Aged induced pluripotent stem cell (iPSCs) as a new cellular model for studying premature aging

Petrini, Stefania; Borghi, Rossella; D’Oria, Valentina; Restaldi, Fabrizia; Moreno, Sandra; Novelli, Antonio; Bertini, Enrico; Compagnucci, Claudia

doi:10.18632/aging.101248

Cited by 30 publications

(34 citation statements)

References 46 publications

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“…However, in our conditions, we observed that SaOS2 cells accumulates nuclear abnormalities and, at the same time, they are low proliferative cells. In support of this, we found in the literature some papers in which nuclear abnormalities are found in low proliferative cells: a high amount of nuclear dysmorphisms have been described in aged, low proliferative iPSC cells and in senescent cells [8,54]. In addition to increased nucleoskeletal dysmorphisms, osteosarcoma cell lines have significant alteration of A-type and B-type lamins, as well as of emerin expression in comparison to normal osteoblasts.…”

Section: Discussionmentioning

confidence: 53%

Nuclear Lamins and Emerin Are Differentially Expressed in Osteosarcoma Cells and Scale with Tumor Aggressiveness

Urciuoli

Petrini

D’Oria

et al. 2020

Cancers

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The nuclear lamina is essential for the maintenance of nuclear shape and mechanics. Mutations in lamin genes have been identified in a heterogeneous spectrum of human diseases known as “laminopathies” associated with nuclear envelope defects and deregulation of cellular functions. Interestingly, osteosarcoma is the only neoplasm described in the literature in association with laminopathies. This study aims characterized the expression of A-type and B-type lamins and emerin in osteosarcoma, revealing a higher percentage of dysmorphic nuclei in osteosarcoma cells in comparison to normal osteoblasts and all the hallmarks of laminopathic features. Both lamins and emerin were differentially expressed in osteosarcoma cell lines in comparison to normal osteoblasts and correlated with tumor aggressiveness. We analysed lamin A/C expression in a tissue-microarray including osteosarcoma samples with different prognosis, finding a positive correlation between lamin A/C expression and the overall survival of osteosarcoma patients. An inefficient MKL1 nuclear shuttling and actin depolymerization, as well as a reduced expression of pRb and a decreased YAP nuclear content were observed in A-type lamin deficient 143B cells. In conclusion, we described for the first time laminopathic nuclear phenotypes in osteosarcoma cells, providing evidence for an altered lamins and emerin expression and a deregulated nucleoskeleton architecture of this tumor.

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Section: Discussionmentioning

confidence: 53%

Nuclear Lamins and Emerin Are Differentially Expressed in Osteosarcoma Cells and Scale with Tumor Aggressiveness

Urciuoli

Petrini

D’Oria

et al. 2020

Cancers

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“…While y-iPSCs appear as well-organized colonies with regular margins, aged iPSCs display progressive loss of their ability to form colonies, and cells are found in small groups with irregular shapes (ma-iPSCs) or isolated (a-iPSCs) (Figure 1 ). Noteworthy, aging iPSCs maintain their pluripotency features, as already demonstrated [ 8 ]. Based on these observations, we explored ultrastructural features of iPSCs using a Dualbeam FIB/SEM Helios Nanolab microscope (FEI, Hillsboro, USA), an instrument that combines an electron beam (SEM column) with a focused gallium ion beam (FIB column), oriented at 52°, and focusing on the same area of the specimen.…”

Section: Resultsmentioning

confidence: 68%

“…For this reason, we performed ultrastructural studies focusing on the nuclear and cytoplasmic features during in vitro maintenance in aerobic environment. The current concept that iPSCs can be indefinitely maintained in culture has been recently challenged by studies on the epigenetic status, the nucleoskeleton, and the mito-chondrial functionality in long-term cultured iPSCs (up to one year) in incubators with O 2 21%; CO 2 5%, which however do not mimic the physiological stem cell niche [ 6 - 8 ]. Moreover, tumorigenic potential is demonstrably increased in “aged” iPSCs [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Senescence-associated ultrastructural features of long-term cultures of induced pluripotent stem cells (iPSCs)

