Toward pluripotency by reprogramming: mechanisms and application

Abstract

The somatic epigenome can be reprogrammed to a pluripotent state by a combination of transcription factors. Altering cell fate involves transcription factors cooperation, epigenetic reconfi guration, such as DNA methylation and histone modification, posttranscriptional regulation by microRNAs, and so on. Nevertheless, such reprogramming is inefficient. Evidence suggests that during the early stage of reprogramming, the process is stochastic, but by the late stage, it is deterministic. In addition to conventional reprogramming methods, dozens of small molecules have been identifi ed that can functionally replace reprogramming factors and signifi cantly improve induced pluripotent stem cell (iPSC) reprogramming. Indeed, iPS cells have been created recently using chemical compounds only. iPSCs are thought to display subtle genetic and epigenetic variability; this variability is not random, but occurs at hotspots across the genome. Here we discuss the progress and current perspectives in the fi eld. Research into the reprogramming process today will pave the way for great advances in regenerative medicine in the future.

Functional AdoMet Isosteres Resistant to Classical AdoMet Degradation Pathways

“…5–15 Consistent with this, alterations in methylation-dependent processes are associated with cancer, 16 neurodegenerative/neuropsychiatric disorders, 17–19 inflammation, 20,21 metabolic disorders, 22 fundamental development/regenerative medicine, 23,24 susceptibility to disease/adverse drug response, 25,26 and drug resistance. 13–15,27,28 While there have been great advances in methylation-dependent bioinformatics and disease-associated biomarkers, 29–31 the study of intracellular MT spatial/temporal resolution, specificity, and/or function remains a challenge.…”

iPSC-Derived Forebrain Neurons from FXS Individuals Show Defects in Initial Neurite Outgrowth

“…Several factors introduce variability and affect the ability to compare data from multiple studies, including patient differences, iPSC reprogramming methods, and neuronal differentiation paradigms. Inherent genetic variation among individuals due to genetic diversity, variability of iPSC clones from a single individual, as well as disease presentation presents major challenges to iPSC disease modeling [51][52][53]. Epigenetic and copy number diversity adds another layer of complexity [54] that may plague iPSCs to a greater extent than other samples.…”

Being human: The role of pluripotent stem cells in regenerative medicine and humanizing Alzheimer's disease models

“…Commonly used factors include the so-called Yamanaka factors, Oct4, KLF4, Sox2, and c-Myc (Takahashi and Yamanaka, 2006), although alternative transcription factors, microRNAs, or chemical factors have also been used (Wang et al, 2013). Only transient over expression of stem cell factors is required before the endogenous network is sufficiently activated, allowing the use of non-integrating approaches, including non-integrating viruses, episomal overexpression, and modified RNA among others (Hu, 2014).…”

“…Typically skin fibroblasts or peripheral blood are used as starting materials as they are easily acquired from patient donation and biorepositories. The precise molecular mechanisms underlying pluripotent reprogramming are still not fully understood, but seem to involve an early stochastic process that becomes increasingly deterministic as the endogenous stem cell transcriptional network is activated, as has been reviewed elsewhere (Hanna et al, 2009;Wang et al, 2013).…”