Stem cell innovation in the USA: the benefits of the minimal state

Stem cell science is an emerging global industry in which nation states compete fiercely for economic advantage. Currently, the USA dominates this international competition but critics have argued that it lacks an innovation strategy to maintain its position. Strong international competition and internal policy problems may pose significant challenges to the future of US stem cell science. At the same time, the governments of the UK, China, India, Australia and Singapore are developing strategies to enhance their competitive edge within the global stem cell economy. How should the US government respond to these developments? Is a federal strategy necessary to protect the advantages of the US stem cell industries or can it be assumed that the present innovation infrastructure is sufficiently flexible and dynamic to cope with the global challenge? In this paper we address these questions through an examination of the US stem cell innovation system from the perspectives of science, society and the market.     

调控癌干细胞凋亡的外来因素

背景：目前收集的证据表明癌干细胞或肿瘤原始细胞是肿瘤形成和进展的关键驱动程序,这些细胞的高抵抗特性使常规治疗模式被阻碍。迄今为止,只有少量的研究发表癌干细胞死亡定向凋亡疗法的潜能。 目的：综述癌干细胞调节其凋亡的外来因素。 方法：由第一作者采用电子检索的方式在PubMed数据及万方数据库中检索1990年1月至2011年12月有关肿瘤干细胞和干细胞凋亡的研究。英文检索词为“cancer stem  cells,apoptosis,extrinsic factors”,中文关键词为“癌干细胞,凋亡,外来因素”。计算机初检得到120篇文献,阅读标题和摘要进行初筛,排除与研究目的相关性差及内容陈旧、重复的文献70篇,纳入50篇符合标准的文献进行综述。 结果与结论：癌干细胞理论在癌症的研究中有重要意义。它不仅在理解恶性肿瘤行为上有重要突破,而且有能力发展新的治疗方法。调节癌干细胞凋亡的外在因素包括微环境提供的外源性因子如分泌存活因子,黏附介导的凋亡抵抗和缺氧条件。潜在调节癌干细胞肿瘤微环境是非常关键的研究领域,并且这领域仍然进一步研究。通过各种已成型的各种机制解释癌干细胞的调控将一定会成为未来的研究趋势。     

Challenges and approaches to the culture of pluripotent human embryonic stem cells

Since the establishment of the first human embryonic stem cell (hESC) lines, several groups have described the derivation and culture of hESC lines in various culture conditions. In this review, we describe how hESC lines have been derived from the inner cell mass of blastocysts or morula-stage embryos and the culture conditions used. In order to be used for therapeutic purposes, the pluripotent hESC lines must be established and propagated according to good manufacturing practice quality requirements. In addition, any use of animal-derived components should be avoided to gain safer hESC lines for clinical purposes. Here, we will describe the development in derivation and chemically defined culturing conditions of hESC towards good manufacturing practice and discuss the future challenges for hESCs in clinical use. Similarly, we discuss the challenges and future directions in optimization of standard culture conditions of hESCs for research purposes.     

Stem cell sources for clinical islet transplantation in type 1 diabetes: embryonic and adult stem cells

Lifelong immunosuppressive therapy and inadequate sources of transplantable islets have led the islet transplantation benefits to less than 0.5% of type 1 diabetics. Whereas the potential risk of infection by animal endogenous viruses limits the uses of islet xeno-transplantation, deriving islets from stem cells seems to be able to overcome the current problems of islet shortages and immune compatibility. Both embryonic (derived from the inner cell mass of blastocysts) and adult stem cells (derived from adult tissues) have shown controversial results in secreting insulin in vitro and normalizing hyperglycemia in vivo. ESCs research is thought to have much greater developmental potential than adult stem cells; however it is still in the basic research phase. Existing ESC lines are not believed to be identical or ideal for generating islets or beta-cells and additional ESC lines have to be established. Research with ESCs derived from humans is controversial because it requires the destruction of a human embryo and/or therapeutic cloning, which some believe is a slippery slope to reproductive cloning. On the other hand, adult stem cells are already in some degree specialized, recipients may receive their own stem cells. They are flexible but they have shown mixed degree of availability. Adult stem cells are not pluripotent. They may not exist for all organs. They are difficult to purify and they cannot be maintained well outside the body. In order to draw the future avenues in this field, existent discrepancies between the results need to be clarified. In this study, we will review the different aspects and challenges of using embryonic or adult stem cells in clinical islet transplantation for the treatment of type 1 diabetes.     

