Overcoming barriers to the clinical utilization of iPSCs: reprogramming efficiency, safety and quality

Cao, Suying; Loh, Kyle M.; Pei, Yangli; Zhang, Wei; Han, Jianyong

doi:10.1007/s13238-012-2078-6

Cited by 17 publications

(15 citation statements)

References 88 publications

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“…These results shed light on the mechanisms governing cell reprogramming, but do not allow transcending the limitations to iPSC clinical translation. Additionally, evidence supporting variability in efficiency of reprogramming and in properties of iPSCs in accordance with the cell type from which iPSCs were generated was also reported . Adult dermal fibroblast has been the first human cell successfully reprogrammed to iPSCs, and, to date, it is still the most used human cell for reprogramming.…”

Section: Introductionmentioning

confidence: 93%

Diversity of dermal fibroblasts as major determinant of variability in cell reprogramming

Sacco

Belviso

Romano

et al. 2019

J Cellular Molecular Medi

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Induced pluripotent stem cells (iPSCs) are adult somatic cells genetically reprogrammed to an embryonic stem cell‐like state. Notwithstanding their autologous origin and their potential to differentiate towards cells of all three germ layers, iPSC reprogramming is still affected by low efficiency. As dermal fibroblast is the most used human cell for reprogramming, we hypothesize that the variability in reprogramming is, at least partially, because of the skin fibroblasts used. Human dermal fibroblasts harvested from five different anatomical sites (neck, breast, arm, abdomen and thigh) were cultured and their morphology, proliferation, apoptotic rate, ability to migrate, expression of mesenchymal or epithelial markers, differentiation potential and production of growth factors were evaluated in vitro. Additionally, gene expression analysis was performed by real‐time PCR including genes typically expressed by mesenchymal cells. Finally, fibroblasts isolated from different anatomic sites were reprogrammed to iPSCs by integration‐free method. Intriguingly, while the morphology of fibroblasts derived from different anatomic sites differed only slightly, other features, known to affect cell reprogramming, varied greatly and in accordance with anatomic site of origin. Accordingly, difference also emerged in fibroblasts readiness to respond to reprogramming and ability to form colonies. Therefore, as fibroblasts derived from different anatomic sites preserve positional memory, it is of great importance to accurately evaluate and select dermal fibroblast population prior to induce reprogramming.

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Section: Introductionmentioning

confidence: 93%

Diversity of dermal fibroblasts as major determinant of variability in cell reprogramming

Sacco

Belviso

Romano

et al. 2019

J Cellular Molecular Medi

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“…Reprogramming efficiency can be enhanced by the inclusion of various factors in addition to those transcription factors responsible for pluripotency. These alternative factors either safeguard the pluripotency of ESCs or play more specific roles in facilitating the reprogramming process but do not maintain pluripotency after it is established 11 . In this study, we found that Rab32 was able to facilitate reprogramming efficiency by regulating lipid metabolism.…”

Section: Discussionmentioning

confidence: 99%

“…The quality of different iPSC lines is variable, and this determines their ability to undergo germ-line transmission and live birth following tetraploid complementation 9 10 . Although reprogramming efficiency can be enhanced by the inclusion of other reported factors in addition to pluripotency-related transcription factors, additional factors that play more specific roles in facilitating the reprogramming process remain to be uncovered 11 12 .…”

mentioning

confidence: 99%

Improvement in Mouse iPSC Induction by Rab32 Reveals the Importance of Lipid Metabolism during Reprogramming

Pei

Yue

Zhang

et al. 2015

Sci Rep

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Induced pluripotent stem cells (iPSCs) have variable expression levels of a series of genes that affect their pluripotent potential, but the regulatory mechanisms controlling reprogramming remain unclear. By testing the efficiency of iPSC generation using Oct4, Sox2, Klf4 (termed OSK) plus one additional gene, we found that Rab32 improved reprogramming efficiency. We established a system for detecting the number and the size of lipid droplets and autophagosomes per cell for tracking their morphological changes during reprogramming. Our results showed that Rab32 increased lipid storage during the early and middle stages, and also increased autophagy during the middle stage of reprogramming. These findings were further confirmed by the up-regulation of lipid biosynthesis and autophagosome formation related genes, of which their expression could improve iPSC induction. The inhibition of lipid biosynthesis and autophagosome formation significantly reduced reprogramming efficiency, and the inhibition of lipid synthesis phenotype could be rescued by the overexpression of Rab32. In addition, the expression of pluripotency genes such as Klf2, Nr5a2 and Tbx3, was up-regulated by Rab32. These results demonstrated that Rab32 could improve the induction of iPSCs through the enhancement of lipid biosynthesis, highlighting the importance of lipid metabolism during reprogramming.

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“…Despite numerous studies underlying the pathophysiological mechanism of ASD using iPSCs, several concerns should be addressed before iPSC research [ 155 , 156 ]. Current advances in iPSC technology have allowed us to successfully derive patient-specific iPSCs regardless of their reprogramming methods.…”

Section: Discussionmentioning

confidence: 99%

Understanding the molecular basis of autism in a dish using hiPSCs-derived neurons from ASD patients

et al. 2015

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Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by deficits in social cognition, language development, and repetitive/restricted behaviors. Due to the complexity and heterogeneity of ASD and lack of a proper human cellular model system, the pathophysiological mechanism of ASD during the developmental process is largely unknown. However, recent progress in induced pluripotent stem cell (iPSC) technology as well as in vitro neural differentiation techniques have allowed us to functionally characterize neurons and analyze cortical development during neural differentiation. These technical advances will increase our understanding of the pathogenic mechanisms of heterogeneous ASD and help identify molecular biomarkers for patient stratification as well as personalized medicine. In this review, we summarize our current knowledge of iPSC generation, differentiation of specific neuronal subtypes from iPSCs, and phenotypic characterizations of human ASD patient-derived iPSC models. Finally, we discuss the current limitations of iPSC technology and future directions of ASD pathophysiology studies using iPSCs.

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Overcoming barriers to the clinical utilization of iPSCs: reprogramming efficiency, safety and quality

Cited by 17 publications

References 88 publications

Diversity of dermal fibroblasts as major determinant of variability in cell reprogramming

Diversity of dermal fibroblasts as major determinant of variability in cell reprogramming

Improvement in Mouse iPSC Induction by Rab32 Reveals the Importance of Lipid Metabolism during Reprogramming

Understanding the molecular basis of autism in a dish using hiPSCs-derived neurons from ASD patients

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