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OPEN ACCESS ARTICLE
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editorial |
IMPACT FACTOR
Our most recent (i.e., for calendar year 2005) Thompson ISI Impact Factor has risen to 6.094, placing STEM CELLS in the top 3% of high-impact international journals, based on this indicator (Fig. 1). This is a testament to the diligent work of our Editorial Board members, who serve as lead reviewers on every reviewed manuscript. The Journal’s acceptance rate is now 38%, reflecting its impressive competitiveness in the field.
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The winners of our first annual STEM CELLS® Young Investigator Award were announced at the Fourth Annual Meeting of the International Society for Stem Cell Research (ISSCR) in Toronto. I was pleased to be joined in making this announcement at the STEM CELLS booth by Dr. Joydeep Goswami, vice president of Invitrogen Corporation, whose unrestricted educational grant helped support the Journal’s award (Fig. 2).
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The judging was performed in three stages by five anonymous members of the Board. When we arrived at the final tally, we had not one but a pair of winners tied for first place: Sergey S. Akimov, Ph.D., of the J.H. Holland Laboratory for the Biomedical Sciences, American Red Cross (Fig. 3) [1]; and Makoto Sahara, M.D., Ph.D., of the Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine (Fig. 4) [2]. They each received a cash prize of $5,000 and a certificate. We are pleased to feature interviews with both winners beginning on the next page. A certificate of honorable mention was awarded to Lin Wang, M.D., Ph.D., of the Department of Pediatrics, School of Medicine, West Virginia University [3].
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EDITORIAL BOARD
Once again, we gratefully acknowledge our good fortune in having the most dynamic, dedicated Editorial Board of leading experts in the field who are committed to the Journal’s motto of the past 25 years: "STEM CELLS is by scientists in the service of science." As we thank those who have recently completed their Editorial Board service, we warmly welcome six new members to our ranks (see below). On behalf of my fellow senior editors and the entire editorial board, we look forward to a brilliant finish to 2006 and another record-setting banner year in 2007 ... with help from you, our subscribers and readers.
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| New Stem Cells Editorial Board Members Steven E. Artandi, M.D., Ph.D. Stanford University School of Medicine
Il-Hoan Oh, M.D., Ph.D.
Thomas A. Rando, M.D., Ph.D.
Miodrag Stojkovic, Ph.D.
Alexander Storch, M.D.
Shahragim Tajbakhsh, Ph.D.
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Received July 18, 2006;
accepted for publication July 18, 2006.
First published online in STEM CELLS EXPRESS July 27, 2006.
REFERENCES
Makoto Sahara, M.D., Ph.D.
CIC: First, let me extend my personal congratulations and those of the entire Editorial Board of STEM CELLS. There were 48 excellent papers among the applicants for this prize, and at least 10 of them were felt to have moved our field considerably. The judges (members of our Editorial Board) had a very hard time deciding which was the most outstanding paper. Indeed, we finally decided to split the very top prize. So, your work has been seriously judged to be field-leading.
MS: I am very honored to be selected as a co-winner of this prize, the STEM CELLS Young Investigator Award, 2006, from among a great number of applicants. Also, I appreciate the considerable efforts of the Editorial Board of STEM CELLS in the selection process. This prize is significantly encouraging as well as exciting. Keeping in mind this encouragement, I will do my best to continue my investigations into medical science.
CIC: Please tell me, in language intended for a general scientific audience rather than for our stem cell "niche," what hypothesis you were testing in the research from your paper.
MS: We tested the contribution and plasticity of a highly purified hematopoietic stem cell (HSC) in the process of atherosclerotic lesion formation. In short, we sought to evaluate whether a highly purified HSC could participate in pathological vascular remodeling after mechanical injury through transdifferentiation into vascular cells—i.e., vascular smooth muscle cells and/or vascular endothelial cells.
CIC: Give me some background rationale, explaining why this hypothesis was important in stem cell research.