The status of human nuclear transfer

Human therapeutic cloning is a recently emerged application of somatic cell nuclear transfer (SCNT), which is currently being performed to produce patient-specific stem cell lines for future stem cell therapies. The advantages in producing human nuclear transfer (NT) embryos to derive NT stem cell lines are that these can be tailor-made (i.e., are autologous in nature) for the patient and may overcome the need to administer life-long immunosuppression following stem cell transplantation. Although the rationale for using NT embryos is not for reproductive purposes, human NT remains clouded in ethical, moral, and religious controversies. The recent retraction of high-impact factor publications in the field of human NT from a research group in South Korea has placed stem cell research in a delicate situation. These heavily publicized issues may hinder the progress of this research and may threaten to bring current research to a complete halt. This review outlines the recent status of human NT, its continuing progress and the difficulties the field faces. Of most concern are the ethical issues, which surround obtaining human oocytes for research. Recent evidence suggests that failed-to-fertilize oocytes are poor sources for human SCNT, but obtaining fresh, viable oocytes may be even more problematic. The current status of human SCNT is outlined in this review with particular reference made to, lessons learnt from animal research, the oocyte dilemma and optimization of human NT.     

Regulation of Stem Cell-Based Therapies in Canada: Current Issues and Concerns

Stem cell therapies offer enormous potential for the treatment of a wide range of diseases and conditions. Despite the excitement over such advances, regulators are faced with the challenge of determining criteria to ensure stem cells and their products are safe and effective for human use. However, stem cell-based products and therapies present unique regulatory challenges because standard drug development models do not wholly apply given the complexity and diversity of these products and therapies. As a result, regulatory requirements are often unclear and ambiguous creating unnecessary barriers for research. In order to better understand the barriers that might affect Canadian stem cell researchers, we sought feedback from stakeholders regarding areas of uncertainty or concern about existing regulatory oversight of cell therapies. A selection of Canadian researchers and clinicians working in the area of stem cell research were interviewed to assess certain key questions: 1) whether current regulatory requirements are easily accessible and well understood; 2) whether regulatory requirements create important challenges or barriers; and 3) whether there is a need for further guidance on the issue. The results of this survey are summarized and compared to issues and concerns experienced in other countries, as reported in the literature, to identify challenges which may be on the horizon and to provide possible solutions for regulatory reform.     

Will regulation determine the science agenda? A look at hESCs

Given the significant controversy over human embryonic stem cell (hESC) isolation and research, regulation of such work around the world has proceeded in an uncoordinated manner. In general, advances in science cause a need or desire for regulation; however, it has been the opposite for hESC research--regulation and policy have set certain boundaries for scientific research and defined other research questions. This is especially evident in the USA, where federal funding policies have engendered specific research towards novel methods for isolating such cells that do not require destruction of human embryos. Due to the multiplicity of national policies, it will be almost impossible to reach global consensus in the near future. Nonetheless, this paradigm of regulation leading science may have significant implications for future research projects. Changes in hESC policy in the short term will influence longer-term research potential.     

Growth factors and the molecular control of haematopoiesis

In the absence of appropriate growth factors, for example interleukin-3 or GM-CSF, cultured bone marrow stem cells die by a process known as apoptosis or programmed cell death. Apoptosis may occur in vivo when concentrations of specific growth factors are limiting and may be a means of regulating cell numbers. Growth factors are also essential for proliferation of bone marrow stem cells but differentiation can occur, provided there is a survival stimulus in the absence of growth factors. Combinations of growth factors may be synergistic in stimulating the survival and proliferation of multipotent stem cells. Although neither stem cell factor, nor GM-CSF alone can significantly induce the proliferation of stem cells, the combination induces the proliferation of these cells. Committed progenitor cells such as granulocyte-macrophage colonyforming cells, however, are stimulated to proliferate by GM-CSF alone, while stem cell factor in combination with GM-CSF results in only a slight additive effect. To date, most research has concentrated on the growth stimulatory factors. GM-CSF has an important role in the reversal of chemotherapy-induced myelosuppression in cancer patients and in other bone marrow disorders. A number of growth inhibitory molecules have now been identified, such as macrophage inhibitory protein-1. In the future, it is possible that improvements in cure rates may be achieved in cancer patients by combining the growth inhibitory factors with the stimulatory factors. Inhibitory factors may be given before chemotherapy to prevent toxicity and stimulatory factors may be given afterwards to treat neutropenic patients.     

