Epigenetic Rejuvenation of Mesenchymal Stromal Cells Derived from Induced Pluripotent Stem Cells

• Published in: Stem cell reports Vol. 3; no. 3; pp. 414 - 422
• Main Authors: Frobel, Joana, Hemeda, Hatim, Lenz, Michael, Abagnale, Giulio, Joussen, Sylvia, Denecke, Bernd, Šarić, Tomo, Zenke, Martin, Wagner, Wolfgang
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09-09-2014; Elsevier
• Subjects: Cell Differentiation; Cells, Cultured; DNA Methylation; Epigenesis, Genetic; Humans; Induced Pluripotent Stem Cells - cytology; Induced Pluripotent Stem Cells - metabolism; Mesenchymal Stromal Cells - cytology; Mesenchymal Stromal Cells - metabolism; Transcriptome
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2014.07.003

Standardization of mesenchymal stromal cells (MSCs) remains a major obstacle in regenerative medicine. Starting material and culture expansion affect cell preparations and render comparison between studies difficult. In contrast, induced pluripotent stem cells (iPSCs) assimilate toward a ground state and may therefore give rise to more standardized cell preparations. We reprogrammed MSCs into iPSCs, which were subsequently redifferentiated toward MSCs. These iPS-MSCs revealed similar morphology, immunophenotype, in vitro differentiation potential, and gene expression profiles as primary MSCs. However, iPS-MSCs were impaired in suppressing T cell proliferation. DNA methylation (DNAm) profiles of iPSCs maintained donor-specific characteristics, whereas tissue-specific, senescence-associated, and age-related DNAm patterns were erased during reprogramming. iPS-MSCs reacquired senescence-associated DNAm during culture expansion, but they remained rejuvenated with regard to age-related DNAm. Overall, iPS-MSCs are similar to MSCs, but they reveal incomplete reacquisition of immunomodulatory function and MSC-specific DNAm patterns—particularly of DNAm patterns associated with tissue type and aging.
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•MSC-derived iPSCs are redifferentiated toward MSCs in a one-step protocol•Gene expression profiles of iPS-MSCs closely resemble those of primary MSCs•DNA methylation (DNAm) profiles of iPS-MSCs lag behind those of MSCs•Age-related and tissue-specific DNAm patterns remain erased in iPS-MSCs
Wagner and colleagues redifferentiated MSC-derived iPSCs toward MSCs. These iPS-MSCs reveal similar morphology, immunophenotype, and in vitro differentiation potential as primary MSCs, but they were impaired in suppressing T cell proliferation. Furthermore, there are marked differences in DNA methylation profiles that can, at least partially, be attributed to persistent reset of tissue-specific and age-related DNA methylation changes.