Cell Reprogramming via RNA Therapies
Gene therapies delivering mRNA produce a temporary production of proteins. An RNA molecule acts as a blueprint for a ribosome to assemble many copies of a specific protein, but this doesn't last long, and a few days of protein expression from a single treatment is a reasonable expectation in practice. This make RNA therapies suitable to produce partial reprogramming in an animal or patient. The Yamanaka factors are delivered for a long enough period of time to rejuvenate epigenetic patterns and restore mitochondrial function, but (hopefully) not long enough to convert any meaningful number of somatic cells into induced pluripotent stem cells. The former outcome is desirable, while the latter outcome would damage tissue function and create the risk of cancer.
Induced pluripotent stem cells (iPSCs) reprogrammed from replicative senescing or centennial cells had restored the telomere and mitochondrial functions with a gene expression profile similar to embryonic stem cells (ESCs). This and other avenues of research confirm that cellular age can be reversed. These seminal results led the scientific community to ask whether cellular rejuvenation due to reprogramming could take place in vivo.
To answer this question, researchers generated transgenic mouse models, expressing Yamanaka factors (OSKM) under the control of doxycycline. Strikingly, they observed the emergence of teratomas in several organs, thus demonstrating the feasibility of in vivo reprogramming. However, to prevent deterioration related to aging or to rejuvenate the organism, it is important not to generate fully dedifferentiate cells, as this leads to a deterioration of the animal's health or tumor formation. Consequently, it was judicious to think to trigger the reprogramming process and stop it before obtaining pluripotent cells, hoping that it might erase cellular aging marks instead of favoring senescence. Researchers envisioned such a strategy and proposed a protocol to induce partial reprogramming in a homozygous progeria transgenic mouse model. They induced OSKM expression for 2 days per week during the lives of the animals with doxycycline and observed a significant increase in the lifespan of these animals, as well as the improvements in age-related hallmarks.
The use of strategies based on mRNA to express the factors needed for cell reprogramming has rapidly emerged as a promising technology to achieve the goal of partial reprogramming. Hence, in this review, after a brief revisiting of the state-of-the-art various technologies, we will focus on methods based on RNA that induce the conversion of somatic cells into pluripotent cells. We will frame these technological advances in the context of recent cutting-edge approaches to reverse age-related cell and tissue phenotypes by reprogramming them towards pluripotency.