From the Guidelines
Yamanaka factors are a crucial tool in reprogramming adult cells into induced pluripotent stem cells (iPSCs), offering promising clinical applications, but their use is associated with significant risks, including tumor formation, genetic instability, and immunogenicity, as highlighted in recent studies 1. The primary clinical applications of Yamanaka factors include:
- Disease modeling
- Drug screening
- Regenerative medicine
- Personalized cell therapies These factors allow researchers to create patient-specific stem cells that can be differentiated into various cell types for studying disease mechanisms and testing potential treatments without ethical concerns associated with embryonic stem cells. In regenerative medicine, iPSCs can potentially be used to replace damaged tissues in conditions like Parkinson's disease, spinal cord injury, and macular degeneration, with some early-phase clinical trials already underway, as noted in a recent update on stem cell research and clinical translation 1. However, significant risks exist, including:
- Potential for tumor formation due to the oncogenic properties of c-Myc and incomplete reprogramming
- Genetic instability during the reprogramming process
- Immunogenicity despite being patient-derived
- Possibility of premature aging in derived cells Additionally, the reprogramming efficiency remains low (typically 0.01-1%), and the process is time-consuming (weeks to months), limiting immediate clinical applications, as discussed in the context of reproducibility issues in stem cell technologies 1. Current research focuses on developing non-integrating delivery methods like Sendai virus vectors or episomal plasmids to reduce genomic integration risks, and exploring alternative reprogramming factors to enhance safety while maintaining efficacy, in line with guidelines for responsible translational stem cell research 1.
From the Research
Clinical Applications of Yamanaka Factors
- Induced pluripotent stem cells (iPSCs) generated using Yamanaka factors have vast opportunities for disease modeling, pathogenesis understanding, therapeutic drug development, toxicology, organ synthesis, and treatment of degenerative disease 2
- iPSCs can be used for cell therapy, new drug development, and cell derivation in clinical settings 3
- Yamanaka factors can be used to reprogram somatic cells into iPSCs, which can be differentiated toward diverse fates, serving as a resource for basic and translational research 4
Risks Associated with Yamanaka Factors
- The use of Yamanaka factors, particularly Klf4 and c-Myc, which are oncogenes, poses a potential tumor risk 2
- Reprogramming somatic cells to iPSCs can result in partially reprogrammed colonies, somatic coding mutations in the genome, and epigenetic aberrations 2, 5
- Overexpression of Oct4 during reprogramming can lead to off-target gene activation and epigenetic aberrations in resulting iPSCs 5
Alternatives to Yamanaka Factors
- Other transcription factors, such as NKX3-1, can replace OCT4 in mouse and human iPSC induction 4
- The combination of Sox2, Klf4, and cMyc (SKM) can suffice for reprogramming mouse somatic cells to iPSCs, resulting in improved developmental potential of iPSCs 5
- Mathematical approaches can be used to model the landscape between cell states during reprogramming and predict the time necessary to create a given number of iPSC colonies 6