Dental pulp stem cells as a promising model to study imprinting diseases

Giabicani, Éloïse; Pham, Aurélie; Sélénou, Céline; Sobrier, Marie-Laure; Andrique, Caroline; Lesieur, Julie; Linglart, Agnès; Poliard, Anne; Miller, Catherine; Netchine, Irène

doi:10.1038/s41368-022-00169-1

Cited by 7 publications

(3 citation statements)

References 39 publications

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“…All the methylation studies have been assessed by using the allele-specific methylated multiplex real-time quantitative PCR technique using designed and validated TaqMan MGB probes (covering two to three CpG islands each) and primers as previously described [14]. The normal band of methylation indices represented by a shaded area corresponds to normal values obtained in control individuals' leukocytes and validated for IDs diagnosis in our molecular biology laboratory [14][15][16].…”

Section: Resultsmentioning

confidence: 99%

Maintenance of methylation profile in imprinting control regions in human induced pluripotent stem cells

et al. 2022

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Background Parental imprinting is an epigenetic mechanism that leads to monoallelic expression of a subset of genes depending on their parental origin. Imprinting disorders (IDs), caused by disturbances of imprinted genes, are a set of rare congenital diseases that mainly affect growth, metabolism and development. To date, there is no accurate model to study the physiopathology of IDs or test therapeutic strategies. Human induced pluripotent stem cells (iPSCs) are a promising cellular approach to model human diseases and complex genetic disorders. However, aberrant hypermethylation of imprinting control regions (ICRs) may appear during the reprogramming process and subsequent culture of iPSCs. Therefore, we tested various conditions of reprogramming and culture of iPSCs and performed an extensive analysis of methylation marks at the ICRs to develop a cellular model that can be used to study IDs. Results We assessed the methylation levels at seven imprinted loci in iPSCs before differentiation, at various passages of cell culture, and during chondrogenic differentiation. Abnormal methylation levels were found, with hypermethylation at 11p15 H19/IGF2:IG-DMR and 14q32 MEG3/DLK1:IG-DMR, independently of the reprogramming method and cells of origin. Hypermethylation at these two loci led to the loss of parental imprinting (LOI), with biallelic expression of the imprinted genes IGF2 and DLK1, respectively. The epiPS™ culture medium combined with culturing of the cells under hypoxic conditions prevented hypermethylation at H19/IGF2:IG-DMR (ICR1) and MEG3/DLK1:IG-DMR, as well as at other imprinted loci, while preserving the proliferation and pluripotency qualities of these iPSCs. Conclusions An extensive and quantitative analysis of methylation levels of ICRs in iPSCs showed hypermethylation of certain ICRs in human iPSCs, especially paternally methylated ICRs, and subsequent LOI of certain imprinted genes. The epiPS™ culture medium and culturing of the cells under hypoxic conditions prevented hypermethylation of ICRs in iPSCs. We demonstrated that the reprogramming and culture in epiPS™ medium allow the generation of control iPSCs lines with a balanced methylation and ID patient iPSCs lines with unbalanced methylation. Human iPSCs are therefore a promising cellular model to study the physiopathology of IDs and test therapies in tissues of interest.

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Section: Resultsmentioning

confidence: 99%

Maintenance of methylation profile in imprinting control regions in human induced pluripotent stem cells

et al. 2022

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“…Its expression is regulated by several upstream factors, and it regulates numerous downstream effectors. The application of new high-throughput technologies (i.e., next-generation sequencing, evaluations of DNA methylation and RNA sequencing) to imprinted disorders in mice or induced pluripotent stem cells and promising dental pluripotent stem cells models should make it possible to decipher more precisely the upstream and downstream actors involved in multiple tissue-specific functions of IGF-II [ 144 , 145 ]. The potential breakthroughs associated with such modeling of IGF2 -linked diseases open up new challenges and expand this field of research still further.…”

Section: Discussionmentioning

confidence: 99%

IGF2: Development, Genetic and Epigenetic Abnormalities

Sélénou

Brioude

Giabicani

et al. 2022

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In the 30 years since the first report of parental imprinting in insulin-like growth factor 2 (Igf2) knockout mouse models, we have learnt much about the structure of this protein, its role and regulation. Indeed, many animal and human studies involving innovative techniques have shed light on the complex regulation of IGF2 expression. The physiological roles of IGF-II have also been documented, revealing pleiotropic tissue-specific and developmental-stage-dependent action. Furthermore, in recent years, animal studies have highlighted important interspecies differences in IGF-II function, gene expression and regulation. The identification of human disorders due to impaired IGF2 gene expression has also helped to elucidate the major role of IGF-II in growth and in tumor proliferation. The Silver–Russell and Beckwith–Wiedemann syndromes are the most representative imprinted disorders, as they constitute both phenotypic and molecular mirrors of IGF2-linked abnormalities. The characterization of patients with either epigenetic or genetic defects altering IGF2 expression has confirmed the central role of IGF-II in human growth regulation, particularly before birth, and its effects on broader body functions, such as metabolism or tumor susceptibility. Given the long-term health impact of these rare disorders, it is important to understand the consequences of IGF2 defects in these patients.

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“…Diseases are mainly because of methylation defects in imprinting control regions that lead to the abnormal expression of imprinted genes. The study by Giabicani et al [197] aimed to characterise the methylation of imprinting regions in dental pulp stem cells and during their differentiation in osteogenic cells (involved in growth regulation) to assess the interest of these cells in modelling imprinting diseases. The researchers collected dental pulp stem cells from five controls, three patients with Silver-Russell syndrome and one with Beckwith-Wiedemann syndrome.…”

Section: The Regenerative Potential Of the Pulp Stem Cells For Mainta...mentioning

confidence: 99%

The Role of Cellular Metabolism in Maintaining the Function of the Dentine-Pulp Complex: A Narrative Review

et al. 2023

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The cellular metabolic processes ensure the physiological integrity of the dentine-pulp complex. Odontoblasts and odontoblast-like cells are responsible for the defence mechanisms in the form of tertiary dentine formation. In turn, the main defence reaction of the pulp is the development of inflammation, during which the metabolic and signalling pathways of the cells are significantly altered. The selected dental procedures, such as orthodontic treatment, resin infiltration, resin restorations or dental bleaching, can impact the cellular metabolism in the dental pulp. Among systemic metabolic diseases, diabetes mellitus causes the most consequences for the cellular metabolism of the dentine-pulp complex. Similarly, ageing processes present a proven effect on the metabolic functioning of the odontoblasts and the pulp cells. In the literature, several potential metabolic mediators demonstrating anti-inflammatory properties on inflamed dental pulp are mentioned. Moreover, the pulp stem cells exhibit the regenerative potential essential for maintaining the function of the dentine-pulp complex.

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Dental pulp stem cells as a promising model to study imprinting diseases

Cited by 7 publications

References 39 publications

Maintenance of methylation profile in imprinting control regions in human induced pluripotent stem cells

Maintenance of methylation profile in imprinting control regions in human induced pluripotent stem cells

IGF2: Development, Genetic and Epigenetic Abnormalities

The Role of Cellular Metabolism in Maintaining the Function of the Dentine-Pulp Complex: A Narrative Review

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