Governing stem cell banks and registries: Emerging Issues

The expansion of national and international research efforts in stem cell research is increasingly paired with the trend of establishing stem cell banks and registries. In jurisdictions crossing the spectrum of restrictive to liberal stem cell policies, banks and registries are emerging as an essential resource for transnational access to quality-controlled and ethically sourced stem cell lines. In this study, we report the preliminary findings of a survey of stem cell banks participating in the International Stem Cell Forum's International Stem Cell Banking Initiative (ISCBI). The questionnaire circulated to all ISCBI members addressed both general issues surrounding research policies (e.g., national policies regulating the permissibility of conducting embryonic stem cell research (hESCR)) and, more specifically, issues relating to the governance of stem cell banking projects. The results of the questionnaire were complemented by scholarly research conducted by the authors. This article provides an overview of the current international hESC banking landscape (I). For this purpose, the policy and governance approaches adopted in the surveyed stem cell banks at the national level will be analyzed and areas of convergence and variance will be identified (II). It is beyond the scope of this paper to provide a comprehensive analysis of the wide range of possible governance approaches, policy responses, and their implications. However, we want to provide a starting point for discussion surrounding key questions and challenges as concerns provenance, access, and deposit of hESC lines (III). Finally, while our analysis is focused on research grade hESCs, the lessons to be gleaned from this examination will encourage further thought, analysis, and research into the issues raised in the banking and governance of other sources of stem cell lines (e.g., SCNT, parthenogenesis, iPs) (IV).     

Derivation and propagation of human embryonic stem cell lines from frozen embryos in an animal product-free environment

The protocols described here are comprehensive instructions for deriving human embryonic stem (hES) cell lines in xeno-free conditions from cryopreserved embryos. Details are included for propagation, cryopreservation and characterization. Initial derivation is on feeder cells and is followed by adaptation to a feeder-free environment; competent technicians can perform these simplified methods easily. From derivation to cryopreservation of fully characterized initial stocks takes 3-4 months. These protocols served as the basis for standard operating procedures (SOPs), with both operational and technical components, that we set to meet good manufacturing practice (GMP) and UK regulatory body requirements for derivation of clinical-grade cells. As such, these SOPs are currently used in our current GMP compliant facility to derive hES cell lines ab initio, in an animal product-free environment; these lines are suitable for research and potentially for clinical use in cell therapy. So far, we have derived eight clinical-grade lines, which will be freely available to the scientific community after submission/accession to the UK Stem Cell Bank.     

Microbiological contamination in stem cell cultures

Cell therapy and regenerative medicine are potentially two of the most exciting aspects of the novel therapeutic methods currently under development. However, these treatments present a number of important biosafety issues, like the possible transmission of microorganisms to the recipients. The most common potential form of contamination in these cell products is by bacteria (including Mycoplasma), yeast and fungi. In our study, 32 stem cell lines and feeder cell lines were analysed. There were 19 contaminated cell passages (12%). The main contaminants were gram positive cocci and Mycoplasma species, followed by gram negative rods and gram positive rods. The Mycoplasma contamination rate was 4%. Stem cell banks and other research centres aim to screen all processed stem cell lines for these microorganisms, and to assure that no contaminants are introduced in the banking procedures. It is a standard part of current good practice in stem cell banks to carry out routine microbiological controls of the stem cell lines and to work in a controlled environment to reduce the probability of contamination in the final product.     

Governing stem cell research in California and the USA: towards a social infrastructure

Owing to the restrictive human embryonic stem cell (hESC) policies of the US government, the question of whether to pursue human embryonic stem cell experiments has dominated the ethical and political discourse concerning such research. Explicit attention must now turn to problems of implementing the research on a large scale: in the 2004 US elections, California voters approved a state initiative for stem cell research, earmarking $3 billion in direct spending over 10 years. This article explores three ethical and political problem areas emerging out of the California program, the resolution of which will help set the trajectory of hESC research in the US and abroad, and then proposes an institutional approach to help address them: a network of public stem cell banks in the US that feature transparent and shared governance.     

