The Yamanaka transcription factors can be used to recreate the transformation of cell type that occurs in early embryonic development, inducing a process of reprogramming that can transform any somatic cell into an induced pluripotent stem cell. Initially, this discovery was applied to the development of cell therapies and tissue engineering, a way to produce cells of a specific type matched to the recipient, or to generate cell banks able to reliably supply cells of specific types, or to chase the grail of universal cell lines that can be used in any patient. After nearly twenty years of development, some of the first therapies to transplant cells derived from induced pluripotent stem cells have reached clinical trials - progress in the highly regulated field of medicine is slow at best.
Separately, researchers have discovered that reprogramming doesn't just change cell type, it also rejuvenates a cell by restoring youthful epigenetic control over gene expression. That in turn restores youthful mitochondrial function and numerous other aspects of cell behavior and performance. It cannot repair DNA damage, and cannot enable cells to break down molecular waste that even youthful cells struggle to handle. Nonetheless, there is a great deal of interest in finding ways to use this phenomenon as a basis for therapy. What is known as partial reprogramming involves exposing cells to the Yamanaka factors for long enough to produce this desirable outcome of epigenetic rejuvenation, but not long enough to turn cells into induced pluripotent stem cells. Cells retain their state, with improved function.
Today's open access review provides a good introduction to the science behind the promise and the challenges of partial reprogramming as a basis for therapy. Positive results have been produced in animal studies, but sizable hurdles are involved in trying to reprogram large portions of the body rather than employing a very narrow, restricted use in isolated tissues such as the retina. Different cell types in different tissues have different requirements and restrictions for partial reprogramming. What is good for lung cells is bad for liver cells. What is good for one type of cell in the liver is bad for its neighbor. "Bad" in this context means cell death, tissue dysfunction, and cancer. There is no good solution at this time that would lead to a simple partial reprogramming therapy that affects the whole body without either (a) watering it down to produce negligible benefits, or (b) causing severe issues in some tissues.
Organ-Specific Dedifferentiation and Epigenetic Remodeling in In Vivo Reprogramming
The advent of in vivo reprogramming through transient expression of the Yamanaka factors (OCT4, SOX2, KLF4, and c-MYC, abbreviated OSKM) holds strong promise for regenerative medicine, despite ongoing concerns about safety and clinical applicability. This review synthesizes recent advances in in vivo reprogramming, focusing on its potential to restore regenerative competence and promote rejuvenation across diverse tissues, including the retina, skeletal muscle, heart, liver, brain, and intestine.
In physiologically aged mice, long-term cyclic induction of OSKM restores youthful multi-omics signatures - including DNA methylation, transcriptomic, and lipidomic profiles - across multiple organs such as the spleen, liver, skin, kidney, lung, and skeletal muscle. Importantly, this regimen also promotes functional regeneration: while short-term reprogramming enhances muscle repair through local niche control, sustained cyclic reprogramming improves wound healing and reduces fibrosis in both muscle and skin. Consistent with these findings, even a single 1-week cycle of OSKM in aged mice (55 weeks old) elicits systemic rejuvenation, evidenced by DNA methylation reprogramming across the pancreas, liver, spleen, and blood.
Nevertheless, significant challenges to its application remain, including tumor formation, intestinal and liver failure, and loss of cellular identity. Achieving precise spatiotemporal control over reprogramming will be essential to minimize these risks while preserving therapeutic benefits. Future efforts should prioritize refining delivery methods and exploring safer alternatives such as small molecules or modified gene sets.
Interest in this field is rapidly growing within the biotech sector, summarized in recent reviews which provide detailed accounts of company pipelines and translational strategies. In this review, we instead focus on mechanistic insights into injury-induced and OSKM-induced reprogramming, offering a framework for understanding how regenerative competence can be harnessed across tissues. With careful modulation, OSKM-based approaches hold strong potential to transform regenerative medicine and the treatment of age-related diseases.
View the full article at FightAging