MS: Although it was assumed that HSCs give rise to hematopoietic cells, recent evidence suggests that bone marrow-derived cells (or HSCs) may have the broader potential to differentiate into nonhematopoietic cells and that bone marrow-derived cells (or HSCs) may participate in regeneration and/or remodeling of remote organs. On the contrary, it is also a fact that there are the papers which have proposed negative data about the possibility for adult HSCs to transdifferentiate into nonhematopoietic lineages. In pathological vascular remodeling, it has also been suggested that HSCs may have the plasticity to transdifferentiate into vascular cells. However, the HSCs used in these studies were not a homogeneous population. The CD34–, c-Kit+, Sca-1+, and Lineage- (CD34–KSL) bone marrow cells have been assumed as the most primitive HSCs and frequently have been used as HSCs in these studies, although only approximately one of three CD34–KSL bone marrow cells is considered an HSC. Even the CD34–KSL cells are considered a heterogeneous population containing nonhematopoietic cells, and it is possible that nonhematopoietic cells among the CD34–KSL cells might be responsible for the plasticity observed in the HSC studies. At the same time, our collaborators (Y. Matsuzaki and H. Okano) have revealed that the murine bone marrow cells that have both the strongest dye-efflux activity ("Tip"-side population [SP] cells) and a phenotype of CD34–KSL represent the most primitive HSCs with nearly complete hematopoietic engraftment activity. In their study, approximately nine of ten among the Tip-SP CD34–KSL cells are considered primitive HSCs. Consequently, the use of the TipSP CD34–KSL cells, which are almost equal to HSCs, enabled us to investigate whether a highly purified HSC can contribute to vascular remodeling after severe vascular injury.
CIC: Briefly outline your experimental approach to test your hypothesis.
MS: First, we transplanted either total bone marrow cells (TBM group), KSL bone marrow cells (KSL group), or a single TipSP CD34–KSL cell (HSC group) derived from GFP-transgenic mice into lethally irradiated wild-type mice (C57BL/6 background). At 12 weeks after irradiation and stem cell transplantation, an endovascular arterial injury was induced to the femoral artery of the bone marrow chimeric mice by inserting a large wire. Four weeks after the wire-injury, the injured femoral arteries were excised and fixed in 4% paraformaldehyde for histological analyses. The sections were observed under confocal microscopes. Cell number (GFP+ / total) was counted in the neointima and thickened media of a cross-section of each injured artery.
CIC: Was there a specific methodological technique that was very important in these studies?
MS: First, to highly purify HSCs, we combined the "Tip"-SP cells with a phenotype of CD34–KSL using fluorescence-activated cell sorting. Second, we induced wire-mediated endovascular injury in femoral artery by inserting a straight spring wire (0.38 mm in diameter, No. C-SF-15-15, Cook, Bloomington, IN). Third, to preserve GFP signal for histological analyses, the excised arteries were embedded in plastic resin (Technovit 8100, Heraeus Kulzer, Wehrheim, Germany).
CIC: What was the outcome (results) of your experiments?
MS: A single Tip-SP CD34-KSL cell showed significant prolonged donor cell engraftment, just like total bone marrow cells or KSL bone marrow cells. The lesions in the injured femoral arteries contained a significant number of (bone marrow-derived) GFP-positive cells in the TBM and KSL groups. Many of those GFP-positive cells in the neointima and media expressed alpha-smooth muscle actin, and some of those on the luminal side expressed endothelial markers. In contrast, GFP-positive cells were seldom detected in the lesions of the HSC group.
CIC: How do you interpret these results? What does this mean for stem cell biology?
MS: Our results suggest that it is rare for a highly purified HSC to transdifferentiate into vascular cells, if at all. In contrast, the KSL fraction of bone marrow cells, which is considered to be enriched in HSCs, contained a distinct population that could substantially contribute to lesion formation (vascular remodeling). The KSL fraction could include not only HSCs but also mesenchymal stem cells or multipotent cells that are more primitive than HSCs. It is plausible that those nonhematopoietic cells in the KSL fraction might be responsible for bone marrow-derived smooth muscle-like or endothelial-like cells observed in the vascular lesions after mechanical injury.
CIC: What hypotheses should the field test now?
MS: Bone marrow cells including the KSL fraction, not HSCs, can give rise to vascular cells that contribute to lesion formation (vascular remodeling).Total bone marrow cells or the KSL fraction of bone marrow cells might include putative vascular progenitor cells which might be classified into nonhematopoietic lineage(s). Putative bone marrow-derived smooth muscle progenitor cells might have a potential to become additional therapeutic targets in a variety of progressive vascular diseases. Further studies are needed to identify and characterize putative vascular progenitor cells. Particularly, we consider that it is very important to evaluate what nonhematopoietic population included in the KSL fraction of bone marrow cells is associated with the vascular progenitor cells and can participate in vascular remodeling.