Experiences and lessons learned as a Chair of anatomy—An 18-year journey

In 1998, I was appointed Chair of the Department of Anatomy at Monash University in Melbourne, Australia. On commencing as Chair, I had three main goals: (a) to maintain and extend the high quality of anatomy teaching in the medical program; (b) to introduce significantly more developmental biology, cell biology, and neuroscience into our existing Bachelor of Science major in human anatomy; and (c) to establish an active research program in the department. Over the next 18 years, I worked with staff and students at all levels of the university to turn this vision into a reality, with the Monash Department of Anatomy and Developmental Biology now arguably the top ranked anatomy department in Australia. During my tenure, countless challenges were faced and while some errors were made, and a good number of goals were never realized the general outcome was a vibrant scholarly environment where that rich nexus of research and teaching was realized. This personal account provides some insights into that 18-year journey, which I hope may prove useful for current and future Chairs of anatomy. For me personally, it was definitely a journey worth taking.     

Growth factors and the molecular control of haematopoiesis

In the absence of appropriate growth factors, for example interleukin-3 or GM-CSF, cultured bone marrow stem cells die by a process known as apoptosis or programmed cell death. Apoptosis may occur in vivo when concentrations of specific growth factors are limiting and may be a means of regulating cell numbers. Growth factors are also essential for proliferation of bone marrow stem cells but differentiation can occur, provided there is a survival stimulus in the absence of growth factors. Combinations of growth factors may be synergistic in stimulating the survival and proliferation of multipotent stem cells. Although neither stem cell factor, nor GM-CSF alone can significantly induce the proliferation of stem cells, the combination induces the proliferation of these cells. Committed progenitor cells such as granulocyte-macrophage colonyforming cells, however, are stimulated to proliferate by GM-CSF alone, while stem cell factor in combination with GM-CSF results in only a slight additive effect. To date, most research has concentrated on the growth stimulatory factors. GM-CSF has an important role in the reversal of chemotherapy-induced myelosuppression in cancer patients and in other bone marrow disorders. A number of growth inhibitory molecules have now been identified, such as macrophage inhibitory protein-1γ. In the future, it is possible that improvements in cure rates may be achieved in cancer patients by combining the growth inhibitory factors with the stimulatory factors. Inhibitory factors may be given before chemotherapy to prevent toxicity and stimulatory factors may be given afterwards to treat neutropenic patients.     

Research progress in the cell origin of basal cell carcinoma

Identification of the cell origin of human neoplasms remains a challenging but important task in cancer research. The outcomes in this area of study may allow us to design novel strategies for early cancer detection and targeted cancer therapeutics. Skin is a great organ to study cancer stem cells because stem cells in skin have been well investigated and approaches of genetic manipulation in specific cell compartments are available to mimic clinical skin cancer in a mouse model. Recently, by using different genetic engineered mouse models, several groups have tried to discover which cell type in skin was responsible for the initiation of basal cell carcinoma, the most common type of skin cancer. These studies raised more questions but also showed more ways for future investigation.     

Stem Cells in Amniotic Fluid as New Tools to Study Human Genetic Diseases

In future, the characterization and isolation of different human stem cells will allow the detailed molecular investigation of cell differentiation processes and the establishment of new therapeutic concepts for a wide variety of diseases. Since the first successful isolation and cultivation of human embryonic stem cells about 10 years ago, their usage for research and therapy has been constrained by complex ethical consideration as well as by the risk of malignant development of undifferentiated embryonic stem cells after transplantation into the patient’s body. Adult stem cells are ethically acceptable and harbor a low risk of tumor development. However, their differentiation potential and their proliferative capacity are limited. About 4 years ago, the discovery of amniotic fluid stem cells, expressing Oct-4, a specific marker of pluripotent stem cells, and harboring a high proliferative capacity and multilineage differentiation potential, initiated a new and promising stem cell research field. Inbetween, amniotic fluid stem cells have been demonstrated to harbor the potential to differentiate into cells of all three embryonic germlayers. These stem cells do not form tumors in vivo and do not raise the ethical concerns associated with human embryonic stem cells. Further investigations will reveal whether amniotic fluid stem cells really represent an intermediate cell type with advantages over both, adult stem cells and embryonic stem cells. The approach to generate clonal amniotic fluid stem cell lines as new tools to investigate molecular and cell biological consequences of human natural occurring disease causing mutations is discussed.     

