The novel tool of cell reprogramming for applications in molecular medicine

Abstract

Recent discoveries in the field of stem cell biology have enabled scientists to "reprogram" cells from one type to another. For example, it is now possible to place adult skin or blood cells in a dish and convert them into neurons, liver, or heart cells. It is also possible to literally "rejuvenate" adult cells by reprogramming them into embryonic-like stem cells, which in turn can be differentiated into every tissue and cell type of the human body. Our ability to reprogram cell types has four main implications for medicine: (1) scientists can now take skin or blood cells from patients and convert them to other cells to study disease processes. This disease modeling approach has the advantage over animal models because it is directly based on human patient cells. (2) Reprogramming could also be used as a "clinical trial in a dish" to evaluate the general efficacy and safety of newly developed drugs on human patient cells before they would be tested in animal models or people. (3) In addition, many drugs have deleterious side effects like heart arrhythmias in only a small and unpredictable subpopulation of patients. Reprogramming could facilitate precision medicine by testing the safety of already approved drugs first on reprogrammed patient cells in a personalized manner prior to administration. For example, drugs known to sometimes cause arrhythmias could be first tested on reprogrammed heart cells from individual patients. (4) Finally, reprogramming allows the generation of new tissues that could be grafted therapeutically to regenerate lost or damaged cells.

Keywords: Cell fate; Reprogramming; Stem cell biology.

Fig. 1

Common technologies to reprogram cell fate. a Somatic cell nuclear transfer (SCNT), in which an oocyte is enucleated to receive a nucleus from a donor cell such as a fibroblast uses the cytoplasmic machinery to reprogram the donor cell to pluripotency. Similar methods were used to clone entire animals such as Dolly the sheep and generate human stem cell lines. b Analogous to SCNT diffusible factors can reprogram the expression program of a donor cell such as a human amniocyte upon induced cell fusion with heterologous cells such as mouse myocytes to induce the expression of human muscle genes. c Alternatively, strong cell fate determination transcription factors can be overexpressed using different methods to change a cell fate. For example, the transcription factors Oct4, Sox2, Klf4, and c-Myc (OSKM) can convert a fibroblast into an induced pluripotent stem cell

Fig. 2

Cell fate roadblocks for lineage reprogramming. Cell identity is a function of many parameters including gene expression, epigenetic configuration, protein composition, signaling pathway activity, and metabolism. Several studies suggest that modulation of any of these parameters not only follows but also dictates physiological and induced cell fate changes. It will therefore be essential to devise methods to monitor and potentially modulate all these parameters in order to faithfully generate cells for disease modeling and regenerative medicine

Fig. 3

Current cellular reprogramming technologies and future biomedical applications. Cell fate changes can be induced to generate human cells for (1) in vitro disease modeling and (2) drug discovery as well as for potential (3) personalized drug screens in precision medicine and (4) regenerative applications in the near future. Donor cells such as fibroblasts can be directly reprogrammed to many cell types of biomedical interest, while this process usually is very fast it often only generates a limited amount of cells. Alternatively, donor cells can first be reprogrammed to induced pluripotency and subsequently directed to the intended fate, in general this procedure is more time consuming but in theory generates unlimited amounts of cells for biomedical applications