Direct cell reprogramming for tissue engineering and regenerative medicine

Direct cell reprogramming, also called transdifferentiation, allows for the reprogramming of one somatic cell type directly into another, without the need to transition through an induced pluripotent state. Thus, it is an attractive approach to develop novel tissue engineering applications to treat diseases and injuries where there is a shortage of proliferating cells for tissue repair. In certain tissue damage, terminally differentiated somatic cells lose their ability to proliferate, as a result, damaged tissues cannot heal by themselves. Examples of these scenarios include myocardial infarctions, neurodegenerative diseases, and cartilage injuries. Transdifferentiation is capable of reprogramming cells that are abundant in the body into desired cell phenotypes that are able to restore tissue function in damaged areas. Therefore, direct cell reprogramming is a promising direction in the cell and tissue engineering and regenerative medicine fields. In recent years, several methods for transdifferentiation have been developed, ranging from the overexpression of transcription factors via viral vectors, to small molecules, to clustered regularly interspaced short palindromic repeats (CRISPR) and its associated protein (Cas9) for both genetic and epigenetic reprogramming. Overexpressing transcription factors by use of a lentivirus is currently the most prevalent technique, however it lacks high reprogramming efficiencies and can pose problems when transitioning to human subjects and clinical trials. CRISPR/Cas9, fused with proteins that modulate transcription, has been shown to improve efficiencies greatly. Transdifferentiation has successfully generated many cell phenotypes, including endothelial cells, skeletal myocytes, neuronal cells, and more. These cells have been shown to emulate mature adult cells such that they are able to mimic major functions, and some are capable of promoting regeneration of damaged tissue in vivo. While transdifferentiated cells have not yet seen clinical use, they have had promise in mice models, showing success in treating liver disease and several brain-related diseases, while also being utilized as a cell source for tissue engineered vascular grafts to treat damaged blood vessels. Recently, localized transdifferentiated cells have been generated in situ, allowing for treatments without invasive surgeries and more complete transdifferentiation. In this review, we summarized the recent development in various cell reprogramming techniques, their applications in converting various somatic cells, their uses in tissue regeneration, and the challenges of transitioning to a clinical setting, accompanied with potential solutions.