Ten years of progress and promise of induced pluripotent stem cells: historical origins, characteristics, mechanisms, limitations, and potential applications

Abstract

The discovery of induced pluripotent stem cells (iPSCs) by Shinya Yamanaka in 2006 was heralded as a major breakthrough of the decade in stem cell research. The ability to reprogram human somatic cells to a pluripotent embryonic stem cell-like state through the ectopic expression of a combination of embryonic transcription factors was greeted with great excitement by scientists and bioethicists. The reprogramming technology offers the opportunity to generate patient-specific stem cells for modeling human diseases, drug development and screening, and individualized regenerative cell therapy. However, fundamental questions have been raised regarding the molecular mechanism of iPSCs generation, a process still poorly understood by scientists. The efficiency of reprogramming of iPSCs remains low due to the effect of various barriers to reprogramming. There is also the risk of chromosomal instability and oncogenic transformation associated with the use of viral vectors, such as retrovirus and lentivirus, which deliver the reprogramming transcription factors by integration in the host cell genome. These challenges can hinder the therapeutic prospects and promise of iPSCs and their clinical applications. Consequently, extensive studies have been done to elucidate the molecular mechanism of reprogramming and novel strategies have been identified which help to improve the efficiency of reprogramming methods and overcome the safety concerns linked with iPSC generation. Distinct barriers and enhancers of reprogramming have been elucidated, and non-integrating reprogramming methods have been reported. Here, we summarize the progress and the recent advances that have been made over the last 10 years in the iPSC field, with emphasis on the molecular mechanism of reprogramming, strategies to improve the efficiency of reprogramming, characteristics and limitations of iPSCs, and the progress made in the applications of iPSCs in the field of disease modelling, drug discovery and regenerative medicine. Additionally, this study appraises the role of genomic editing technology in the generation of healthy iPSCs.

Effects of neural stem cell transplantation in Alzheimer’s disease models

“…Nonetheless, to what extend these iPSCs are uniformed in their quality remain in question. Moreover, during iPSCs establishment, reprogramming efficiency is depended on donor-cell-type and reprogramming method [73,74]. The optimum somatic cell type for reprogramming into iPSCs and subsequent differentiation into NSCs remains to be determined.…”

Global trends in clinical trials involving pluripotent stem cells: A systematic multi-database analysis

“…This also implies that only a minority of studies (22.9%) were of an interventional study type, where cells were actually transplanted into patients for therapeutic purposes. From the view point of translational medicine, these interventional studies are of greater interest, since the introduction of the iPSC technology was associated with a signi cant hope for future clinical use in the sense of cellular transplantation (8,(47)(48)(49)(50). While the total number of clinical trials involving iPSCs (74.8%) was substantially higher than the ones involving ESCs (25.2%), the picture changes completely when focusing on interventional studies.…”

Endothelial Differentiation G Protein-Coupled Receptor 5 Plays an Important Role in Induction and Maintenance of Pluripotency

“…Since the discovery that somatic cells could be reprogrammed to iPSCs in 2006 by Yamanaka and colleagues , vast amount of research has be performed to try to improve the reprogramming efficiency and to better understand the molecular machinery of pluripotency acquisition and maintenance. Undoubtedly, numerous studies which reported identification of a new effectors or barriers of reprogramming process have broaden our knowledge about complex interaction of the different signaling pathway and reprogramming mechanisms and have highlighted an important role for MET, metabolism, apoptosis, cytoskeleton rearrangement, autophagy, immune response, cell cycle alterations, epigenetics, and many others for the effective hiPSCs generation.…”