After a heart attack, the restoration of the cardiac function depends on the ability of the heart to generate cardiomyocytes, or new muscle cells. The ability is, however, weak and wanes with age. The alternative strategy involves delivering the newly grown cardiomyocytes to the damaged heart tissue. It requires the use of either induced pluripotent stem (iPS) or the embryonic stem (ES) cells. Embryos are the only sources of ES cells. On the other hand, the in vitro reprogramming of adult differentiated cells transforms them into undifferentiated stem cells. The method allows the production of iPS cells from adult cells. Cardiomyocytes prepared from iPS cells are autologous. The recipient’s body, therefore, does not reject them after transplantation. The technique is, however, time-consuming and problematic. In their search for a better approach, Efe et al. discovered that fibroblasts could form cardiomyocytes, before the completion of their transformation into the iPS cells. They modified various culture conditions and induced the cardiomyocyte differentiation in about 40% of the cells. The researchers identified the new cells using specific staining for cardiac troponin T. They also tested the cells for particular properties such as the calcium gradients. The new technique was an efficient alternative to the technically challenging and indirect earlier method of yielding autologous tissue. The discovery simplified the procedure, increased the production of functional cardiomyocytes, and saved time for the patients. The cardiomyocytes generated using the new method, however, mainly resemble atrial cardiac muscle.
Since the mammalian heart has a reduced capacity for regeneration, the in vitro production of autologous cardiac cells for the treatment of heart diseases is a significant area for research. The process identified by Efe et al. is almost three times faster than the previous method that required a pluripotent intermediate. It also produces contracting cardiomyocytes at a faster rate than the previous system. The researchers, for example, obtained nearly 1.2 cTnT+ cells from each of the plated fibroblasts. The production of the mitotically active antecedent cells that are similar to the multipotent Isl1+ cardiovascular progenitors explained the high efficiency of the cardiomyocyte generation. They speculated that the successful isolation and stabilization of the intermediate cells in culture could become a renewable source for other differentiated cardiovascular cells.
The new system resembles the blastema formation that occurs during regeneration in frogs and teleost fish (Suzuki, Satoh, Ide, and Tamura). In frogs, transdifferentiation occurs by low-level and transient expression of the factors that induce pluripotency.
A thorough understanding of the molecular evidence of reprogramming is, however, necessary in order to confirm the standard mechanism shared by both processes. A multitude of cell types may emerge from very unstable intermediate populations as they swiftly return into the epigenetically stable states. The transdifferentiation scheme of Efe et al., therefore, has the potential to derive specialized cell types from several lineages by using the various inductive signals.
The transdifferentiation process is a more attractive approach than the slow iPS cell system. The protocol, however, needs improvement in order to be fully effective in the production of autologous tissue. First, scientists should determine the most appropriate method for transgene expression that does not cause permanent genetic modification. The protocol discovered by Efe et al. has a transient prerequisite for factor overexpression. The requirement promotes the process of finding functional substitutes. Secondly, adequate research in transplantation is required in order to ensure the necessary functional longevity of the cardiomyocytes. In addition, the study would prevent the generation of cells that cause teratoma formation. Lastly, the proper and temporal regulation of the overexpression of transcription factors would increase efficiency and yield. The protocol’s adjustment to the human system and therapeutic usefulness greatly depend on increasing the efficiency of the process.
The new reprogramming technique for pluripotency has a capacity for the shortening and quick steering of the process towards cardiogenesis. Within a few days, scientists can directly reprogram fibroblasts to form patches of the specialized cardiomyocytes that contract spontaneously. They also believe that the process does not involve a pluripotent intermediate. The strategy is unique because it allows a temporary state formed in the early stage of reprogramming to function as a cellular platform for transdifferentiation. The study has immense and potential implications for the reprogramming based on the iPS cell factors.
Efe, Jem A., Simon Hilcove, Janghwan Kim, Hongyan Zhou, Kunfu Ouyang, Gang Wang, Ju Chen and Sheng Ding. “Conversion of Mouse Fibroblasts into Cardiomyocytes Using a Direct Reprogramming Strategy.” Nature Cell Biology 13 (2011): 215–222. Web. 5 June 2014.
Suzuki, Makoto, Akira Satoh, Hiroyuki Ide and Koji Tamura. “Nerve-dependent and -independent Events in Blastema Formation during Xenopus Froglet Limb Regeneration.” Developmental Biology 286.1 (2005): 361–375. Web. 6 June 2014.