Zhao T, Zhang ZN, Rong Z, Xu YImmunogenicity of induced pluripotent stem cells. Nature 474:212-215

Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0322, USA.
Nature (Impact Factor: 41.46). 05/2011; 474(7350):212-5. DOI: 10.1038/nature10135
Source: PubMed


Induced pluripotent stem cells (iPSCs), reprogrammed from somatic cells with defined factors, hold great promise for regenerative medicine as the renewable source of autologous cells. Whereas it has been generally assumed that these autologous cells should be immune-tolerated by the recipient from whom the iPSCs are derived, their immunogenicity has not been vigorously examined. We show here that, whereas embryonic stem cells (ESCs) derived from inbred C57BL/6 (B6) mice can efficiently form teratomas in B6 mice without any evident immune rejection, the allogeneic ESCs from 129/SvJ mice fail to form teratomas in B6 mice due to rapid rejection by recipients. B6 mouse embryonic fibroblasts (MEFs) were reprogrammed into iPSCs by either retroviral approach (ViPSCs) or a novel episomal approach (EiPSCs) that causes no genomic integration. In contrast to B6 ESCs, teratomas formed by B6 ViPSCs were mostly immune-rejected by B6 recipients. In addition, the majority of teratomas formed by B6 EiPSCs were immunogenic in B6 mice with T cell infiltration, and apparent tissue damage and regression were observed in a small fraction of teratomas. Global gene expression analysis of teratomas formed by B6 ESCs and EiPSCs revealed a number of genes frequently overexpressed in teratomas derived from EiPSCs, and several such gene products were shown to contribute directly to the immunogenicity of the B6 EiPSC-derived cells in B6 mice. These findings indicate that, in contrast to derivatives of ESCs, abnormal gene expression in some cells differentiated from iPSCs can induce T-cell-dependent immune response in syngeneic recipients. Therefore, the immunogenicity of therapeutically valuable cells derived from patient-specific iPSCs should be evaluated before any clinic application of these autologous cells into the patients.

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Available from: Zhili Rong, Mar 10, 2014
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    • "Later, in 2006, Takahashi et al. described the IPS (induced pluripotent stem cells) [8] [9] [10]. Several categories of stem cells can be used in regenerative medicine including embryonic stem cells (ESC), fetal stem cells (FSC), and adult stem cells (ASC) [11] [12]. Not all stem cells are of equal interest in terms of ability for clinical applications and are able to evolve into different specialized cells. "
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    ABSTRACT: Since the 1960s and the therapeutic use of hematopoietic stem cells of bone marrow origin, there has been an increasing interest in the study of undifferentiated progenitors that have the ability to proliferate and differentiate into various tissues. Stem cells (SC) with different potency can be isolated and characterised. Despite the promise of embryonic stem cells, in many cases, adult or even fetal stem cells provide a more interesting approach for clinical applications. It is undeniable that mesenchymal stem cells (MSC) from bone marrow, adipose tissue, or Wharton’s Jelly are of potential interest for clinical applications in regenerative medicine because they are easily available without ethical problems for their uses. During the last 10 years, these multipotent cells have generated considerable interest and have particularly been shown to escape to allogeneic immune response and be capable of immunomodulatory activity. These properties may be of a great interest for regenerative medicine. Different clinical applications are under study (cardiac insufficiency, atherosclerosis, stroke, bone and cartilage deterioration, diabetes, urology, liver, ophthalmology, and organ’s reconstruction). This review focuses mainly on tissue and organ regeneration using SC and in particular MSC.
    Stem cell International 08/2015; 2015(11):1-19. DOI:10.1155/2015/734731 · 2.81 Impact Factor
    • "We have recently shown the effectiveness of MSCs growing on a nanofibre scaffold for the treatment of ocular surface injuries in mouse and rabbit models (Zajicova et al., 2010; Cejkova et al., 2013). When being mindful of the ethical problems associated with the use of embryonic stem cells (Robertson, 2001; Lo and Parham, 2009), or when considering the immunogenicity of induced pluripotent cells (Dhodapkar et al., 2010; Wu and Hochedlinger, 2011; Zhao et al., 2011), we suggest that MSCs pre-activated by a complex differentiation protocol , and easily handled when grown on a nanofibre scaffold , could represent a suitable tool for cell-based therapy of various neural injuries and neurological disorders. "
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    ABSTRACT: Damaged neural tissue is regenerated by neural stem cells (NSCs), which represent a rare and difficult-to-culture cell population. Therefore, alternative sources of stem cells are being tested to replace a shortage of NSCs. Here we show that mouse adipose tissue-derived mesenchymal stem cells (MSCs) can be effectively differentiated into cells expressing neuronal cell markers. The differentiation protocol, simulating the inflammatory site of neural injury, involved brain tissue extract, fibroblast growth factor, epidermal growth factor, supernatant from activated splenocytes and electrical stimulation under physiological conditions. MSCs differentiated using this protocol displayed neuronal cell morphology and expressed genes for neuronal cell markers, such as neurofilament light (Nf-L), medium (Nf-M) and heavy (Nf-H) polypeptides, synaptophysin (SYP), neural cell adhesion molecule (NCAM), glutamic acid decarboxylase (GAD), neuron-specific nuclear protein (NeuN), βIII-tubulin (Tubb3) and microtubule-associated protein 2 (Mtap2), which are absent (Nf-L, Nf-H, SYP, GAD, NeuN and Mtap2) or only slightly expressed (NCAM, Tubb3 and Nf-M) in undifferentiated cells. The differentiation was further enhanced when the cells were cultured on nanofibre scaffolds. The neural differentiation of MSCs, which was detected at the level of gene expression, was confirmed by positive immunostaining for Nf-L protein. The results thus show that the simulation of conditions in an injured neural tissue and inflammatory environment, supplemented with electrical stimulation under physiological conditions and cultivation of cells on a three-dimensional (3D) nanofibre scaffold, form an effective protocol for the differentiation of MSCs into cells with neuronal markers. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.
    Journal of Tissue Engineering and Regenerative Medicine 06/2015; DOI:10.1002/term.2059 · 5.20 Impact Factor
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    • "Unfortunately, these studies do not fully address the safety and the efficacy of iPS for periodontal regeneration. It is well described that iPS cells may not exhibit phenotypic stability once transplanted in vivo (Hynes et al., 2013) and might become immunogenic due to abnormal gene expression upon differentiation (Zhao et al., 2011). Defining the number of cells that will suffice the threshold for tissue regeneration will also need to be accomplished in future investigations in order to avoid uncontrollable regeneration of tissues (Lin et al., 2015). "
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    ABSTRACT: Periodontal diseases are highly prevalent and are linked to several systemic diseases.The goal of periodontal treatment is to halt the progression of the disease and regenerate the damaged tissue. However, achieving complete and functional periodontal regeneration is challenging because the periodontium is a complex apparatus composed of different tissues, including bone, cementum, and periodontal ligament. Stem cell-based regenerative therapy may represent an effective therapeutic tool for periodontal regeneration due to their plasticity and ability to differentiate into different cell lineages. This review presents and critically analyzesthe available information on stem cell-based therapyfor the regeneration of periodontal tissues and suggests new avenues for the development of more effective therapeutic protocols. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Cellular Physiology 06/2015; 231(1). DOI:10.1002/jcp.25067 · 3.84 Impact Factor
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