Views of Human Embryonic Stem Cell Epigenomic Landscape Open up the Future of Stem Cells to Transparency

San Diego Regenerative Medicine Institute and Xcelthera announce the publication of Dr. Parsons’ original research article supported by the National Institutes of Health, titled “Human Stem Cell Derivatives Retain More Open Epigenomic Landscape When Derived from Pluripotent Cells than from Tissues”, in Journal of Regenerative Medicine at http://dx.doi.org/10.4172/2325-9620.1000103 & http://scitechnol.com/jrgmhome.php.

The growing number of identified stem cell derivatives and escalating concerns for safety and efficacy of these cells towards clinical applications have made it increasingly crucial to be able to assess the relative risk-benefit ratio of a given stem cell from a given source for a particular disease. Genomic and proteomic profiling in isolation has not provided such a tool. Gene expression analysis has indicated that stem cell derivatives do not seem to have a common core transcription profile that dictates the undifferentiated self-renewing state, which suggests that gene expression alone is not sufficient to define either intrinsic plasticity or developmental potential of a given stem cell. A search for a common set of transcribed genes that defines the characters of all stem cell derivatives, known as stemness, has been unsuccessful; there is virtually no overlap in the gene expression profiles of various types or derivations of stem cells, in spite of their apparent phenotypic similarity. Even the expression of a lineage-defining gene within stem cells seems to require additional epigenetic cues. It is clear that epigenetic processes are providing additional regulatory dimensions to stem cell behavior.

The eukaryotic genome is packaged into a nucleoprotein complex known as chromatin, in which the DNA helix is wrapped around an octamer of core histone proteins to form a nucleosomal DNA structure. Packaging of eukaryotic genome into chromatin confers higher order structural control over the lineage programming processes. Discerning the intrinsic plasticity and regenerative potential of human stem cell populations might reside in chromatin modifications that shape the respective epigenomes of their derivation routes. Previously, we have generated engraftable human neuronal progenitors direct from pluripotent human embryonic stem cells (hESCs) by small molecule induction (hESC-I hNuPs). Unlike the prototypical neuroepithelial-like nestin-positive human neural stem cells (hNSCs), these in vitro neuroectoderm-derived Nurr1-positive hESC-I hNuPs are a more neuronal lineage-specific and plastic hESC derivative. In this study, the global chromatin landscape changes in pluripotent hESCs and their neuronal lineage-specific derivative hESC-I hNuPs were profiled using genome-wide mapping and compared to CNS tissue-derived hNSCs. This study found that the broad potential of pluripotent hESCs is defined by an epigenome constituted of open conformation of chromatin mediated by a pattern of Oct-4 global distribution that corresponds closely with those of acetylated nucleosomes genome-wide. The epigenomic transition from pluripotency to restriction in lineage choices is characterized by genome-wide increases in histone H3K9 methylation that mediates global chromatin-silencing and somatic identity. Tissue-resident CNS-derived hNSCs have acquired a substantial number of additional histone H3K9 methylation, therefore, more silenced chromatin. These data suggest that the intrinsic plasticity and regenerative potential of human stem cell derivatives can be differentiated by their epigenomic landscape features, and that human stem cell derivatives retain more open epigenomic landscape, therefore, more developmental potential for scale-up regeneration, when derived from the hESCs in vitro than from the CNS tissue in vivo.