Role of the embryology laboratory in the human embryonic stem cell line derivation process

With the introduction of regenerative medicine and cell therapy programmes by means of human embryonic stem cells (hESC), several research centres have begun projects of derivation of hESC lines. In some stem cell banks, such as the Andalusian Stem Cell Bank, the law also permits the creation of these cell lines. Therefore, the recovery of cryopreserved embryos, their culture and the subsequent derivation to hESC lines requires a suitable embryology laboratory and specialized and highly qualified staff. Moreover, new techniques, from therapeutic nuclear transfer, need this type of laboratory and staff, too. Several International Associations have drawn up some guidelines for laboratories where embryos are manipulated and they reflect the physical space, the staff and the equipment needed in these kinds of laboratories. Nevertheless, we can see that these guidelines do not distinguish between IVF laboratories and other laboratories that obtain hESC lines, so it would be convenient to make a distinction. Following these guidelines, we have tried to draw up concurrent aspects applicable to areas of embryology within stem cell banks. So, the design and the specific implementation programmes for these areas and other research centres with this area but which do not use IVF techniques is vital to develop embryonic cell lines in optimum conditions for future therapeutic applications, although maybe it is rather premature to standardize this type of research.     

围产期干细胞库质量管理体系构建

围产期干细胞库质量管理体系（QMS）建设是保障干细胞产品和服务健康发展的基础工作。本文比较分析美国输血协会（AABB）、细胞疗法认证基金会（FACT）和ISO 9001的标准的架构、内容和侧重点,重点论述围产期干细胞库QMS构建的方法、步骤和参考模式。参照权威机构标准建立和运行QMS,能够保障我国围产期干细胞库标准化、规范化和科学化的建设和管理,提升我国干细胞库能力和信任水平。良好的QMS进一步促进干细胞与精准医疗战略性新兴产业升级,为建设健康中国提供动力。     

Immunological considerations for embryonic and induced pluripotent stem cell banking

Recent advances in stem cell technology have generated enthusiasm for their potential to study and treat a diverse range of human disease. Pluripotent human stem cells for therapeutic use may, in principle, be obtained from two sources: embryonic stem cells (hESCs), which are capable of extensive self-renewal and expansion and have the potential to differentiate into any somatic tissue, and induced pluripotent stem cells (iPSCs), which are derived from differentiated tissue such as adult skin fibroblasts and appear to have the same properties and potential, but their generation is not dependent upon a source of embryos. The likelihood that clinical transplantation of hESC- or iPSC-derived tissues from an unrelated (allogeneic) donor that express foreign human leucocyte antigens (HLA) may undergo immunological rejection requires the formulation of strategies to attenuate the host immune response to transplanted tissue. In clinical practice, individualized iPSC tissue derived from the intended recipient offers the possibility of personalized stem cell therapy in which graft rejection would not occur, but the logistics of achieving this on a large scale are problematic owing to relatively inefficient reprogramming techniques and high costs. The creation of stem cell banks comprising HLA-typed hESCs and iPSCs is a strategy that is proposed to overcome the immunological barrier by providing HLA-matched (histocompatible) tissue for the target population. Estimates have shown that a stem cell bank containing around 10 highly selected cell lines with conserved homozygous HLA haplotypes would provide matched tissue for the majority of the UK population. These simulations have practical, financial, political and ethical implications for the establishment and design of stem cell banks incorporating cell lines with HLA types that are compatible with different ethnic populations throughout the world.     

间充质干细胞过滤分离器制备人羊膜间充质干细胞的研究

自然存在的间充质干细胞数量少,限制了其研究应用。依靠自主发明的间充质干细胞过滤分离器,分离制备了人羊膜间充质干细胞,并对制备的干细胞进行了三维培养扩增。结果表明,制备的干细胞形态长势良好,并能诱导分化为类胰岛样组织。与常规方法相比,干细胞收获率提高了8倍以上,且细胞活性状态良好。间充质干细胞过滤分离器可以批量制备高质量的各种间充质干细胞,有利于高效率地建设各种间充质干细胞库,以促进间充质干细胞的研究应用。     

Efficient expansion of clinical-grade human fibroblasts on microcarriers: cells suitable for ex vivo expansion of clinical-grade hESCs

Human embryonic stem cells hold considerable potential for cell-based treatments of a variety of degenerative diseases, including diabetes, ischemic heart failure, and Parkinson's disease. However, advancing research to provide clinical-grade product requires scale-up to therapeutic quantities of stem cells and their differentiated progeny. Most human embryonic stem cell culture platforms require direct support by a fibroblast feeder layer or indirect support using fibroblast conditioned medium. Accordingly, large numbers of clinically compliant fibroblasts will be requisite for stem cell production. Published platforms for feeder production are insufficient for stem cell scale-up, being costly to operate and requiring considerable effort to prepare, maintain and harvest. Here we describe the expansion of cGMP-grade, FDA-approved human foreskin fibroblasts using cGMP-grade reagents and polystyrene-based cationic trimethyl ammonium-coated microcarriers in spinner flasks. Fibroblasts attach rapidly to the microcarriers (T(1/2)=75 min), and expand with a maximum doubling time of 22.5h. Importantly, microcarrier-expanded fibroblasts and their conditioned medium support pluripotent stem cell growth through >5 passages, enabling extended self-renewal and expansion while retaining full differentiation potential. In summary, the method described is an economical and cGMP-compliant means of producing human fibroblast cells in support of cGMP human embryonic stem cell culture.     

