Skip to main content

Table 1 Recapitulative table of human neuronal models of TSC

From: Recent advances in human stem cell-based modeling of Tuberous Sclerosis Complex

Source Genotype Control Cells generated Model Main findings Treatment
Fibroblasts TSC1+/−
TSC2+/−
Familial Cortical neurons and oligodendrocytes (OL) [24]. 2D Increased network activity, cellular hypertrophy, augmentation of OL proliferation and decrease of OL maturation [24]. Rapamycin and guanabenz improved the reduced maturation observed in TSC neuron-OL co-cultures [24].
Only rapamycin showed regulating effects on soma size when co-cultures contained TSC neurons and/or TSC OLs [24].
Fibroblasts and peripheral blood mononuclear cells TSC2+/−
TSC2−/−
Familial and CRISPR/Cas9 Cerebellar Purkinje neurons [25] 2D Reduced synaptic activity, hypoexcitability, mTORC1 pathway hyperactivation [25]. Rapamycin treatment rescued the deficits in differentiation, synaptic dysfunction, and hypoexcitability of TSC2 mutant hiPSC-PCs in vitro [25].
Peripheral blood mononuclear cells TSC2+/−
TSC2−/−
Familial and CRISPR/Cas9 Cortical neurons co-culture with wild-type astrocytes [26] 2D Loss of one allele of TSC2 is sufficient to cause some morphological and physiological changes in human neurons [26].
Biallelic mutations in TSC2 are necessary to induce gene expression dysregulation present in cortical tubers [26].
Rapamycin treatment reduced neuronal activity and partially reversed gene expression abnormalities [26].
Peripheral blood mononuclear cells TSC2+/− Familial Neurons and astrocytes [27] 2D Enlargement of the soma, perturbed neurite outgrowth, and abnormal connections among cells [27].
Increased saturation density and higher proliferative activity in astrocytes [27].
Rapamycin treatment decreased proliferation [27].
Peripheral blood mononuclear cells TSC2+/− Familial Neurons [28] 2D Delayed in their ability to differentiate into neurons [28].
Heterozygous TSC2 mutations disrupt neuronal development potentially due to dysregulated PI3K/AKT signaling [28].
Rapamycin analogue (RAD001) treatment failed to correct the neuronal differentiation defect in patient cells and did not alter the differentiation of control cells [28].
AKT inhibitor (MK2206) and PI3K inhibitor (LY294002) treatments significantly reduced the fraction of HuC/D+ cells in control cultures derived from both unaffected individuals, mimicking the phenotype of TSC2 haploinsufficient cell lines [28].
Gene editing in human embryonic stem cells TSC2+/−
TSC2−/−
Heterozygous and homozygous deletions of TSC2 Neurons [29] 2D Gene-dosage-dependent mTORC1 hyperactivity in neurodevelopment [29].
Altered synaptic transmission paralleled by molecular changes in pathways associated with autism [29].
Rapamycin treatment at different developmental stages suggests that the neurodevelopment and synaptogenesis can be uncoupled and corrected independently of each other [29].
Gene editing in human embryonic stem cells TSC1+/−
TSC1−/−
TSC2+/−
TSC2−/−
CRISPR/Cas9 Cortical spheroids [30] 3D Mosaic biallelic inactivation during neural progenitor expansion is necessary for the formation of dysplastic cells and increased glia production [30]. Rapamycin treatment results suggest that there is a developmental window for pharmacological mTORC1 suppression to prevent neuronal differentiation defects caused by loss of TSC2. Later rapamycin treatment cannot reverse cell fate decisions that have already been made but can rescue mTORC1 hyperactivation and reduce neuronal and glial hypertrophy. Sustained mTORC1 inhibition is required to prevent the re-emergence of mTORC1 hyperactivity in differentiated cells [30].