Colasuonno

Borghi

Niceforo

et al. 2017

Aging

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Induced pluripotent stem cells (iPSCs) hold great promise for developing personalized regenerative medicine, however characterization of their biological features is still incomplete. Moreover, changes occurring in long-term cultured iPSCs have been reported, suggesting these as a model of cellular aging. For this reason, we addressed the ultrastructural characterization of iPSCs, with a focus on possible time-dependent changes, involving specific cell compartments. To this aim, we comparatively analysed cultures at different timepoints, by an innovative electron microscopic technology (FIB/SEM). We observed progressive loss of cell-to-cell contacts, associated with increased occurrence of exosomes. Mitochondria gradually increased, while acquiring an elongated shape, with well-developed cristae. Such mitochondrial maturation was accompanied by their turnover, as assessed by the presence of autophagomes (undetectable in young iPSCs), some containing recognizable mitochondria. This finding was especially frequent in middle-aged iPSCs, while being occasional in aged cells, suggesting early autophagic activation followed by a decreased efficiency of the process with culturing time. Accordingly, confocal microscopy showed age-dependent alterations to the expression and distribution of autophagic markers. Interestingly, responsivity to rapamycin, highest in young iPSCs, was almost lost in aged cells. Overall, our results strongly support long-term cultured iPSCs as a model for studying relevant aspects of cellular senescence, involving intercellular communication, energy metabolism, and autophagy.

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“…Due to rejuvenation of neurons from iPSCs, our results also raise concerns on using iPSCs to model age-dependent neurodegenerations. Such concerns have already drawn attention, as strategies are emerging to induce aging-like features in iPSC-derived cells, for example, by telomerase manipulation ( Vera et al, 2016 ), progerin treatment ( Miller et al, 2013 ), or prolonged culture ( Petrini et al, 2017 ). Clearly, a cell culture system maintaining aging features such as our directly reprogrammed MNs will greatly facilitate our understanding of neurodegeneration and therapeutic identification and validation.…”

Section: Discussionmentioning

confidence: 99%

Direct Reprogramming Rather than iPSC-Based Reprogramming Maintains Aging Hallmarks in Human Motor Neurons

Tang

Liu²,

Zang

et al. 2017

Front. Mol. Neurosci.

139

142

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In vitro generation of motor neurons (MNs) is a promising approach for modeling motor neuron diseases (MNDs) such as amyotrophic lateral sclerosis (ALS). As aging is a leading risk factor for the development of neurodegeneration, it is important to recapitulate age-related characteristics by using MNs at pathogenic ages. So far, cell reprogramming through induced pluripotent stem cells (iPSCs) and direct reprogramming from primary fibroblasts are two major strategies to obtain populations of MNs. While iPSC generation must go across the epigenetic landscape toward the pluripotent state, directly converted MNs might have the advantage of preserving aging-associated features from fibroblast donors. In this study, we confirmed that human iPSCs reset the aging status derived from their old donors, such as telomere attrition and cellular senescence. We then applied a set of transcription factors to induce MNs from either primary fibroblasts or iPSC-derived neural progenitor cells. The results revealed that directly reprogrammed MNs, rather than iPSC-derived MNs, maintained the aging hallmarks of old donors, including extensive DNA damage, loss of heterochromatin and nuclear organization, and increased SA-β-Gal activity. iPSC-derived MNs did not regain those aging memories from old donors. Collectively, our study indicates rejuvenation in the iPSC-based model, as well as aging maintenance in direct reprogramming of MNs. As such, the directly reprogrammed MNs may be more suitable for modeling the late-onset pathogenesis of MNDs.

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Aged induced pluripotent stem cell (iPSCs) as a new cellular model for studying premature aging

Cited by 30 publications

References 46 publications

Nuclear Lamins and Emerin Are Differentially Expressed in Osteosarcoma Cells and Scale with Tumor Aggressiveness

Nuclear Lamins and Emerin Are Differentially Expressed in Osteosarcoma Cells and Scale with Tumor Aggressiveness

Senescence-associated ultrastructural features of long-term cultures of induced pluripotent stem cells (iPSCs)

Direct Reprogramming Rather than iPSC-Based Reprogramming Maintains Aging Hallmarks in Human Motor Neurons

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