technological advances in stem cell research: developing a consensus

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STEM CELLS AND DEVELOPMENT 13:323–324 (2004) © Mary Ann Liebert, Inc. Editorial Technological Advances in Stem Cell Research: Developing a Consensus 323 I F I MAY USE METAPHORICAL LANGUAGE, it could be ar- gued that technological advances in stem cell research are currently entering the Bronze Age. There remain many controversial issues in the field of stem cell biol- ogy that Stem Cells and Development wishes to address over the next 12 months. In the current issue of the Jour- nal, we have for the first time attempted to address the controversy of one of the most fundamental of problems facing stem cell investigators today: that is to say, to gather a forum of methodological and technological in- formation that may be used to develop a consensus on the ways by which stem cells and cellular progenitors can appropriately be cultured in the laboratory. It is clear that many laboratories have at their disposal a vast array of cellular engineering tools and tricks of the trade. However, in the current climate of legal and ethi- cal concerns in stem cell research and regenerative ther- apy, there exists an urgent need for the establishment of good laboratory practice and accreditation of translational stem cell laboratories. This is important if advances in stem cell research are ever to be translated to the bed- side, and quite clearly there is a need for standardization of the technologies and methods that stem cell investi- gators employ in their laboratories. This would not only serve to create a national and ideally an international stan- dardization in stem cell culture practices, but it would also provide appropriate benchmarks for collaborating university medical schools to employ rigorously ap- praised consensus protocols for eventual use in the ther- apeutic targeting of intractable disease and in regenera- tive medicine. It is perhaps beyond the scope of this current issue of the Journal to critically discuss and resolve the many con- troversial issues of stem cell culture practices that exist in the laboratory. The objective of this issue of the Jour- nal was to collate a number of technological manuscripts and critical reviews from national and international in- vestigators. It was intended that this would provide a plat- form of rational discussion and publication of detailed laboratory experience of the technologies that are avail- able to us in the context of the stem cell type under in- vestigation, and the clinical platform that would support the therapeutic application of those manipulated stem cells. It is hoped that this will encourage follow-up cor- respondence, discussion, and submission of technologi- cal manuscripts that will in time define the field of good laboratory stem cell culture practice, especially in the context of its therapeutic application. In the absence of a consensus and of an attempt to define standard practices in translational stem cell research, it will be almost im- possible to standardize across the board any therapeutic intervention that employs cultured and engineered stem cells from institute to institute. This is not a trivial un- dertaking. However, by taking a lead in tackling the con- troversial problems outlined above, Stem Cells and De- velopment is encouraging a forum of national and international discourse on the most appropriate ways to develop standardization in stem cell culture and practice. The technological reports in this special focus issue of Stem Cells and Development have brought to the fore a number of important practical and technological chal- lenges. It is generally accepted that current cell culture techniques are not optimal and include the widespread use of poorly defined supplements, such as fetal bovine serum or proprietary additives, that by their very nature are also ill-defined. Such culture supplements are poten- tially biohazardous in the context of their eventual use in clinical programs. Despite the availability of relatively ill-defined serum replacement supplements and the practice of individual laboratories supplementing the culture medium with non- standardized agents to support the growth of embryonic stem cells (ES) or other types of stem cells, we are a long way off from establishing congruous and reproducible re- search standards. This is a critical consideration for trans- lation of these cultured cells to the clinical forum. More-

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Page 1: Technological Advances in Stem Cell Research: Developing a Consensus

STEM CELLS AND DEVELOPMENT 13:323–324 (2004)© Mary Ann Liebert, Inc.

Editorial

Technological Advances in Stem Cell Research: Developing a Consensus

323

IF I MAY USE METAPHORICAL LANGUAGE, it could be ar-gued that technological advances in stem cell research

are currently entering the Bronze Age. There remainmany controversial issues in the field of stem cell biol-ogy that Stem Cells and Development wishes to addressover the next 12 months. In the current issue of the Jour-nal, we have for the first time attempted to address thecontroversy of one of the most fundamental of problemsfacing stem cell investigators today: that is to say, togather a forum of methodological and technological in-formation that may be used to develop a consensus onthe ways by which stem cells and cellular progenitors canappropriately be cultured in the laboratory.

It is clear that many laboratories have at their disposala vast array of cellular engineering tools and tricks of thetrade. However, in the current climate of legal and ethi-cal concerns in stem cell research and regenerative ther-apy, there exists an urgent need for the establishment ofgood laboratory practice and accreditation of translationalstem cell laboratories. This is important if advances instem cell research are ever to be translated to the bed-side, and quite clearly there is a need for standardizationof the technologies and methods that stem cell investi-gators employ in their laboratories. This would not onlyserve to create a national and ideally an international stan-dardization in stem cell culture practices, but it wouldalso provide appropriate benchmarks for collaboratinguniversity medical schools to employ rigorously ap-praised consensus protocols for eventual use in the ther-apeutic targeting of intractable disease and in regenera-tive medicine.