A cGMP-applicable Expansion Method for Aggregates of Human Neural Stem and Progenitor Cells Derived From Pluripotent Stem Cells or Fetal Brain Tissue

A cell expansion technique to amass large numbers of cells from a single specimen for research experiments and clinical trials would greatly benefit the stem cell community. Many current expansion methods are laborious and costly, and those involving complete dissociation may cause several stem and progenitor cell types to undergo differentiation or early senescence. To overcome these problems, we have developed an automated mechanical passaging method referred to as “chopping” that is simple and inexpensive. This technique avoids chemical or enzymatic dissociation into single cells and instead allows for the large-scale expansion of suspended, spheroid cultures that maintain constant cell/cell contact. The chopping method has primarily been used for fetal brain-derived neural progenitor cells or neurospheres, and has recently been published for use with neural stem cells derived from embryonic and induced pluripotent stem cells. The procedure involves seeding neurospheres onto a tissue culture Petri dish and subsequently passing a sharp, sterile blade through the cells effectively automating the tedious process of manually mechanically dissociating each sphere. Suspending cells in culture provides a favorable surface area-to-volume ratio; as over 500,000 cells can be grown within a single neurosphere of less than 0.5 mm in diameter. In one T175 flask, over 50 million cells can grow in suspension cultures compared to only 15 million in adherent cultures. Importantly, the chopping procedure has been used under current good manufacturing practice (cGMP), permitting mass quantity production of clinical-grade cell products.     

Infrastructural expectations: exploring the promise of international large-scale induced pluripotent stem cell banks

This paper investigates the recent emergence of several major projects to bank and distribute large numbers of human induced pluripotent stem cells (hiPSCs) for translational research. The conceptual framework of the sociology of expectations is applied to interrogate the promise underpinning these developments. An analytic distinction is made between expectations associated with the field of hiPSC research more broadly and those specifically invested in cell banks as a form of scientific infrastructure, with the focus predominantly on the latter element. Empirical data for the analysis comes from qualitative interviews with stem cell scientists involved in a major European hiPSC banking project. In order to unpack these expectations, parallels to previous infrastructures of dissemination will be highlighted, with an emphasis on the functions of circulating and securing the quality of biological research materials.     

Perspectives on human stem cell research

Human stem cell research draws not only scientists' but the public's attention. Human stem cell research is considered to be able to identify the mechanism of human development and change the paradigm of medical practices. However, there are heated ethical and legal debates about human stem cell research. The core issue is that of human dignity and human life. Some prefer human adult stem cell research or iPS cell research, others hES cell research. We do not need to exclude any type of stem cell research because each has its own merits and issues, and they can facilitate the scientific revolution when working together. J. Cell. Physiol. 220: 535–537, 2009. © 2009 Wiley‐Liss, Inc.     

Current status of stem cell research: An editorial

The purpose of this editorial is to highlight recent developments in molecular biology tools and techniques in stem cell research and their applications to human diseases. Recent advancements in stem cell research and regenerative medicine are offering immense hope to cure human diseases and injuries, such as cancer, diabetes, Alzheimer's disease, Parkinson's disease, and traumatic brain injuries. In the last three decades, especially in the last decade, major breakthroughs have been seen in the conversion of adult stem cells into induced pluripotent stem cells, which in turn has led the way to developing stem cell therapies for human diseases. This article summarizes contributions of research into stem cell therapies.     

Advances in cell lineage reprogramming

As a milestone breakthrough of stem cell and regenerative medicine in recent years,somatic cell reprogramming has opened up new applications of regenerative medicine by breaking through the ethical shackles of embryonic stem cells.However,induced pluripotent stem(iPS) cells are prepared with a complicated protocol that results in a low reprogramming rate.To obtain differentiated target cells,iPS cells and embryonic stem cells still need to be induced using step-by-step procedures.The safety of induced target cells from iPS cells is currently a further concerning matter.More broadly conceived is lineage reprogramming that has been investigated since 1987.Adult stem cell plasticity,which triggered interest in stem cell research at the end of the last century,can also be included in the scope of lineage reprogramming.With the promotion of iPS cell research,lineage reprogramming is now considered as one of the most promising fields in regenerative medicine,will hopefully lead to customized,personalized therapeutic options for patients in the future.     

