MicroRNAs Contribute to Induced Pluripotent Stem Cell Somatic Donor Memory

Vitaloni, Marianna; Pulecio, Julián; Bilić, Josipa; Kuebler, Bernd; Laricchia-Robbio, Leopoldo; Belmonte, Juan Carlos Izpisúa

doi:10.1074/jbc.m113.538702

Cited by 35 publications

(29 citation statements)

References 52 publications

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“…However, the low-passage iPSCs used here did not show a biased differentiation capacity to hematopoietic cells. In addition, miR-155 has been shown to be associated with epigenetic memory in hematopoietic cell-derived iPSCs [34]; however, a differential expression pattern of miR-155 was not observed in iPSCs derived from the previously established sequential reprogramming system [18]. Notably, the subtype of HPCs used in that study (CD133 + ) was also different from the one used here (c-kit + ), in which miR-155 may not exert a dominant role [34].…”

Section: Discussionmentioning

confidence: 99%

Integrated analysis of hematopoietic differentiation outcomes and molecular characterization reveals unbiased differentiation capacity and minor transcriptional memory in HPC/HSC-iPSCs

et al. 2017

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BackgroundTranscription factor-mediated reprogramming can reset the epigenetics of somatic cells into a pluripotency compatible state. Recent studies show that induced pluripotent stem cells (iPSCs) always inherit starting cell-specific characteristics, called epigenetic memory, which may be advantageous, as directed differentiation into specific cell types is still challenging; however, it also may be unpredictable when uncontrollable differentiation occurs. In consideration of biosafety in disease modeling and personalized medicine, the availability of high-quality iPSCs which lack a biased differentiation capacity and somatic memory could be indispensable.MethodsHerein, we evaluate the hematopoietic differentiation capacity and somatic memory state of hematopoietic progenitor and stem cell (HPC/HSC)-derived-iPSCs (HPC/HSC-iPSCs) using a previously established sequential reprogramming system.ResultsWe found that HPC/HSCs are amenable to being reprogrammed into iPSCs with unbiased differentiation capacity to hematopoietic progenitors and mature hematopoietic cells. Genome-wide analyses revealed that no global epigenetic memory was detectable in HPC/HSC-iPSCs, but only a minor transcriptional memory of HPC/HSCs existed in a specific tetraploid complementation (4 N)-incompetent HPC/HSC-iPSC line. However, the observed minor transcriptional memory had no influence on the hematopoietic differentiation capacity, indicating the reprogramming of the HPC/HSCs was nearly complete. Further analysis revealed the correlation of minor transcriptional memory with the aberrant distribution of H3K27me3.ConclusionsThis work provides a comprehensive framework for obtaining high-quality iPSCs from HPC/HSCs with unbiased hematopoietic differentiation capacity and minor transcriptional memory.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-016-0466-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Integrated analysis of hematopoietic differentiation outcomes and molecular characterization reveals unbiased differentiation capacity and minor transcriptional memory in HPC/HSC-iPSCs

et al. 2017

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“…Such a residual transcriptional and epigenetic memory may be in favor of an in vitro differentiation potential of iPSCs back into their tissue of origin rather than into other cell types (Bar-Nur et al, 2011;Kim et al, 2010). Remarkably, this tendency of early-passage iPSCs to differentiate toward the cell lineage of origin seems to be lost over time after extending culture passaging ( > 25 passages) (Vitaloni et al, 2014).…”

Section: Discussionmentioning

confidence: 98%

Generation of Human β-Thalassemia Induced Pluripotent Cell Lines by Reprogramming of Bone Marrow–Derived Mesenchymal Stromal Cells Using Modified mRNA

Varela

Karagiannidou²,

Oikonomakis³

et al. 2014

Cellular Reprogramming

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Synthetic modified mRNA molecules encoding pluripotency transcription factors have been used successfully in reprogramming human fibroblasts to induced pluripotent stem cells (iPSCs). We have applied this method on bone marrow-derived mesenchymal stromal cells (BM-MSCs) obtained from a patient with β-thalassemia (β-thal) with the aim to generate trangene-free β-thal-iPSCs. Transfection of 10(4) BM-MSCs by lipofection with mRNA encoding the reprogramming factors Oct4, Klf4, Sox2, cMyc, and Lin28 resulted in formation of five iPSC colonies, from which three were picked up and expanded in β-thal-iPSC lines. After 10 serial passages in vitro, β-thal-iPSCs maintain genetic stability as shown by array comparative genomic hybridization (aCGH) and are capable of forming embryoid bodies in vitro and teratomas in vivo. Their gene expression profile compared to human embryonic stem cells (ESCs) and BM-MSCs seems to be similar to that of ESCs, whereas it differs from the profile of the parental BM-MSCs. Differentiation cultures toward a hematopoietic lineage showed the generation of CD34(+) progenitors up to 10%, but with a decreased hematopoietic colony-forming capability. In conclusion, we report herein the generation of transgene-free β-thal-iPSCs that could be widely used for disease modeling and gene therapy applications. Moreover, it was demonstrated that the mRNA-based reprogramming method, used mainly in fibroblasts, is also suitable for reprogramming of human BM-MSCs.

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“…The expression of these miRNAs was lost upon extensive passaging, resulting in an adjustment of the miRNA profiles of iPSCs and ESCs. Furthermore, HPC-specific miRNAs still expressed in iPSCs favored the differentiation of these iPSCs towards HPCs (71).…”

Section: Induced Pluripotent Stem Cellsmentioning

confidence: 99%