CIC: Why did you select the journal Stem Cells for your paper?
MS: We have seen that the journal STEM CELLS has recently attracted much interest among a general scientific readership as well as among scientists who specialize in stem cell biology; and moreover, we think that it is one of the most exciting and interesting scientific journals in the modern era. The contents of this journal are rich, and the quality is excellent. Those are the reasons we selected the journal STEM CELLS for the publication of our paper.
CIC: Finally, on a more personal note, tell me a little about you, your education, training. What is your position right now? What would you like to do in the near future? What impact do you expect this award to have on your career aspirations?
MS: I am a cardiologist who specializes in cardiac catheterization and percutaneous coronary interventions, and I am also a final-year graduate student in the Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine. I research the molecular mechanisms and cellular pathophysiology in the various cardiovascular diseases, including aortic atherosclerosis, ischemic heart disease, peripheral vascular disease, and pulmonary arterial hypertension. The association between tissue stem cells, including HSCs, and a wide variety of cardiovascular diseases is one of the most interesting themes for me. After graduation, I would like to continue my research in these fields and to contribute to advances in medical science. Concurrently, I hope to study abroad in the near future in order to gain experience, although my destination to study abroad has not yet been determined. I expect this award to be helpful in my acceptance as a foreign postdoctoral researcher and/or fellow in some vigorous and proven laboratory.
Sergey S. Akimov, Ph.D.
CIC: First, let me extend my personal congratulations and those of the entire Editorial Board of Stem Cells. There were 48 excellent papers among the applicants for this prize, and at least 10 of them were felt to have moved our field considerably. The judges (members of our Editorial Board) had a very hard time deciding which was the most outstanding paper. Indeed, we finally decided to split the very top prize. So, your work has been seriously judged to be field-leading.
SA: Thank you very much. I would like to express again my appreciation to the Editors and Editorial Board of STEM CELLS for choosing me as a co-recipient of the STEM CELLS Young Investigator Award, 2006. I am proud to be honored with the award, and I believe it is an important achievement in my scientific career. I am also grateful to Dr. Robert Hawley, who supervised this project, and to all my colleagues who participated in the study.
CIC: Please tell me, in language intended for a general scientific audience rather than for our stem cell "niche," what hypothesis you were testing in the research from your paper.
SA: Adult stem cells such as hematopoietic stem cells cannot grow in culture for a long time because of spontaneous differentiation and proliferative senescence, entering into a non-dividing state after a finite number of cell divisions. These processes are regulated by several cell-signaling pathways such as those involving tumor suppressor genes. Proliferative senescence is also induced by the shortening of chromosome ends called telomeres. The integrity of telomeres is maintained by a specific ribonucleoprotein complex referred to as telomerase; the key regulatory component of which is its catalytic subunit, telomerase reverse transcriptase (TERT). Telomerase activity is high in embryonic stem cells; it is also present in adult stem cells but it decreases upon culturing in vitro during their differentiation. We hypothesized that inactivation of tumor suppressor genes and reactivation of telomerase activity by a gene transfer-based approach might allow hematopoietic stem cells in human umbilical cord blood to continue to grow, perhaps generating permanent cell lines. Additionally, because proliferative senescence also provides a barrier to malignant transformation, we hypothesized that artificial expression of certain oncogenes would transform the immortalized cell lines into leukemic cells.
CIC: Give me some background rationale, explaining why this hypothesis was important in stem cell research.
SA: Using human embryonic stem cells (hESCs) in biomedical research is restricted by ethical and technical problems. Cell lines derived from adult stem cells of different human tissue origin could replace hESCs in certain applications. For instance, they could serve as a model to study the molecular mechanisms of symmetric versus asymmetric cell division and differentiation as well as the multistep malignant transformation of human stem/progenitor cells.
CIC: Briefly outline your experimental approach to test your hypothesis.
SA: Our experimental approach was mostly based on a gene delivery technique using lentiviral vectors generated by scientists in Dr. Hawley’s group, on multicolor fluorescence activated cell sorting, and on culture conditions that others had previously demonstrated to transiently support hematopoietic stem cell proliferation.
CIC: Was there a specific methodological technique that was very important in these studies?
