The Therapeutic Potential of Transdifferentiation – Fight Aging!

Transdifferentiation is the use of various techniques to convert a somatic cell of one type directly into a somatic cell of another type. This is an alternative to first using Yamanaka factors to dedifferentiate somatic cells into induced pluripotent stem cells, then guiding differentiation into the desired final somatic cell type. For both differentiation from pluripotency to somatic cell and transdifferentiation between somatic cells, a suitable recipe of factors and altered gene expression must be discovered for any given destination. A few of these protocols are now well known, but the vast majority have yet to be robustly established, or even attempted at all.

In today’s open access paper, researchers refer to transdifferentiation as direct reprogramming, not to be confused with the various forms of reprogramming via Yamanaka factors, either to produce induced pluripotent stem cells, or to restore youthful epigenetic patterns via what is known as partial reprogramming or epigenetic reprogramming. Transdifferentiation offers the potential to treat aspects of aging and age-related disease that involve the loss of small, specific cell populations, such as dopaminergenic neurons or sensory hair cells. These critical populations are surrounded by other, more numerous, less critical cells, which might be targets for transdifferentiation given a sufficiently selective therapy. Proof of concept in these and a few other cases has been achieved in animal studies, and it remains to be seen as to how rapidly this can advance to the clinic.

Next-generation direct reprogramming

While the concept that mature cell states are stable holds the key for homeostasis of an organism, the long-held believe was that this state cannot ever be reversed. This fallacy has gradually broken down. Now, the Yamanaka factors are now widely used not only for reprogramming but also for partial reprogramming that leads to rejuvenation of tissues. Yet another kind of reprogramming was emerging from the basic science field, now dubbed direct reprogramming, or transdifferentiation (we use the terms interchangeably from here on). During transdifferentiation a differentiated cell changes its fate to another, more desired differentiated cell type, without entering a pluripotent stage. The first identified transcription factor capable of directly reprogramming fibroblasts to skeletal muscles was MyoD. Many other lineage-specific transcription factors capable of transdifferentiating a target cell have since been identified.

Whether induced or endogenous process, in general, pioneer factors (PF) act as the first responders in direct reprogramming by binding and opening closed chromatin. It is not clear if each transdifferentiation lineage is regulated by a specific pioneer factor, or if a universal PF for transdifferentiation (capable of initiating multitude of direct lineage reversions) is still to be identified. Transdifferentiation studies have unveiled the opportunities and offer applications in regenerative therapies, such as cell replacement therapy or immunotherapy. The key question, and the topic of this review is to identify new, feasible methods to induce specific, high efficiency and targeted transdifferentiation.

These next-generation transdifferentiation approaches will come with better efficiency and plausibly with potential to treat diseases like Alzheimer’s disease, muscle injury, diabetes, or myocardial infarction, resulting in elimination of the unsurmountable treatment issues at the moment (for example, finding a right donor or graft rejections). These novel approaches will enhance the efficacy and safety of direct reprogramming, allowing the ultimate decoding of the process towards plausibly resulting in 21st century personalized regenerative medicine.