Mammalian Stem Cells Reprogramming in Response to Terahertz Radiation

et al. (2010) Mammalian Stem Cells Reprogramming in Response to Terahertz Radiation. PLoS ONE 5(12): e15806. doi:10.1371/journal.pone.0015806 Mammalian Stem Cells Reprogramming in Response to Terahertz Radiation Jonathan Bock 0 Yayoi Fukuyo 0 Sona Kang 0 M. Lisa Phipps 0 Ludmil B. Alexandrov 0 Kim . Rasmussen 0 Alan R. Bishop 0 Evan D. Rosen 0 Jennifer S. Martinez 0 Hou-Tong Chen 0 George Rodriguez 0 Boian S. Alexandrov 0 Anny Usheva 0 Maurizio Pesce, Centro Cardiologico Monzino, Italy 0 1 Department of Medicine , Endocrinology , Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America, 2 Center for Integrated Nanotechnologies, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America, 3 Theoretical Division, Los Alamos National Laboratory , Los Alamos, New Mexico , United States of America We report that extended exposure to broad-spectrum terahertz radiation results in specific changes in cellular functions that are closely related to DNA-directed gene transcription. Our gene chip survey of gene expression shows that whereas 89% of the protein coding genes in mouse stem cells do not respond to the applied terahertz radiation, certain genes are activated, while other are repressed. RT-PCR experiments with selected gene probes corresponding to transcripts in the three groups of genes detail the gene specific effect. The response was not only gene specific but also irradiation conditions dependent. Our findings suggest that the applied terahertz irradiation accelerates cell differentiation toward adipose phenotype by activating the transcription factor peroxisome proliferator-activated receptor gamma (PPARG). Finally, our molecular dynamics computer simulations indicate that the local breathing dynamics of the PPARG promoter DNA coincides with the gene specific response to the THz radiation. We propose that THz radiation is a potential tool for cellular reprogramming. - Funding: This work was performed, in part, at the Center for Integrated Nanotechnologies, U.S. Department of Energy, Office of Basic Energy Sciences user facility at Los Alamos National Laboratory (Contract DE- AC52-06NA25396) and Sandia National Laboratories (Contract DE- AC04-94AL85000); NIH grants R01GM73911; NIH ARRA supplement (3R01GM73911-4S1); Richard and Susan Smith Family Foundation Pinnacle Award ADA 1-08-PPG-02. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. . These authors contributed equally to this work. " These authors also contributed equally to this work. Terahertz (THz) radiation occurs ubiquitously in our environment, as part of the solar spectrum and through the natural blackbody radiation within the earths atmosphere. Despite this abundance, the non-ionizing character of this radiation, and the lack of practical and powerful THz emitters, has left the biological significance of this region of the electromagnetic spectrum relatively unexplored. Interestingly, the energy scale of THz radiation is within the range of hydrogen bonds, van-der-Waals interactions, and charge-transfer reactions. This energy overlap is associated with the unique sensitivity of the emerging THz techniques [1,2] to the molecular motions that underlie intricate biological functions. These distinctive properties, together with the nascent development of powerful THz sources [1] and the resulting broad spectrum of applications [3], now pose optimal conditions for understanding the nature of the interactions between THz radiation and biomolecules. Unfortunately, the available data related to the influence of THz radiation on biological systems, and the understanding of the precise mechanisms governing this influence, are limited and the subject of debate [4]. Previous in vitro and in vivo studies were mostly conducted at frequencies below 0.15 THz, at low power, and with short exposure times (1030 min), and did not provide conclusive evidence regarding the influence of THz radiation on mammalian cells. Further, results from the multi-national THzbridge project aimed at investigating the interaction of THz radiation with biological systems [5], reported potential genotoxic and epigenetic effects on human lymphocytes and changes in the membrane permeability of liposomes, but most critically was unable to clarify the exact irradiation conditions necessary to cause these effects. More recent studies confirm that a weak THz field may cause genomic instability in human lymphocytes [6] after extended (6 hours) exposure. Likewise, it was reported that neurons briefly exposed in vitro to powerful THz radiation (over 30 mW/cm2), at a specific frequency, develop infringements on the morphology of the cellular membranes and intracellular structures [7]. Finally, changes in the gene expression have been documented after prolonged exposure (72 hours) to low-power broad-spectrum THz radiation centered at ,30 THz [8]. Importantly, all these experiments were conducted under controlled thermal conditions to ensure that temperature is unrelated to the observed effects. It thus appears that THz radiation can interfere with biological functions in genomic materials. While, it remains unclear whether THz radiation is influencing specific genomic functions or whether the impact is more general resulting in cellular damage, it is apparent that the mechanisms by which the non-ionizing THz radiation influences biological functions must be fundamentally different from those at play when high-energy (UV, x-ray, gamma, etc.) radiation interacts with bio-matter. Indeed, prior research [910] provides ample evidence that exposure to THz radiation can affect intramolecular vibrations and hence dynamically induce new conformational states of proteins [11]. These new conformations may easily perturb, for example, protein-DNA binding and thereby induce changes in cellular transcription and replication. Here we report that extended exposure to broad-spectrum THz radiation (centered at ,10 THz) results in specific (rather than global) changes in the functionality of cellular DNA. Certain genes in irradiated mouse stem cell (MSC) cultures are activated, while other genes are repressed. Many of the MSC genes do not respond to the selected radiation conditions at all, showing that the effect is specific. Additionally, 9 hours of exposure causes significant changes in the MSC gene expression, while the response to shorter duration (2 and 4 hours) is appreciably less pronounced. Hence, we argue that the effect of THz radiation is gene and exposure specific and most likely is at the level of DNA transcription. In this context, our EPBD-based [12,13] Langevin computer simulation modeling shows that the promoter DNA propensity for local breathing is likely to be one of the factors that underlie the gene specific re (...truncated)