Redox regulation of stem and progenitor cells

The field of stem and progenitor cell biology is expanding. Much of the enthusiasm is based on the potential of using stem and progenitor cells as a cellular therapy for the treatment of human disease. Although the concept of using human embryonic stem cells for therapeutic indications is intriguing, significant challenges face investigators pursuing research in this area. Therefore, renewed scientific energy is focusing on the molecular pathways that differentiate a pluripotent embryonic stem cell from more-committed tissue-specific cells. Molecular mechanisms that govern tissue-specific stem and progenitor cell function are also topics of intense investigation, given that altered function of these cells may promote a variety of human pathologies including aging, vascular disease, and cancer. Considerable progress has been made, but a clear identification of the molecular signatures of stem and progenitor cells remains elusive. A growing body of literature demonstrates that distinct functional characteristics of stem and progenitor cells are under redox regulation. In this Forum Issue, evidence for redox regulation of tissue-specific stem and progenitor cells involved in hematopoiesis and vasculogenesis/angiogenesis is presented.     

Differentiation of Human Embryonic Stem Cells to Cardiomyocytes for In Vitro and In Vivo Applications

The ability of human embryonic stem cells to differentiate into spontaneously contracting cardiomyocyte-like cells has attracted substantial interest from the scientific community over the last decade. From having been difficult to control, human cardiomyogenesis in vitro is now becoming a process which, to a certain extent, can be effectively manipulated and directed. Although much research remains, new and improved protocols for guiding pluripotent stem cells to the cardiomyocyte lineage are accumulating in the scientific literature. However, the stem cell derived cardiomyocytes described to date, generally resemble immature embryonic/fetal cardiomyocytes, and they are in some functional and structural aspects different from adult cardiomyocytes. Thus, a future challenge will be to design strategies that eventually may allow the cells to reach a higher degree of maturation in vitro. Nevertheless, the cells which can be prepared using current protocols still have wide spread utility, and they have begun to find their way into the drug discovery platforms used in the pharmaceutical industry. In addition, stem cell derived cardiomyocytes and cardiac progenitors are anticipated to have a tremendous impact on how heart disease will be treated in the future. Here, we will discuss recent strategies for the generation of cardiomyocytes from human embryonic stem cells and recapitulate their features, as well as highlight some in vitro applications for the cells. Finally, opportunities in the area of cardiac regenerative medicine will be illustrated.     

Stem Cell Policy Exceptionalism: Proceed with Caution

The term "stem cell exceptionalism" has been used to characterize the policy response to controversies surrounding human embryonic stem cell research. For example, governments and funding agencies have adopted policies governing the derivation and use of human embryonic stem cell lines. These policies have effectively served to fill gaps in existing guidelines and regulations and signal that scientists are committed to a responsible framework for the conduct of research involving human embryos. Recent publications discuss whether ethical and policy issues associated with induced pluripotent cells (iPSCs) from non-embryonic sources create a need for further policy intervention. We suggest many of the issues identified by commentators may be addressed through the application of established policy frameworks governing the use of tissue, human stem cells, and research participation by human research subjects. To the extent, iPSC research intersects with hESC research (e.g. the creation of human gametes and/or embryos), the policy framework governing hESC appears sufficiently robust at this time.     

