Generating Late-Onset Human iPSC-Based Disease Models by Inducing Neuronal Age-Related Phenotypes through Telomerase Manipulation

Abstract

SUMMARY Modeling late onset disorders such as Parkinson’s disease (PD) using iPSC technology remains a challenge as current differentiation protocols yield cells with the properties of fetal-stage cells. Here we tested whether it is possible to accelerate aging in vitro to trigger late onset disease phenotypes in an iPSC model of PD. In order to manipulate a factor that is involved in natural aging as well as in premature aging syndromes, we used telomere shortening as an age-inducing tool. We show that shortened telomeres result in age-associated as well as potentially disease-associated phenotypes in human pluripotent stem cell (hPSC) derived midbrain dopamine (mDA) neurons. Our approach provides proof of concept for the further validation of telomere shortening as an induced aging tool for late onset diseases modeling.

Cellular models of alpha‐synuclein toxicity and aggregation

“…Potentially related to this, α‐synuclein accumulation and aggregation is not so far a common feature in iPSC‐derived models unless they are maintained in culture for extremely long periods of time. Therefore, more studies must be performed where aging of iPSC‐DA neurons is provoked pharmacologically or another method (Vera et al ; Tagliafierro et al ). Alternatively, technological advances in cell differentiation may improve our ability to directly convert patient somatic cells into specific neuronal populations (iNeurons) without altering the epigenetic profile.…”

Enhanced maturation of human stem cell derived interneurons by mTOR activation

“…The maturation of human PSC-derived neurons has been accelerated through overexpression of progerin (Miller et al, 2013) and pharmacological inhibition of telomerase (Vera et al, 2016). Here, we use conditional and reversible activation of mTOR signaling to accelerate the maturation of CIns.…”

Next‐generation disease modeling with direct conversion: a new path to old neurons

“…We expect such criteria to become more and more popular, extending our knowledge of cell identity, and that they will eventually largely replace classical means of neuronal characterization. The rejuvenation effect of iPSC reprogramming is a major drawback when attempting to model late-onset diseases [17,157,158], and artificial induction of the factor age by overexpressing progerin [151], shortening of telomeres [159], or exposing cells to age-related stressors [12,160] is an upcoming and widely used strategy to elicit a relevant phenotype in iPSC models for neurodegenerative diseases [12,148,[161][162][163]. In vitro generation of patient-specific neurons from iPSCs for modeling diseases of the brain has evolved into an integral part of neuroscience [144][145][146], and employing human iPSC technology to investigate aspects of age-related neurodegenerative diseases in a patient-specific genetic context at a cellular level has yielded important human neuron-specific insights [147][148][149][150].…”

“…2) [10,[151][152][153][154][155][156]. The rejuvenation effect of iPSC reprogramming is a major drawback when attempting to model late-onset diseases [17,157,158], and artificial induction of the factor age by overexpressing progerin [151], shortening of telomeres [159], or exposing cells to age-related stressors [12,160] is an upcoming and widely used strategy to elicit a relevant phenotype in iPSC models for neurodegenerative diseases [12,148,[161][162][163]. Direct iN conversion of human fibroblasts from elderly human patients and healthy donors into iNs circumvents this issue and has attracted broad attention.…”