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Review
. 2017 Feb 1:1656:14-26.
doi: 10.1016/j.brainres.2015.11.013. Epub 2015 Nov 17.

Back and forth in time: Directing age in iPSC-derived lineages

Daniela Cornacchia  1 , Lorenz Studer  2
Affiliations
Review

Back and forth in time: Directing age in iPSC-derived lineages

Daniela Cornacchia et al. Brain Res. .

Abstract

The advent of induced pluripotent stem cells (iPSC) has transformed the classic approach of studying human disease, providing in vitro access to disease-relevant cells from patients for the study of disease pathogenesis and for drug screening. However, in spite of the broad repertoire of iPSC-based disease models developed in recent years, increasing evidence suggests that this technology might not be fully suitable for the study of conditions of old age, such as neurodegeneration. The difficulty in recapitulating late-stage features of disease in cells of pluripotent origin is believed to be a discrepancy between the fetal-like nature of iPSC-progeny and the advanced age of onset of neurodegenerative syndromes. In parallel to the issue of functional immaturity known to affect derivatives of pluripotent cells, latest findings suggest that reprogramming also subjects cells to a process of "rejuvenation", giving rise to cells that are too "young" to manifest phenotypes of age-related diseases. Thus, following the significant progress in manipulating cellular fate, the stem cell field will now have to face the new challenge of controlling cellular age, in order to fully harness the potential of iPSC-technology to advance the research and cure of diseases of the aging brain. This article is part of a Special Issue entitled SI: Exploiting human neurons.

Keywords: Aging; Induced in vitro aging; Maturation; Neurodegenerative diseases; Rejuvenation; iPSC-disease modeling.

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Figures

Figure 1
Figure 1
Waddington Landscape depicting the continuity of the developmental phase of specifying cell identity with the later stages of ontogenesis including cell maturation and aging. Reversibility of all three steps can be achieved through the reprogramming process. Cells are represented as spheres and the subsequent temporal dynamics of for a given type through maturation and age are reflected by their changing colors.
Figure 2
Figure 2
Techniques to promote cellular maturation of hPSC derived lineages. A) 2D strategies include the identification of optimized cocktails of directed differentiation, co-cultures with developmentally relevant cell types such as astroglia, or directed conversion of somatic cells to induced neurons through forced expression of defined factors such as NGN2. B) Accelerated maturation has also been achieved through three-dimensional approaches such as the in vitro generation of organoids with highly complex structures including cerebral (mini-brains) or retinal organoids. Improved connectivity and network formation was achieved by culturing primary neurons in microfluidic devices (organ-on-a-chip), however this approach has not yet been fully implemented for PSC-derived neurons (dashed line).
Figure 3
Figure 3
Inducing cellular age in hPSC-derived lineages for improved modeling of late-onset disorders. Somatic cells are isolated via biopsy from a patient (as illustrated here for PD). These primary cells are reprogrammed to iPSC and re-differentiated into disease-relevant neuronal subtypes for in vitro disease modeling and drug-screening. Cell fate transitions in vitro (upper part of the figure) represent matched developmental and ontological stages in vivo (lower part of the figure). For example, the iPSC stage is equivalent to the pre-implantation embryo (blastocyst/early epiblast), while mature iPSC-derived neurons correspond to brain cells of young adults. In fact, neurons differentiated from iPSCs appear rejuvenated and apparently healthy in spite of the presence of a disease-causing genetic mutation (purple nuclei), similarly to their in vivo equivalents in young, pre-symptomatic patients. The onset of neurodegenerative symptoms in patients requires the synergistic action of genetic background, environmental factors and importantly, age. Accordingly, manifestation of late-onset disease-phenotypes in iPSC-derived neurons is dependent on challenging cells with either toxic compounds (ROS, pesticide toxins) or age-inducing genetic factors (progerin). While the exposure to toxic agents has proven successful in revealing early biochemical indicators of disease susceptibility and hypersensitivity to metabolic stress (red neurons with intact structures, cell death represented as faded neurons), treatment of cell with progerin has succeeded in triggering typical age-dependent degenerative phenotypes such as dendrite shortening and neuromelanin accumulation (grey neurons with dark spots). However, it remains to be determined whether alternative approaches based on known molecular aging mechanisms (transcriptional networks, signaling pathways, epigenetic manipulations or other progeroid syndromes) can further improve on currently available patient-specific models. Alternatively, it will be important to assess whether induced neurons established via direct conversion will prove efficient in faithfully inducing physiological age in vitro (dashed arrow lines) and modeling age-dependent disorders.
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