Nuclear Reprogramming by Defined Factors: Quantity Versus Quality

Sebban, Shulamit; Buganim, Yosef

doi:10.1016/j.tcb.2015.08.006

Cited by 23 publications

(14 citation statements)

References 114 publications

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“…Cell plasticity confers flexibility to change the fate of terminally differentiated cells into a pluripotent state or other cell types 1, 2 . Induced pluripotent stem cells (iPSCs) are pivotal resources to provide desired cell types, but the generation of iPSCs possibly entails unexpected incorporation and mutation in genomic DNA due to transfection of exogenous DNA delivered by viruses or plasmids, which might cause undesired effects after transplantation 3 .…”

Section: Introductionmentioning

confidence: 99%

Direct conversion of human fibroblasts to brown adipocytes by small chemical compounds

Takeda

Harada

Yoshikawa

et al. 2017

Sci Rep

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Brown adipocytes play an important role in human energy metabolism and prevention of obesity and diabetes. Induced pluripotent stem cells (iPSCs) represent a promising source for brown adipocytes; however, exogenous gene induction is generally required for iPSCs generation, which might cause undesired effects particularly in long-term treatment after transplantation. We have previously reported a cocktail of six small chemical compounds that enables a conversion of human fibroblasts into chemical compound-induced neuronal cells (CiNCs). Here, we report that modified combinations of the chemical compounds and rosiglitazone, a PPARγ agonist, afforded direct conversion of human fibroblasts into brown adipocytes. The chemical compound-induced brown adipocytes (ciBAs) exhibit induction of human brown adipocyte-specific genes such as Ucp1, Ckmt1, Cited1 and other adipocyte-specific genes such as Fabp4, AdipoQ, and Pparγ. Treatment with either isoproterenol or Forskolin further induced the expression of Ucp1, suggesting that β adrenergic receptor signalling in ciBAs could be functional for induction of thermogenic genes. Moreover, oxygen consumption rates were elevated in ciBAs along with increase of cellular mitochondria. Our findings might provide an easily accessible approach for generating human brown adipocytes from fibroblasts and offer therapeutic potential for the management of obesity, diabetes, and related metabolic disorders.

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Section: Introductionmentioning

confidence: 99%

Direct conversion of human fibroblasts to brown adipocytes by small chemical compounds

Takeda

Harada

Yoshikawa

et al. 2017

Sci Rep

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“…When compared with hESC-based cell therapy, iPSCs were thought to provide certain advantages, including the lack of ethic concerns and immune rejection by the recipient (13). However, recent studies have demonstrated the increased genomic instability, epigenetic abnormality, and immunogenicity of iPSCs, raising safety concerns of iPSC-based cell therapy (14, 15). Therefore, to improve the feasibility of iPSC-based therapy, it is important to understand the underlying reprogramming mechanism and develop strategies to minimize these safety concerns.…”

Section: The Promise Of Pluripotent Stem Cell (Psc)-derived Cells In mentioning

confidence: 99%

The Immunogenicity and Immune Tolerance of Pluripotent Stem Cell Derivatives

Liu

et al. 2017

Front. Immunol.

122

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Human embryonic stem cells (hESCs) can undergo unlimited self-renewal and differentiate into all cell types in human body, and therefore hold great potential for cell therapy of currently incurable diseases including neural degenerative diseases, heart failure, and macular degeneration. This potential is further underscored by the promising safety and efficacy data from the ongoing clinical trials of hESC-based therapy of macular degeneration. However, one main challenge for the clinical application of hESC-based therapy is the allogeneic immune rejection of hESC-derived cells by the recipient. The breakthrough of the technology to generate autologous-induced pluripotent stem cells (iPSCs) by nuclear reprogramming of patient’s somatic cells raised the possibility that autologous iPSC-derived cells can be transplanted into the patients without the concern of immune rejection. However, accumulating data indicate that certain iPSC-derived cells can be immunogenic. In addition, the genomic instability associated with iPSCs raises additional safety concern to use iPSC-derived cells in human cell therapy. In this review, we will discuss the mechanism underlying the immunogenicity of the pluripotent stem cells and recent progress in developing immune tolerance strategies of human pluripotent stem cell (hPSC)-derived allografts. The successful development of safe and effective immune tolerance strategy will greatly facilitate the clinical development of hPSC-based cell therapy.

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“…This may be explained by the shared cell progeny and the degree of similarity between epigenetic marks and profile. Basically, this mutual epigenetic profile indicates that less epigenetic barriers have to be crossed (Sebban and Buganim 2016; Bernstein et al 2007). Indeed, in Waddington’s epigenetic landscape, cell lineages within a germ layer are separated by lower ‘hills’ compared to the hills between different germ layer-originating cell types (Ladewig et al 2013).…”

Section: Direct Reprogramming Into Chondrocytesmentioning

confidence: 99%

“…Ideally, transgene integration is avoided in order to prevent teratoma formation, increasing the suitability for clinical application (Sebban and Buganim 2016). Nevertheless, it is acknowledged that continuous expression of the reprogramming factors c-Myc, Klf4 and especially Sox9 is required.…”

Section: Direct Reprogramming Into Chondrocytesmentioning

confidence: 99%

Cellular reprogramming for clinical cartilage repair

2017

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The repair of articular cartilage needs a sufficient number of chondrocytes to replace the defect tissue, and therefore, expansion of cells is generally required. Chondrocytes derived by cellular reprogramming may provide a solution to the limitations of current (stem) cell-based therapies. In this article, two distinct approaches—induced pluripotent stem cell (iPSC)-mediated reprogramming and direct lineage conversion—are analysed and compared according to criteria that encompass the qualification of the method and the derived chondrocytes for the purpose of clinical application. Progress in iPSC generation has provided insights into the replacement of reprogramming factors by small molecules and chemical compounds. As follows, multistage chondrogenic differentiation methods have shown to improve the chondrocyte yield and quality. Nevertheless, the iPSC ‘detour’ remains a time- and cost-consuming approach. Direct conversion of fibroblasts into chondrocytes provides a slight advantage over these aspects compared to the iPSC detour. However, the requirement of constitutive transgene expression to inhibit hypertrophic differentiation limits this approach of being translated to the clinic. It can be concluded that the quality of the derived chondrocytes highly depends on the characteristics of the reprogramming method and that this is important to keep in mind during the experimental set-up. Further research into both reprogramming approaches for clinical cartilage repair has to include proper control groups and epigenetic profiling to optimize the techniques and eventually derive functionally stable articular chondrocytes.

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Nuclear Reprogramming by Defined Factors: Quantity Versus Quality

Cited by 23 publications

References 114 publications

Direct conversion of human fibroblasts to brown adipocytes by small chemical compounds

Direct conversion of human fibroblasts to brown adipocytes by small chemical compounds

The Immunogenicity and Immune Tolerance of Pluripotent Stem Cell Derivatives

Cellular reprogramming for clinical cartilage repair

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