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OPEN ACCESS ARTICLE
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EDITORIAL |
Received November 27, 2007;
accepted for publication November 27, 2007.
First published online in STEM CELLS EXPRESS November 29, 2007.
In the month of November 2007, three groundbreaking publications [1–3] attracted both scientific and a large amount of public attention as well as contributed new fodder to the scientific and ethical debates surrounding stem cell research.
In the first publication [1], Mitalipov's group described the derivation of non-human primate embryonic stem cells (ESC) via somatic cell nuclear transfer (SCNT). Therein, the researchers took skin cells from a 9-year-old rhesus macaque and inserted the nuclei from these cells into enucleated oocytes. The team used 304 oocytes to derive only two primate SCNT lines. Nevertheless, the success of this procedure was credited in large part to an imaging system, named Oosight, which allows the enucleation of oocytes without the use of DNA binding dyes and ultraviolet light, which may have detrimental effects on the developmental and reprogramming potential of oocytes.
In the other publications, two separate groups [2, 3] described methods to reprogram adult human fibroblasts into an induced pluripotent (iPS) state such that their differentiation potential recapitulated that of ESC. Specifically, Yamanaka and colleagues generated 10 pluripotent iPS cell lines from approximately 50,000 facial skin cells via ectopic expression from retroviruses of four genes that were shown previously to reprogram mouse somatic cells [4]. The commercially available skin cells had been taken from a 36-year-old Caucasian woman, and the authors confirmed their results using cells from synovial fluid obtained from a 69-year-old man. The manuscript describing these data was rapidly published online in Cell (received October 29, 2007; revised November 7; and accepted November 12).
In a separate paper published at nearly the same time in Science Express [3], Thomson and colleagues reported success in reprogramming human cells obtained from fetal skin and from a newborn's foreskin. Interestingly, Thomson's group reported reprogramming efficiency similar to that of the Yamanaka group but used a different viral vector and cocktail of genes: Thomson and coworkers used lentiviral vectors to ectopically express OCT4, SOX2, NANOG, and LIN28 in cells [3], while Yamanaka's group used retroviral vectors encoding OCT3/4, SOX2, KLF4, and c-MYC [2]. Surprisingly, Yamanaka's group was not able to reprogram somatic cells using NANOG, and Thomson's team tested Yamanaka's four genes without success.
NANOG, OCT4, and SOX2 play important roles in maintaining the pluripotency of ESC. However, the specific contributions of c-MYC, KLF4, and LIN28 to reprogramming remain indeterminate. KLF4 is known to regulate gene transcription by modulating histone acetylation and therefore may modify chromatin structure so that pluripotency factors can bind to their target sequences in DNA [5]. c-MYC is a proto-oncogene and therefore may impart cells with a selective growth advantage, although it has been implicated in tumor formation in mice [6]. Although LIN28, which participates in mRNA processing, influences the frequency of reprogramming, it does not appear to be absolutely required for the initial reprogramming process or for the expansion of reprogrammed cells [3].
What is unique about these three [1–3] publications? The answer is that the authors use different approaches to turn back the biological clock of adult somatic cells to derive pluripotent stem cells. While the work by Mitalipov's group suggests that with the proper source of viable oocytes, SCNT may be used to obtain patient-specific ESC for therapy, the low efficiency of this process and limited access to viable human oocytes have limited the pace of development of this technique. In contrast, the work by Yamanaka and by Thomson indicates that pluripotent stem cells can be generated from adult somatic cells. However, it remains to be determined whether iPS cells will replace the need for human ESC. Certainly, from a scientific standpoint, they will not. Research on ESC conducted over many decades has elucidated a large array of genes that contribute to pluripotency and lineage-specific differentiation, which has contributed greatly to our understanding of human development. This information was critical toward the development of iPS cells, and comparative studies between iPS cells and bona fide ESC will be necessary to reveal the full potential of the former. Moreover, studies show that iPS cells and ESC do differ at the level of the transcriptome and epigenetic modification of DNA [2, 3]. How such differences may affect the biology of iPS cells will need to be clearly elaborated prior to employing the cells clinically. Finally, iPS cells still retain all the pitfalls associated with the clinical application of ESC, such as their propensity to form teratomas and the fact that they are transduced with viruses. Therefore, it is premature to assume that iPS cells will replace ESC because of their ability to sidestep moral and ethical issues. The advent of iPS cells should also not overshadow the global effort put forth to maintain surplus embryos for scientific and clinical studies. While much more research is needed, it is likely that iPS cells will not replace but rather complement ESC research.
Together, these scientific achievements represent a major advance in the field of stem cell research and will aid in the current efforts to generate patient-specific stem cells for a therapeutic intent. Future research will likely focus on elucidating the molecular mechanism necessary for reprogramming and identifying small molecules to trigger such processes in somatic cells. Even so, only human embryos and ESC remain as the biological origin of more than 200 different cell types in the human body.
REFERENCES
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