The International Stem Cell Banking Initiative (ISCBI): raising standards to bank on

The International Stem Cell Banking Initiative (ISCBI) aims to create a global network of stem cell banks to facilitate best practice in stem cell research and clinical cell delivery, primary objectives of national and local governments worldwide and stem cell organizations such the International Stem Cell Forum and the International Society of Stem Cell Research. This paper is a brief overview of ISCBI, its primary activities, potential network participants, and the challenges for harmonizing stem cell banking on a global level.     

Environmental microbial contamination in a stem cell bank

AIM: The aim of this study was to evaluate the main environmental microbial contaminants of the clean rooms in our stem cell bank. METHODS AND RESULTS: We have measured the microbial air contamination by both passive and active air sampling and the microbial monitoring of surfaces by means of Rodac plates. The environmental monitoring tests were carried out in accordance with the guidelines of European Pharmacopeia and US Pharmacopeia. The micro-organisms were identified by means of an automated system (VITEK 2). During the monitoring, the clean rooms are continually under good manufacturing practices specifications. The most frequent contaminants were Gram-positive cocci. CONCLUSIONS: The main contaminants in our stem cell bank were coagulase-negative staphylococci and other opportunistic human pathogens. In order to assure the levels of potential contamination in both embryonic and adult stem cell lines, a continuous sampling of air particles and testing for viable microbiological contamination is necessary. SIGNIFICANCE AND IMPACT OF THE STUDY: This study is the first evaluation of the environmental contaminants in stem cell banks and can serve as initial evaluation for these establishments. The introduction of environmental monitoring programmes in the processing of stem cell lines could diminish the risk of contamination in stem cell cultures.     

干细胞研究伦理

干细胞具有＂分化＂和＂脱分化＂的特点和潜能,干细胞研究有着良好的医学前景,许多人类严重疾病的治疗有了新的希望。伴随着干细胞研究的开展和深入,出现了诸多伦理问题的争论。拟就干细胞研究的希望和现实、伦理争论的主要观点及干细胞研究伦理准则的构建,作一简要介绍,并就加强干细胞管理提出建议。     

Stem cell therapies and regenerative medicine in China

Stem cells are the core of tissue repair and regeneration,and a promising cell source for novel therapies.In recent years,research into stem cell therapies has been particularly exciting in China.The remarkable advancements in basic stem cell research and clinically effective trials have led to fresh insights into regenerative medicine,such as treatments for sweat gland injury after burns,diabetes,and liver injury.High hopes have inspired numerous experimental and clinical trials.At the same time,government investment and policy support of research continues to increase markedly.However,numerous challenges must be overcome before novel stem cell therapies can achieve meaningful clinical outcomes.     

Stem cell research in China

In the past 5 years, China has increased its efforts in the field of stem cell research and practice. Basic research mainly focuses on bone marrow and embryonic stem cells. Clinical applications of stem cells in the treatment of acute heart failure, acute liver failure and lower limb ischaemia have been reported by many hospitals. China enacted its 'Ethical Guidelines for Human Embryonic Stem Cell Research' in 2003. At present, China has the most liberal and favourable environments for human embryonic stem cell research.     

Stem cell applications for pathologies of the urinary bladder

New stem cell based therapies are undergoing intense research and are widely investigated in clinical fields including the urinary system. The urinary bladder performs critical complex functions that rely on its highly coordinated anatomical composition and multiplex of regulatory mechanisms. Bladder pathologies resulting in severe dysfunction are common clinical encounter and often cause significant impairment of patient’s quality of life. Current surgical and medical interventions to correct urinary dysfunction or to replace an absent or defective bladder are sub-optimal and are associated with notable complications. As a result, stem cell based therapies for the urinary bladder are hoped to offer new venues that could make up for limitations of existing therapies. In this article, we review research efforts that describe the use of different types of stem cells in bladder reconstruction, urinary incontinence and retention disorders. In particular, stress urinary incontinence has been a popular target for stem cell based therapies in reported clinical trials. Furthermore, we discuss the relevance of the cancer stem cell hypothesis to the development of bladder cancer. A key subject that should not be overlooked is the safety and quality of stem cell based therapies introduced to human subjects either in a research or a clinical context.