |
| Neural progenitor cells (NPCs) | • Reduced proliferation Weick et al. (2013); Hibaoui et al. (2014); Meharena et al. (2022)
• Altered differentiation Shi et al. (2012a); Briggs et al. (2013); Jiang et al. (2013); Lu et al. (2013); Weick et al. (2013); Chen et al. (2014); Hibaoui et al. (2014); Hirata et al. (2020); Klein et al. (2021) • Oxidative stress and mitochondrial abnormalities Sobol et al. (2019); Mollo et al. (2021); Prutton et al. (2022); Prutton et al. (2023) • Senescence-like chromatin architecture and transcriptional signature Meharena et al. (2022) |
What is the mechanism underlying altered fate specification and senescence-like signature? • NPC cultures |
| Neurons | • Synaptic deficits Weick et al. (2013); Hibaoui et al. (2014)
• Oxidative stress-induced apoptosis Weick et al. (2013); Sobol et al. (2019) • Dysregulation protein homeostasis and endoplasmic reticulum (ER) stress Hirata et al. (2020) • AD pathology: Aβ and pTau Shi et al. (2012a); Dashinimaev et al. (2017); Toshikawa et al. (2021) |
Why are some neuronal subtypes more vulnerable to T21? • Neuronal subtype-specific cultures |
| Oligodendrocytes | n/a | Does T21 impact oligodendrocyte differentiation and/or myelination? • Oligodendrocyte-neuron-astrocyte-microglia co-cultures and/or oligodendrocyte-enriched organoids |
| Astrocytes | • Altered calcium signaling dynamics Mizuno et al. (2018)
• Elevated oxidative stress Chen et al. (2014); Mizuno et al. (2018) • Induce neuronal toxicity Chen et al. (2014); Araujo et al. (2018); Mizuno et al. (2018) • Perturbed migration Ponroy Bally et al. (2020) |
What is the consequence of T21 on astrocyte function? • Improved astrocyte differentiation methods; co-culture systems |
| Cerebral organoids | • AD pathology: A β and pTau Gonzalez et al. (2018); Zhao and Haddad (2022); Campbell et al. (2023); Czerminski et al. (2023)
• Altered proliferation and delayed neurogenesis Tang et al. (2021); Li et al. (2022); Campbell et al. (2023) • Altered neuronal network activity and impaired excitatory-to-inhibitory balance Foliaki et al. (2021) |
What is the mechanism underlying altered NPC fate specification? • Unguided cerebral organoids |
| Brain region-specific organoids • Cortical • Hippocampal • Ventral forebrain • Cerebellar • Retinal |
• Altered NPC proliferation and delayed neurogenesis in cortical organoids Gonzalez et al. (2018); Tang et al. (2021); Li et al. (2022); Zhao and Haddad (2022); Campbell et al. (2023); Czerminski et al. (2023)
• Ventralized medial ganglionic eminence (MGE)-like organoids showed elevated interneuron differentiation Xu et al. (2019) |
Examination of brain region-specific vulnerability in DS. • Cerebellar, hippocampal, retinal, and cortical organoids Analysis of neuronal circuit activity. • Cortical-hippocampal assembloids |
| Blood-brain barrier and vascularized organoids | n/a | How does T21 impact the BBB and what is the mechanism of cerebrovasculature pathology? • Vascularized organoids |
| Microglia (iMGLs) | n/a | How does T21 impact myeloid lineage differentiation and microglia function? • iMGL-engrafted organoids |
| Human-mouse chimeras | • Altered cortical progenitor differentiation and neuronal functional deficits Real et al. (2018)
• Impaired interneuron migration Huo et al. (2018) • Microglia activation and aberrant synaptic pruning Jin et al. (2022) • Dystrophic microglia in response to pathological Tau Jin et al. (2022) |
Examination of the neuro-immune interplay in DS. • Xenotransplanted microglia How do T21 neurons integrated into specific circuits impact behavior? • Xenotransplanted NPCs |