Adult mammals display very limited regeneration capacity. Certain mammalian tissues can regenerate after an injury, but severely damaged organs cannot recover. For instance, nephron epithelium of the mammalian kidney can regenerate after a minor acute injury, but stronger insults result in irreversible nephron loss, causing diminished renal function. This is in stark contrast to many phylogenetically lower animals, which can regenerate a diverse array of organs. These organisms are equipped with toti-/pluri-potent stem cells and/or the ability to de-differentiate their cells to a similar plastic state. On the other hand, adult mammals contain only tissue-specific stem cells with limited plasticity, which contribute only to the regeneration of specific cellular lineages. Therefore, a more extensive regeneration potential may be conferred to mammals by inducing superior cellular plasticity. Such induction has been achieved in vitro by expressing the four Yamanaka factors (4F) (Oct4, Sox2, Klf4 and cMyc) and thus, it may be possible to harness 4F expression in vivo to enhance mammalian regeneration (long-term goal). Preliminary results showed that intermittent expression of 4F extends the life span of Progeria mice, which typically exhibit accelerated aging. This observation correlated with significant histological improvement in multiple organs, including the kidneys, indicating a regenerative effect of 4F. To specifically characterize whether 4F expression can promote renal regeneration after an injury, a mouse line has been developed that allows lineage tracing of 4F-expressing cells, as well as reporter lines that indicate if renal tubular cells revert to the embryonic progenitor states in response to the in vivo induction of 4F expression. In parallel experiments, conditions have been established for culturing embryonic nephrogenic progenitors, and for transplanting them into mouse hosts. This advancement will allow transplantation of 4F-expressing nephrogenic progenitors into a wild-type mouse to induce 4F expression specifically in the renal parenchyma. Together, these tools provide a unique experimental platform to explore the regenerative effect of 4F. This proposal specifically addresses whether 4F expression can enhance murine renal regeneration following acute kidney injury (AKI). Nephron epithelium de-differentiates following AKI en route to its regeneration. Therefore, one can hypothesize that 4F expression will enhance recovery from AKI by promoting the de-differentiation and plasticity of nephron epithelial cells. This hypothesis will be addressed by transiently expressing 4F ubiquitously or specifically in the kidney and assessing the impact on recovery from AKI. Thus, these exploratory studies seek to reveal a regenerative effect of 4F against AKI, which has the potential to lead to a therapeutic intervention against acute renal failure since chemical-based strategies for boosting or replacing 4F in reprogramming have been reported. Moreover, successful completion of these studies will pave the way toward using this technology to treat a wide range of acute injuries in other organs.

Public Health Relevance

Because of the limited regeneration capacity in mammals, often the only recourse for treating a patient with organ failure is transplantation. However, the demand for organ transplantation is rapidly rising due to the aging human population and this is reflected by the rising prevalence of end-stage renal disease. Here we explore a potentially transformative healthcare intervention that aims to enhance renal regeneration by expressing the four Yamanaka factors (i.e., genes that induce cellular reprogramming and rejuvenation) in acutely damaged mouse kidneys.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Exploratory/Developmental Grants (R21)
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Pathobiology of Kidney Disease Study Section (PBKD)
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Williams, John
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Salk Institute for Biological Studies
La Jolla
United States
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Beyret, Ergin; Martinez Redondo, Paloma; Platero Luengo, Aida et al. (2018) Elixir of Life: Thwarting Aging With Regenerative Reprogramming. Circ Res 122:128-141