Human stem cell transplantation represents a promising therapeutic approach closest to provide a cure to restore the lost nerve tissue and function for a wide range of devastating and untreatable neurological disorders. However, to date, lack of a clinically-suitable source of engraftable human stem/progenitor cells with adequate neurogenic potential has been the major setback in developing safe and effective cell-based therapy as a treatment option for restoring the damaged or lost CNS structure and circuitry. The traditional sources of engraftable human stem cells with neural potential for transplantation therapies have been multipotent human neural stem cells (hNSCs) isolated directly from the human fetal CNS. Under protocols presently employed in the field, the prototypical neuroepithelial-like nestin-positive hNSCs, either isolated from CNS in vivo or derived from pluripotent cells in vitro via conventional multi-lineage differentiation, appear to exert their therapeutic effects primarily by their non-neuronal progenies through producing trophic and/or neuroprotective molecules to rescue endogenous dying host neurons, but not related to regeneration from the graft or host remyelination. Under conventional multi-lineage differentiation approaches, hESC-derived cellular products consist of a heterogeneous population of mixed cell types, including fully differentiated cells, high levels of various degrees of partially differentiated or uncommitted cells, and low levels of undifferentiated hESCs, posing a constant safety concern when administered to humans. We recently reported that pluripotent hESCs maintained under a defined platform can be uniformly converted into a cardiac or neural lineage by small molecule induction. This technology breakthrough enables well-controlled generation of a large supply of neuronal lineage-specific derivatives across the spectrum of developmental stages direct from the pluripotent state of hESCs with small molecule induction. This novel lineage-specific differentiation approach by small molecule induction of pluripotent hESCs not only provides a model system for investigating human embryogenesis, but also dramatically increases the clinical efficacy of graft-dependent repair and safety of hESC-derived cellular products. This study by high-resolution genome-wide mapping of chromatin modifications in human stem cell derivatives further supported the view that the tissue-resident CNS-derived hNSCs have acquired more silenced chromatin, therefore, they are likely resides at a more advanced stage of development with more limited developmental potential or plasticity for tissue or organ regeneration. Conversely, the hESC derivatives retain more open epigenomic landscapes, therefore, they might start at an earlier embryonic developmental stage with more plasticity for scale-up regeneration.

CIRM Embezzle State Fund and Resources to Waste on Induced Adult Stem Cell Scam (CIRM iPS Cell Initiative) Against Prop 71 – ISSCR Stem Cell Conman’s Thick Skin

Like a self-testimony to California Institute for Regenerative Medicine (CIRM) alleged favoritism in doling out grants to conflicts of interest (COI), CIRM this week & next week’s ICOC meetings will not consider funding CA Prop 71 stem cell research, but waste CA taxpayers’ money to give CIRM’s acquaintances preferential treatment for hundreds of millions of CA State bond, in simultaneous proceeds with bond sells of the State for the convenience of embezzling State fund to COI. It is called CIRM stem cell con man leadership awards, one corrupted way invented by CIRM COI so they could preferably give their own out-of-state acquaintances excess amount of easy money without having to follow Prop 71 without any competition, because those out of state stem cell con men, including Andrew Mcmahon of USC & Robert Wechsler-Reya of Sanford-Burnham, have never demonstrated any record of achievement in the areas of pluripotent stem cell and progenitor cell biology and medicine in accordance with Proposition 71 & pursuant to Proposition 71, besides their known relationships with Larry Goldstein, Alan Trounson, or somebody on CIRM board. So, it is no surprise that those stem cell con men of CIRM awards favoritism, after sucking in hundreds of millions of active state fund for 6-7 years, still do not have anything of their “good sciences” to disclose to the public or show in the “best stem cell meeting of Alan Trounson”, besides their thickest faces self-stamped with stem cell con man leaders not any shy of showing in the news. Such enormous waste and embezzlement of State Fund and resources to COI would not happen if the government funding agency, such as CIRM, is held accountable, and if CIRM has high level of transparency and high standards of review in accordance with Proposition 71 & pursuant to Proposition 71 & consistence with Proposition 71.

CIRM next week’s ICOC meetings will not consider funding CA Prop 71 stem cell research, but waste hundreds of millions of CA State bond in doling out grants to induced adult stem cell scam or so-called CIRM iPS cell initiative, favoritism to Larry Goldstein & Craig Venter of UCSD, Kristin Baldwin of Scripps, and other associates of Sanford consortium & Gladstone & Cedar Sinai & ISSCR in CIRM. Larry Goldstein and his favoritism in UC & Sanford Consortium have financially benefited hundreds of millions from CIRM iPS cell initiative, which is just another corrupted way invented by CIRM COI, such as Larry Goldstein & those in Sanford Burnham, to get CIRM preferential treatment for hundreds of millions more of taxpayers’ money to waste without any competition by getting around Prop 71, in simultaneous proceeds with bond sells of the State for the convenience of embezzling State fund to COI.

