Abstract
Stem cell therapies show great potential for use in regenerative medicine, though advancements in safe stem cell technology need to be realized. Human induced pluripotent stem cells (hiPSCs) hold an advantage over other stem cell types for use in cell-based therapies due to their potential as an unlimited source of rejuvenated and immunocompatible SCs which do not elicit the ethical and moral debates associated with the destruction of human embryos. Towards realization of this potential this review focuses on the recent progress in DNA-and xeno-free reprogramming methods, particularly small molecule methods, as well as addresses some of the latest insights on donor cell gene expression, telomere dynamics, and epigenetic aberrations that are a potential barrier to successful widespread clinical applications.
Highlights
The promise of stem cell-based rejuvenation therapy has long been heralded and has recently been previewed with interim reports of success by companies such as StemCell, Inc
Estaben et al’s hypothesis that Vitamin C (Vc) can modulate dioxygenase hypoxia inducible factor (HIF) target genes as a cofactor for HIF reactions is supported in research by Yoshida et al [58] whom had first shown that hypoxic (5% O2) culture conditions could improve Human induced pluripotent stem cells (hiPSCs) reprogramming efficiency; HIF-2α is known to directly bind hypoxia response elements (HREs) located in Oct4 promoter and the conserved regions 3 & 4 of the Oct4 distal enhancers (DE) known to drive expression in the ICM and in ES cells [59]
There are many regulatory and biological concerns to be resolved before commercialization of SCs for clinical therapy can be achieved, : the use of human embryonic SCs (hESCs) in such therapies carries great ethical debate and poses an immunogenicity risk; somatic cell nuclear transfer (SCNT) technology is technically challenging and controversial; allogeneic mesenchymal stem cells (MSCs) may still pose an immunogenicity risk while autologous MSCs may be susceptible to senescence
Summary
The promise of stem cell-based rejuvenation therapy has long been heralded and has recently been previewed with interim reports of success by companies such as StemCell, Inc. Takahashi & Yamanaka [18] first defined the core transcription factors (TFs) for inducing pluripotency in somatic cells of mice as Oct3/4, Sox, Klf, and c-Myc (OSKM) using gammaretroviruses with high transduction efficiencies and in human dermal fibroblasts [19] using lentiviruses; these methods resulted in more than 20 retroviral integrations per clone and oncogenic potential too high for clinical therapeutics This is a significant hurdle to regulatory approval as the FDA code of federal regulations (21 CFR Part 1271) and compliance program (7341.002) requires that the iPSCs be xeno- and foreign DNA-free, free of growth abnormalities and mutagenesis, noncontaminated, and consistently manufactured according to cGMP before regulatory approval will be awarded [20]. While there has been great success in animal-based iPSC research, the focus of this review will be on safe and efficient hiPSC methods and genomics
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