Induced pluripotentstem cells are induced pluripotentstem cell-like cells

Liting Song,Emanuel Goldman

1Hope Biomedical Research,Toronto,ON M2K 2J8,Canada;

2DepartmentofMicrobiology and Molecular Genetics,New Jersey MedicalSchool,Rutgers,The State University of New Jersey, Newark,NJ 07103,USA.

Induced pluripotentstem cells are induced pluripotentstem cell-like cells

Liting Song1,✉,Emanuel Goldman2

1Hope Biomedical Research,Toronto,ON M2K 2J8,Canada;

2DepartmentofMicrobiology and Molecular Genetics,New Jersey MedicalSchool,Rutgers,The State University of New Jersey, Newark,NJ 07103,USA.

Gold is rare and precious,while pyrite(FeS2)is abundant and cheap.Pyrite is nicknamed foolˊs gold, since pyrite looks like gold and itis even shinier and brighter than gold.Itis very difficult to recognize the differences between a realnaturalgold and a gold-like rock(pyrite)to non-professional persons[1],but we know thatall thatglitters is notgold.

Similar mistakes can happen in biomedicalresearch as well.Pluripotentembryonic or adultstem cells can self-renew and proliferate into differentcells,and these stem cells are very valuable in transplantation and gene therapy.Because the governmentof the United States of America and other governments have tightregulations restricting embryonic stem cell work,this has driven research towards finding stem cells from adult sources ratherthan embryos.Instead ofacquiring usefuladultstem cells from adulttissues,in recent years some researchers have claimed thatthey could magically turn adult somatic cells into induced pluripotent stem cells[2,3].Isthis real?Oristhis too good to be true?

Dr.Liu has actively challenged the validity of the so-called induced pluripotent stem cells since 2008; he suspected thatpre-existing adult stem cells might have played a vital and essential role in the process of producing those induced pluripotent stem cells[4]. Itwaslaterproven thatonly realadultstem cells(muse cells)can generate those claimed induced pluripotent stem cells[5,6].Several research groups have found that those proclaimed induced stem cellshad more abnormal chromosomes[7],more protein-coding pointmutations[8], more abnormalepigenomic reprogramming and DNA methylation[9-11],and more copy number variations[12,13]than normalsomatic cellsorembryonicstem cells;those supposed induced pluripotent stem cells had more chances to develop tumors,and they could form tumors more rapidly than human embryonic stem cells[14]. Moreover,those hypotheticalinduced pluripotentstem cells caused more immune rejections in recipientmice than normalembryonic stem cells[15].In comparison with normal embryonic stem cells,those so-called induced pluripotentstem cells had differentmetabolic activities[16,17].In a majorturn ofevents,the very same laboratory that pioneered these supposed stem cells has now reported thatthe believed human induced pluripotent stem cells were actually different from real human embryonic stem cells in several aspects[18].

Some researchers have claimed that they could produce mice from the putative induced pluripotent stem cells[19-22],but this is questionable.Rather,they caused confusion by using an inappropriate tetraploid complementation assay.They did notproduce any mouse directly from those claimed induced pluripotentstem cells;instead,they injected those assumed induced pluripotent stem cells into a tetraploid blastocyst. Their experiments only can prove that the so-called induced pluripotentstem cells did notstop or interrupt an embryo from growing into a mouse.Therefore,those claims were misleading.Ithas been known since the early days of in vitro fertilization experiments thatan in vitro fertilized egg can be transplanted into a womband grow into an animaloran infant[23].Dolly the cloned sheep and several other cloned animal experiments proved that the genome of an adultcell can replace the genome ofan egg,and develop into a viable animal if the egg is transplanted into an animal womb[24].In orderto prove thatthese putative pluripotentstem cells can generate a mouse,the researchers need to implant the putative induced pluripotent stem cells into the womb of a female mouse,and to see if indeed a mouse willgrow.

Itisnow clearthatthesaid human induced pluripotent stem cells(iPSCs)are notequalto human embryonic or adultstem cells.They should nothave been misleadingly named induced pluripotent stem cells in the first place.To be scientifically correct,those assumed induced pluripotentstem cells should be redefined as induced pluripotentstem cell-like cells.Itis notthat difficultto make mutated cells from normalcells;but itis extremely hard to convertmutated/abnormalcells into normalcells;otherwise,cancerwould notbea serious health problem,if we were able to treat those mutated cells efficiently and easily.We do notthink thatthose so-called induced pluripotentstem cellswillbe a reliable and feasible source of stem cells for the foreseeable future.A large amountofmoney and extensive resources have been spenton the iPSCs research programs in the world already[25],butthis is a wrong track which will never achieve our goals.This is the unfortunate consequence of politics driving the direction of research, when research on authentic stem cells would otherwise be preferable.