SA: Using lentiviral vectors for gene delivery allowed efficient infection of cord blood-derived hematopoietic stem cells. Notably, these vectors are able to carry relatively large genes and can integrate into slowly dividing and non-dividing cells, as exemplified by hematopoietic stem cells. An important aspect of the experimental approach was the multicolor cell sorting that allowed us to simultaneously use vectors with different fluorescent markers. This feature let us conveniently separate transduced cells from non-transduced cells that could produce inhibitory growth factors inducing cell differentiation.
CIC: What was the outcome (results) of your experiments?
SA: We attempted to immortalize human cord blood-derived hematopoietic stem/progenitor cells by transduction with lentiviral vectors carrying the human TERT (hTERT) gene and/or the human papillomavirus type 16 E6 and E7 oncogenes. The hTERT gene was incapable of prolonging the lifespan of the cord blood progenitor cells. However, cord blood progenitor cells transduced with E6/E7 alone or in concert with hTERT continued to proliferate, giving rise to permanent cell lines with a myeloerythroid/mast cell progenitor pheno-type. Notably, the resulting cord blood cell lines expressing only E6/E7 were highly aneuploid. By comparison, the cord blood cell lines obtained by coexpression of E6/E7 plus hTERT exhibited near-diploid karyotypes with minimal chromosomal aberrations, concomitant with stabilization of telomere length. These results demonstrated a critical role of telomere integrity in genomic stability. Importantly, the immortalized E6/E7 plus hTERT-expressing cord blood cells were not tumorigenic when injected into nonobese diabetic/severe combined immunodeficient mice but could be converted to a malignant state by ectopic expression of a v-H-ras or BCR-ABL oncogene.
CIC: How do you interpret these results? What does this mean for stem cell biology?
SA: I believe that these findings provide proof-of-principle for approaches that might eventually allow establishment of permanent human hematopoietic stem cell lines. In addition, they provide the basis for systematic investigation of experimental transformation of human hematopoietic stem cells in the context of the cancer stem cell paradigm.
CIC: What hypotheses should the field test now?
SA: As an extension of our studies and results, announced by Shinya Yamanaka of Kyoto University in Japan at the recent ISSCR meeting, concerning the programming of mouse skin cells to resemble ESCs, I suggest that using regulated gene expression systems to introduce multiple genes into various adult stem/progenitor cell populations would help to create cell lines with improved differentiation potential. I also think that our approach can be used to test the cancer stem cell hypothesis in different human malignancies.
CIC: Why did you select the journal Stem Cells for your paper?
SA: We selected your journal because of its reputation as one of the leading journals in the field of stem cell biology, because it is specifically focused on stem cell research, and because of its high impact factor.
CIC: Finally, on a more personal note, tell me a little about you, your education, training. What is your position right now? What would you like to do in the near future? What impact do you expect this award to have on your career aspirations?
SA: I graduated in Biophysics from the Nizhnii Novgorod State University (Russia) in 1993. I earned my Ph.D. degree in Molecular Biology and Cell Biology at the Engelhardt Institute of Molecular Biology, Russian Academy of Sciences in Moscow, Russia in 1997. A few months later, I joined the group of Dr. Alexey Belkin in the Biochemistry Department of the American Red Cross Holland Laboratory in Rockville, Maryland as a Research Fellow. In 2001, I joined the Hematopoiesis Department of Dr. Robert Hawley at the same institution. From July 2004 until recently, I have worked as a Research Scientist in Dr. Hawley’s laboratory at the Department of Anatomy and Cell Biology of George Washington University in Washington, DC. Currently, I am holding a Scientist position at the Transmissible Diseases Department of the American Red Cross Holland Laboratory. I work on creating models—including those involving neural stem cells and hematopoietic cells—to study mammalian prions that may potentially be present in blood and blood-derived products of people who were infected, for instance, with bovine spongiform encephalopathy agents causing "mad cow" disease. Misfolded prion proteins play a key role in the development of neurodegenerative disorders such as Creutzfeldt-Jakob disease and other transmissible spongiform encephalopathies. I believe the Stem Cells Young Investigator Award will greatly help to advance my scientific career. It also reinforces my conviction in the significance of stem cell research, and I gratefully commend the decision of the Editorial Board of Stem Cells and Invitrogen Corporation to establish this award.
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