Tumorigenesis in cells derived from induced pluripotent stem cells

Nishimori, Makoto; Yakushiji, Hiromasa; Mori, Michihiro; Miyamoto, Tomoyuki; Yaguchi, Takahiro; Ohno, Setsuyo; Miyake, Yasuyuki; Sakaguchi, Takuya; Ueda, Masatsugu; Ohno, Eiji

doi:10.1007/s13577-013-0078-3

Cited by 26 publications

(21 citation statements)

References 19 publications

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“…We transplanted progenitors, but not pluripotent cells to avoid tumorigenesis. This agrees with the current view that transplantation of undifferentiated stem cells including pluripotent iPSCs may lead to tumorigenesis . Thus lineage‐restricted stem cells or progenitors are less tumorigenic and better candidates for transplantation .…”

Section: Discussionsupporting

confidence: 91%

iPSC Transplantation Increases Regeneration and Functional Recovery After Ischemic Stroke in Neonatal Rats

et al. 2014

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Limited treatments are available for perinatal/neonatal stroke. Induced pluripotent stem cells (iPSCs) hold therapeutic promise for stroke treatment, but the benefits of iPSC transplantation in neonates are relatively unknown. We hypothesized that transplanted iPSC-derived neural progenitor cells (iPSC-NPCs) would increase regeneration after stroke. Mouse pluripotent iPSCs were differentiated into neural progenitors using a retinoic acid protocol. Differentiated neural cells were characterized by using multiple criteria and assessments. Ischemic stroke was induced in postnatal day 7 (P7) rats by occluding the right middle cerebral artery and right common carotid artery. iPSC-NPCs (400,000 in 4 ml) were transplanted into the penumbra via intracranial injection 7 days after stroke. Trophic factor expression in the peri-infarct tissue was measured using Western blot analysis. Animals received daily bromodeoxyuridine (BrdU) injections and were sacrificed 21 days after stroke for immunohistochemistry. The vibrissae-elicited forelimb placement test was used to evaluate functional recovery. Differentiated iPSCs expressed mature neuronal markers, functional sodium and potassium channels, and fired action potentials. Several angiogenic and neurogenic trophic factors were identified in iPSC-NPCs. Animals that received iPSC-NPC transplantation had greater expression of stromal cell-derived factor 1-a (SDF-1a) and vascular endothelial growth factor (VEGF) in the peri-infarct region. iPSC-NPCs stained positive for neuronal nuclei (NeuN) or glial fibrillary acidic protein (GFAP) 14 days after transplantation. iPSC-NPC-transplanted animals showed greater numbers of BrdU/NeuN and BrdU/Collagen IV colabeled cells in the peri-infarct area compared with stroke controls and performed better in a sensorimotor functional test after stroke. iPSC-NPC therapy may play multiple therapeutic roles after stroke by providing trophic factors, increasing angiogenesis and neurogenesis, and providing new cells for tissue repair. STEM CELLS 2014;32:3075-3087

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Section: Discussionsupporting

confidence: 91%

iPSC Transplantation Increases Regeneration and Functional Recovery After Ischemic Stroke in Neonatal Rats

et al. 2014

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“…Mounting evidence supports the limitless potential of induced pluripotent stem cells towards tissue and organ repair. However, cell‐based therapy with the use of pluripotent stem cells requires almost perfectly optimized differentiation and purification protocols to avoid tumorigenesis by transplanted cells . Alternative approaches are needed to overcome this obstacle.…”

Section: Discussionmentioning

confidence: 99%

Human Induced Pluripotent Stem Cell-Derived Microvesicles Transmit RNAs and Proteins to Recipient Mature Heart Cells Modulating Cell Fate and Behavior