Concise review: putting a finger on stem cell biology: zinc finger nuclease-driven targeted genetic editing in human pluripotent stem cells

Human pluripotent stem cells (hPSCs) encompassing human embryonic stem cells and human induced pluripotent stem cells (hiPSCs) have a wide appeal for numerous basic biology studies and for therapeutic applications because of their potential to give rise to almost any cell type in the human body and immense ability to self-renew. Much attention in the stem cell field is focused toward the study of gene-based anomalies relating to the causative affects of human disease and their correction with the potential for patient-specific therapies using gene corrected hiPSCs. Therefore, the genetic manipulation of stem cells is clearly important for the development of future medicine. Although successful targeted genetic engineering in hPSCs has been reported, these cases are surprisingly few because of inherent technical limitations with the methods used. The development of more robust and efficient means by which to achieve specific genomic modifications in hPSCs has far reaching implications for stem cell research and its applications. Recent proof-of-principle reports have shown that genetic alterations with minimal toxicity are now possible through the use of zinc finger nucleases (ZFNs) and the inherent DNA repair mechanisms within the cell. In light of recent comprehensive reviews that highlight the applications, methodologies, and prospects of ZFNs, this article focuses on the application of ZFNs to stem cell biology, discussing the published work to date, potential problems, and future uses for this technology both experimentally and therapeutically.     

The Limbal Epithelial Progenitors in the Limbal Niche Environment

Limbal epithelial progenitors are stem cells located in limbal palisades of vogt. In this review, we present the audience with recent evidence that limbal epithelial progenitors may be a powerful stem cell resource for the cure of human corneal stem cell deficiency. Further understanding of their mechanism may shed lights to the future successful application of stem cell therapy not only to the eye tissue, but also to the other tissues in the human body.     

美国干细胞领域的相关政策及研发和投入分析

背景：美国在干细胞领域的研究居世界顶级水平,但其相关的监管及政策一直在变化。 目的：研究美国政府及企业对干细胞研究政策和投入的变化,及其可能对世界格局产生的重大影响。 方法：由第一作者检索2000-01/2010-10 SCI数据库,万方数据库,维普数据库,美国国家卫生研究院(National Institutes of Health,NIH)的官方网站,及GBI Research公司的研究报告。英文检索词为“stem cell,USA,policy,invest”,中文检索词为“干细胞,美国”。共收集到128篇有关美国干细胞政策和投入的相关的文献,排除发表时间较早、重复及类似研究,共有30篇符合标准的文献。 结果与结论：美国对于干细胞研究政策及投入的争议,主要集中在联邦经费是否可以用于人类胚胎干细胞研究,但对非联邦资助的人类胚胎干细胞研究没有太多限制。奥巴马总统上任后对联邦政府资助胚胎干细胞研究的限制较以前有了部分松绑,但目前政策的后继影响还不明显。美国虽然在联邦政府层面对干细胞的研究投入有限,但地方政府以及私人资金对其大力支持,加上产业界对于干细胞治疗的巨大投入,美国的干细胞研究和产业前景乐观,胚胎干细胞可能成为以后的优先发展领域。     

Regulation of Human Stem Cell Research in South Korea

Human stem cell research has been performed for many years in South Korea. It has been supported by the South Korean government, like other biomedical research. Like many other countries, human embryonic stem cell research, human adult stem cell research and iPS cell research have been performed in South Korea. The Bioethics and Safety Act is the main law which regulates human stem cell research. It took effect on 1 January 2005. However, this Act does not include all the fields of biomedical research and some provisions were not clear. After Hwang’s scandal, there have been heated debates about the revision of the Bioethics and Safety Act. It was revised several times and a new revised version is under consideration now.     

Human embryonic stem cells: origin, properties and applications

Human embryonic stem cells originate from the human preimplantation embryo. The derivation of the first human embryonic stem cells was reported in 1998. Since then we have learnt a great deal about how to isolate and culture these cells. Additionally, their stem cell phenotype and differentiation competence have been determined. Although it is expected that many basic biological properties, such as self-renewal and cell specification, are evolutionary conserved, at least from the mouse, we lack significant knowledge about the molecular events that regulate the unique stem cell features of human embryonic stem cells. The pluripotent nature of human embryonic stem cells has attracted great interest in using them as a source of cells and tissues in cell therapy. Recent progress in human somatic cell nuclear transfer suggests that there may be a solution to the immunotolerance problems associated with the use of human embryonic stem cells in cell-replacement therapy. Thus, human embryonic stem cells supply the research community with unique research tools to study basic biological processes in human cells, model human genetic diseases and develop new cell-replacement therapies.