It is perhaps beyond the scope of this current issue ofthe Journal to critically discuss and resolve the many con-troversial issues of stem cell culture practices that existin the laboratory. The objective of this issue of the Jour-nal was to collate a number of technological manuscriptsand critical reviews from national and international in-vestigators. It was intended that this would provide a plat-

form of rational discussion and publication of detailedlaboratory experience of the technologies that are avail-able to us in the context of the stem cell type under in-vestigation, and the clinical platform that would supportthe therapeutic application of those manipulated stemcells. It is hoped that this will encourage follow-up cor-respondence, discussion, and submission of technologi-cal manuscripts that will in time define the field of goodlaboratory stem cell culture practice, especially in thecontext of its therapeutic application. In the absence of aconsensus and of an attempt to define standard practicesin translational stem cell research, it will be almost im-possible to standardize across the board any therapeuticintervention that employs cultured and engineered stemcells from institute to institute. This is not a trivial un-dertaking. However, by taking a lead in tackling the con-troversial problems outlined above, Stem Cells and De-velopment is encouraging a forum of national andinternational discourse on the most appropriate ways todevelop standardization in stem cell culture and practice.

The technological reports in this special focus issue ofStem Cells and Development have brought to the fore anumber of important practical and technological chal-lenges. It is generally accepted that current cell culturetechniques are not optimal and include the widespreaduse of poorly defined supplements, such as fetal bovineserum or proprietary additives, that by their very natureare also ill-defined. Such culture supplements are poten-tially biohazardous in the context of their eventual use inclinical programs.

Despite the availability of relatively ill-defined serumreplacement supplements and the practice of individuallaboratories supplementing the culture medium with non-standardized agents to support the growth of embryonicstem cells (ES) or other types of stem cells, we are a longway off from establishing congruous and reproducible re-search standards. This is a critical consideration for trans-lation of these cultured cells to the clinical forum. More-

Page 2: Technological Advances in Stem Cell Research: Developing a Consensus

over, sustained culture of ES cells in poorly defined me-dia may elicit genetic alterations in their progeny as thecells adapt to in vitro growth conditions.

In this issue of the Journal, Draper and coworkers dis-cuss these concerns in detail. Moreover, the molecularcontrol of the differentiation of ES cells is poorly under-stood. This is complicated by the knowledge that ES cells(of both murine and human origin) may spontaneously dif-ferentiate in culture. Prevention of this undesirable behav-ior of ES cells poses a major challenge, yet it is one thatrequires urgent attention. However, Imreh and co-workersin this issue of the Journal have developed a novel systemthat can be used to detect whether alteration in cell cultureconditions may promote differentiation of stem cells andtheir progenitors. They developed a two-color system thatconsisted of RFP-transfected human foreskin fibroblasts tosupport the growth of GFP-expressing human ES cells.This important technology would permit detailed study andvisualization of the interactions between the growth pro-moting cell and the identification of the differentiating EScells in culture.

In this issue of the Journal, Ishikawa and Asahara dis-cuss an attractive alternative to animal sera or propri-etary supplements in the culture of stem cells. Autolo-gous peripheral blood was used to isolate the mononuclearcell fraction from which endothelial progenitor cells(which were identified and characterized by T. Asaharain 1997) were expanded in a culture matrix containingautologous serum. This is a very clinically relevant re-port. Endothelial progenitor cells cannot be expanded exvivo for therapeutic purposes because of the animalserum products that are used to support cell growth.However, expansion of endothelial progenitor cells inautologous serum would permit their clinical utility indisease settings such as ischemic disease, diabetic reti-nopathy, or any other disease in which the support or in-hibition of neovascularization is important.

In an important survey of the literature with specialemphasis on neural differentiation from ES cells, Du andZhang critically discuss the available methods for deriv-ing both murine and human neural lineage cells from ESprecursors, and a potentially important but novel methodis put forward for derivation of neuroectodermal cellsfrom human ES cells. As the authors point out, it is be-

coming increasingly critical to understand the biologicalclock of cell lineage development if ES cells are to beefficiently directed to any type of derivative cell.

That said, Pryzborski and colleagues report on the ap-plication of human embryonal carcinoma (EC) stem cellsthat may lend themselves to a greater understanding ofthe mechanisms of ES cell development and differentia-tion. Importantly, EC cells overcome many of the prac-tical, ethical, and moral arguments against use of ES cellsfrom certain quarters of the lay community.

By contrast, EC cells offer an alternative experimen-tal platform from which to study mammalian ES cell de-velopment in detail. In a related and highly relevant study,Gertow et al. have used a human ES cell line (calledHS181) to investigate the outcomes and differentiationof these cells in vivo following their injection intoSCID/beige mice recipients. This work is the first to showthat cells derived from the host mouse, as well as ES cellsthat were transferred into the mouse recipients, could bedistinguished and their respective contributions to ter-atoma formation identified. Of clinical relevance was theobservation that the transplanted human ES cell lineHS181 differentiated and developed into more maturecells and tissues that clearly originated from all threegerm layers.

In summary, this special focus issue of Stem Cells andDevelopment provides us with important and novel in-formation relevant to the optimization of stem cell cul-ture and cellular engineering for regenerative medicine.In addition, a number of papers have alluded to noveltechnological advances that permit rigorous investigationof the developmental pathways of embryonic and othertypes of stem cells and their derivatives.

—Marc Adrian Williams, Ph.D.Co-Editor, Stem Cells and Development

600 North Wolfe StreetDepartment of Neurology

The Johns Hopkins University School of MedicineBaltimore, MD 21287

E-mail: [email protected]

EDITORIAL

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