et al. 2015

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Microvesicles (MVs) are membrane-enclosed cytoplasmic fragments released by normal and activated cells that have been described as important mediators of cell-to-cell communication.Although the ability of human induced pluripotent stem cells (hiPSCs) to participate in tissue repair is being increasingly recognized, the use of hiPSC-derived MVs (hiPSC-MVs) in this regard remains unknown. Accordingly, we investigated the ability of hiPSC-MVs to transfer bioactive molecules including mRNA, microRNA (miRNA), and proteins to mature target cells such as cardiac mesenchymal stromal cells (cMSCs), and we next analyzed effects of hiPSC-MVs on fate and behavior of such target cells. The results show that hiPSC-MVs derived from integration-free hiPSCs cultured under serum-free and feeder-free conditions are rich in mRNA, miRNA, and proteins originated from parent cells; however, the levels of expression vary between donor cells and MVs. Importantly, we found that transfer of hiPSC components by hiPSC-MVs impacted on transcriptome and proteomic profiles of target cells as well as exerted proliferative and protective effects on cMSCs, and enhanced their cardiac and endothelial differentiation potential. hiPSC-MVs also transferred exogenous transcripts from genetically modified hiPSCs that opens new perspectives for future strategies to enhance MV content. We conclude that hiPSC-MVs are effective vehicles for transferring iPSC attributes to adult somatic cells, and hiPSC-MV-mediated horizontal transfer of RNAs and proteins to injured tissues may be used for therapeutic tissue repair. In this study, for the first time, we propose a new concept of use of hiPSCs as a source of safe acellular bioactive derivatives for tissue regeneration. STEM CELLS 2015;33:2748-2761 SIGNIFICANCE STATEMENTOur results show, for the first time, that human induced pluripotent stem cells (hiPS cells) may serve as a source of bioactive microvesicles (MVs) that could be potentially utilized for future safe applications in tissue regeneration. For the first time, we extensively characterized bioactive content of MVs released by hiPS cells (hiPS-MVs) on both transcriptomic and proteomic levels and we established their impact on functions and differentiation potential of mature target cells from human heart. These results have obvious translational relevance for developing potential new iPS cell-based strategies in tissue regeneration by employing thier safe acellular bioactive derivatives.

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“…One possibility has been offered by embryonic stem cells (ESCs), but the use of ESCs is limited by their uncontrolled growth, the risk of teratoma formation, and ethical problems associated with their isolation and use [25, 26]. Induced pluripotent stem cells, which could be used as autologous cells, initially appeared to offer great promise, but these cells turned out to be immunogenic even in syngeneic hosts [27] and frequently form teratomas after in vivo application [28]. MSCs represent a convenient type of stem cells with a wide spectrum of potential applications.…”

Section: Discussionmentioning

confidence: 99%

A Comparative Study of the Therapeutic Potential of Mesenchymal Stem Cells and Limbal Epithelial Stem Cells for Ocular Surface Reconstruction

Holáň

Trošan

Čejka

et al. 2015

Stem Cells Translational Medicine

111

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Corneal regeneration x Stem cell-based therapy ABSTRACTStem cell-based therapy has become an attractive and promising approach for the treatment of severe injuries or thus-far incurable diseases. However, the use of stem cells is often limited by a shortage of available tissue-specific stem cells; therefore, other sources of stem cells are being investigated and tested. In this respect, mesenchymal stromal/stem cells (MSCs) have proven to be a promising stem cell type. In the present study, we prepared MSCs from bone marrow (BM-MSCs) or adipose tissue (Ad-MSCs) as well as limbal epithelial stem cells (LSCs), and their growth, differentiation, and secretory properties were compared. The cells were grown on nanofiber scaffolds and transferred onto the alkaliinjured eye in a rabbit model, and their therapeutic potential was characterized. We found that BM-MSCs and tissue-specific LSCs had similar therapeutic effects. Clinical characterization of the healing process, as well as the evaluation of corneal thickness, re-epithelialization, neovascularization, and the suppression of a local inflammatory reaction, were comparable in the BM-MSC-and LSC-treated eyes, but results were significantly better than in injured, untreated eyes or in eyes treated with a nanofiber scaffold alone or with a nanofiber scaffold seeded with Ad-MSCs. Taken together, the results show that BM-MSCs' therapeutic effect on healing of injured corneal surface is comparable to that of tissuespecific LSCs. We suggest that BM-MSCs can be used for ocular surface regeneration in cases when autologous LSCs are absent or difficult to obtain. STEM CELLS

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Tumorigenesis in cells derived from induced pluripotent stem cells

Cited by 26 publications

References 19 publications

iPSC Transplantation Increases Regeneration and Functional Recovery After Ischemic Stroke in Neonatal Rats

iPSC Transplantation Increases Regeneration and Functional Recovery After Ischemic Stroke in Neonatal Rats

Human Induced Pluripotent Stem Cell-Derived Microvesicles Transmit RNAs and Proteins to Recipient Mature Heart Cells Modulating Cell Fate and Behavior

A Comparative Study of the Therapeutic Potential of Mesenchymal Stem Cells and Limbal Epithelial Stem Cells for Ocular Surface Reconstruction

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