CA gave CIRM $3 billions in designated fund Prop 71 to research the developmental and therapeutic potential of pluripotent human embryonic stem cells (hESCs). However, CIRM has been withholding public fund from hESC research, so CIRM could embezzle State fund to their own luxury salaries and give their COIs preferential treatment of hundreds of millions of taxpayers’ money in secrecy, such as CIRM leadership awards, faculty awards, basic biology awards, early translational awards, which have never demonstrated any record of achievement in the areas of pluripotent stem cell and progenitor cell biology and medicine in accordance with Proposition 71 & pursuant to Proposition 71 & consistent with Proposition 71, besides their known relationships with Larry Goldstein, Alan Trounson, Jon Tomas, Ellen Feigal, Duane Roth, or somebody on CIRM board. So, what is CIRM iPS cell initiative? It is a high profile stem cell scam of ISSCR (International Society for Stem Cell Research) to mislead the scientific community & the public to waste hundreds of millions of taxpayers’ money on making very dangerous malicious cancer cells from skin or adult cells/tissues by calling it as induced pluripotent stem cells (iPS cells) to endanger public health. There is no scientific evidence for self-renewal of iPS cells by the definition of stem cells. It is junk sciences of waste that has been turned into Larry Goldstein & stem cell con man’s empty words of “good sciences” after they received millions of financial benefit from CIRM alleged favoritism in doling out grants to COI, so they could cheat more taxpayers’ money to waste without competition by getting around Prop 71.

In today’s molecular biology, in today’s genetic engineering, it is nothing new or difficult to put a few genes into cells. Particularly, those genes are notorious oncogenes. Particularly, those cells are the thickest skin cells, which are very easy to manipulate & tolerate to all kinds of abuse or mistreatment by genetic engineering, unlike the very delicate stem cells. However, cell fate is determined by complex molecular and cellular processes, not just a few genes. The real technique challenge or difficult thing to do is to prove that these cells can self-renew for a long-term, to prove those cells can maintain genetic stability and integrity for a long period of time. The real technique challenge or difficult thing to do is to show those cells can generate functional cells, generate a lot of functional cells, and generate a homogeneous population of functional cells useful for therapy. When Jamie Thomson group made their human embryonic stem cells (hESCs), they had done at least eleven months of observation to make sure their hESCs remained genetically stable after eleven months of proliferation before published in Sciences. Yamanaka of ISSCR has not done even 1 day of observation after he made his iPS cells before published in Cell. Without solid proof for self-renewal and long-term genomic stability, any tumor or cancer cells can also be easily mis-identified as stem cells. Without solid proof for self-renewal and long-term genomic stability, Yamanaka and those stem cell con men of ISSCR’s thick skin became invincible, could become whatever scams they want and could be called by whatever scams they named. Without solid proof for self-renewal and long-term genomic stability, those induced adult stem cell scams & frauds, such as iPS cells, direct differentiation/transdifferentiation/reprogram/deprogram of somatic cells, proliferate like weeds in high profile scientific journals in the last few years, such as Rudy Jaenisch’s Cell and Inder Verma’s PNAS. Therefore, it is not too unfair to say Yamanaka of ISSCR has no scientific integrity at all, cheated Nobel prize with his junk sciences, because he did what a cheater usually does to take the easiest way up by simply changing the name of his dangerous malicious cancer cells to iPS cells to confuse the public & the scientific community, even to endanger public health for his own personal and financial gain. Yamanaka of ISSCR made iPS cells from the skin, now he claims he is going to turn iPS cell back into skin cells to treat eye diseases, so he can con the public for more attention and scam for more money. Well, probably even high school kids would know that the pigment epithelial cells in the eyes are not skin cells, and if Yamanaka of ISSCR put his very dazzling skin-to-iPS-back-to-skin cells into the eye, the only outcome probably would make any diseases even worse, besides hundreds of millions of taxpayers’ money (e.g., NIH & CIRM) have been sucked into these greedy high profile stem cell conman’s own pockets & disappeared. CIRM iPS cell initiative is ISSCR super stem cell con man’s joke, and it is just those high profile stem cell con man’s another excuse to embezzle hundreds of millions of taxpayers’ money to their COI and waste, such as Sanford consortium‘s Larry Goldstein, Craig Venter, Evan Snyder, Kristin Baldwin, Jean Loring, UCLA/CedarSinai Clive Svendensen, Gladstone &Yamanaka, Rudy Jaenisch, George Daley, and other ISSCR associates in connection with CIRM top officials, such as Jon Thomas, Alan Trounson, Ellen Feigal, Duane Roth, or somebody on CIRM board.