[1]Tell the difference between real gold and fools gold: http://www.homegrownfun.com/difference-real-goldfools-gold/smaller-gold-and-pyrite/

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[6]Wakao S,Kitada M,Kuroda Y,etal.Multilineage-differentiating stress-enduring(Muse)cells are a primary source of induced pluripotent stem cells in human fibroblasts.Proc NatlAcad Sci USA 2011;108(24):9875-9880.

[7]Mayshar Y,Ben-David U,Lavon N,et al.Identification and classification of chromosomal aberrations in human induced pluripotent stem cells.Cell Stem Cell 2010;7(4): 521-531.

[8]Gore A,Li Z,Fung HL,et al.Somatic coding mutations in human induced pluripotent stem cells.Nature 2011; 471(7336):63-67.

[9]Doi A,Park IH,Wen B,et al.Differential methylation of tissue-and cancer-specific Cp G island shores distinguishes human induced pluripotent stem cells,embryonic stem cells and fibroblasts.Nat Genet 2009;41(12):1350-1353.

[10]Deng J,Shoemaker R,Xie B,et al.Targeted bisulfite sequencing reveals changes in DNA methylation associated with nuclear reprogramming.Nat Biotechnol 2009;27(4):353-360.

[11]Lister R,Pelizzola M,Kida YS,etal.Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells.Nature 2011;471(7336):68-73.

[12]Hussein SM,Batada NN,Vuoristo S,etal.Copy number variation and selection during reprogramming to pluripotency.Nature 2011;471(7336):58-62.

[13]Laurent LC,Ulitsky I,Slavin I,etal.Dynamic changes in the copy number of pluripotency and cell proliferation genes in human ESCs and iPSCs during reprogramming and time in culture.Cell Stem Cell 2011;8(1):106-118.

[14]Gutierrez-Aranda I,Ramos-Mejia V,Bueno C,et al. Human induced pluripotent stem cells develop teratoma more efficiently and faster than human embryonic stem cells regardless the site of injection.Stem Cells 2010; 28(9):1568-1570.

[15]Zhao T,Zhang Z,Rong Z,et al.Immunogenicity of induced pluripotent stem cells.Nature 2011;474(7350): 212-215.

[16]Panopoulos AD,Yanes O,Ruiz S,et al.The metabolome of induced pluripotent stem cells reveals metabolic changes occurring in somatic cell reprogramming.Cell Research 2011;22(1):168-177.

[17]Meissen JK,Yuen BT,Kind T,etal.Induced pluripotent stem cells show metabolomic differences to embryonic stem cells in polyunsaturated phosphatidylcholines and primary metabolism.PLoS One 2012;7:e46770.doi: 10.1371/journal.pone.0046770.

[18]Koy an agi-Aoi M,Ohnu ki M,Takahashi K,et al. Differentiation-defective phenotypes revealed by largescale analyses of human pluripotent stem cells.Proc Natl Acad Sci USA 2013;110(51):20569-20574.

[19]Zhao XY,Li W,Lv Z,etal.iPS cells produce viable mice through tetraploid complementatio n.Nature 2009; 461(7260):86-90.

[20]Boland MJ,Hazen JL,Nazor KL,et al.Adultmice generated from ind uced pluripotent stem cells.Nature 2009;461(7260):91-94.

[21]Kang L,Wang J,Zhang Y,et al.iPS cells can support full-term development of tetraploid blastocyst-complemented embryos.Cell Stem Cell 2009;5(2):135-138.

[22]Boland MJ,Hazen JL,Nazor KL,et al.Generation of mice derived from induced pluripotent stem cells.J Vis Exp 2012;69:e4003.doi:10.3791/4003.

[23]Steptoe PC,Edwards RG.Birth after the reimplantation of a human embryo.Lancet 1978;2(8085):366-366.

[24]Wilmut I,Schnieke AE,McWhir J,etal.Viable offspring derived from fetal and adult mammalian cells.Nature 1997;385(6619):810-813.

[25]Reardon S.NIH stem-cell programme closes.Nature 2014;508(7495):157-157.

✉Corresponding author:Liting Song,Hope Biomedical Research,809-50 Ruddington Drive,Toronto,ON M2K 2J8,Canada.Tel/Fax:416-733-1573,E-mail:ltsong@yahoo.com.

Received 21 November 2014,Revised 19 December 2014,Accepted 05 January 2015,Epub 12 January 2015

The authors reported no conflictof interests.

©2015 by the Journal of Biomedical Research.All rights reserved.

10.7555/JBR.29.20140166