This review paper looks over the technology of induced pluripotency in the context of its ability to advance the state of regenerative medicine. A little over a decade ago, it was discovered that expression just a few genes in any adult cell reprogrammed it to become an induced pluripotent stem cell, near identical to an embryonic stem cell. Such pluripotent cells are capable of forming any type of cell in the body, given the research and development needed to establish the right recipe of stimuli and signals. This technology is not just interesting as a way to potentially produce supplies of any cell and tissue type needed for regenerative therapies, but also for the fact that reprogrammed cells restore lost mitochondrial function and reverse their epigenetic markers of age - though still retaining many other forms of age-related molecular damage. That second discovery has given rise to companies such as Turn.bio, working on ways to reprogram cells in situ in the body to restore tissue function.
In 2006, researchers reported for the first time the reprogramming of induced pluripotent stem cells (iPSC) from mouse somatic cells by forced expression of the transcription factors Oct4, Sox2, Klf4, and c-Myc, now termed Yamanaka factors. Subsequently, the Yamanaka factors, or other combinations of factors were successfully used to reprogram a wide range of mouse or human somatic cells into iPSC. iPSC achieve a high degree of dedifferentiation and acquire properties similar to those of embryonic stem cells (ESC). Indeed, iPSC and ESC are morphologically indistinguishable, and in vitro these cells have the potential to differentiate into cells of the three germ layers (ectoderm, endoderm, and mesoderm) and to originate virtually all cells of adult organisms.
Work by many researchers worldwide has led to the understanding of the molecular bases and to the improvement of the cell reprogramming process, bringing iPSC closer to safe clinical applications. However, the full translational potential of iPSC is still hampered by flaws, such as the inefficiency and the frequent incomplete reprogramming of the cells, and de novo mutations occurring during the reprogramming process and during the cultivation of generated iPSC. The efficiency to reprogram somatic cells into iPSC remains low (often much less than 1%), and likely further decline in aged cells or in cells with a high number of divisions.
An interesting concept of cell-aging reversion in vivo, which has prolonged the lifespan of a mouse model of premature aging, has also emerged with the reprogramming technology. Indeed, the short-term exposure to Yamanaka factors has contributed to a partial reprogramming of cells, and amended the physiological and cellular hallmarks of aging, due to a probable remodelling of the epigenetic marks which are acquired during aging. Further understanding of the partial reprogramming timings and markers may harness balanced conditions to obtain rejuvenated cells with a full potential to perform their functions and with a minimal dedifferentiation state to avoid oncogenic risks. Partial reprogramming approaches and the consequent epigenetic rejuvenation may serve to develop future interventions for the treatment of age-related diseases, improvement of health and longevity.
The ability to generate pluripotent stem cells, iPSC, from human somatic cells using a simple experimental approach easy to implement, has undeniably opened new possibilities for modelling diseases and to undertake developmental studies that could never have been performed before. The bulk of the molecular mechanisms involved in the reprogramming process has been largely unveiled, which has already allowed great improvements in the iPSC generation process. Consequently, iPSC have achieved a quality sufficient to be used in novel clinical approaches. The use of patient-derived iPSC offers the possibility to develop and test patient-specific pharmacotherapies and derive stem cells which may be corrected for genetic defects before their use for autologous purposes. In the field of cancer, the study of iPSC biology and their reprogramming mechanism has not only provided new insights in epigenetic changes contributing to cancer, but has positioned iPSC as a cell source to originate immune cells with great potential for the development of immunotherapies against cancer.
Although many technical hurdles remain to be surpassed for iPSC technology to fully reach its potential. In just over ten years after its first development this technology has remarkedly led to several clinical applications, and provide new ways of obtaining disease models in vitro to better study the mechanism of human pathologies and to improve patients' treatment in a more adequate and personalized manner. Thus, iPSC technology has already been "a giant leap" in terms of obtaining human cells with incredible versatility and potential for therapeutic applications.