Research Fronts: Stem-Cell Research Slowly Segues into Regenerative Medicine

October 2012
REUTERS/Gareth Watkins

The hoped-for success of the comparatively new discipline of regenerative medicine (“new” in that, for example, the journal Regenerative Medicine began in January, 2006) is based in large part on progress in stem-cell research. The qualifier “in large part” is to emphasize that the subject is multidisciplinary, the need for bioengineering skills being one example.

In a way, the two terms are becoming indistinguishable. Last month the Wellcome Trust and U.K. Medical Research Council announced the setting up of a $12 million Stem Cell Institute, planned to occupy some 8,000 square meters of new laboratory space in Cambridge, to provide an “invigorating environment for cross-fertilisation between fundamental and translational researchers [to] drive stem cell research towards clinical applications,” while in the U.S. the same mission can be found for the National Institutes of Health Center for Regenerative Medicine, providing “the infrastructure to support and accelerate the clinical translation of stem cell-based technologies.”

The relative status of the two activities at present is nicely shown by papers indexed under the respective terms in Thomson Reuters Web of Science in the last decade. Since 2002, Thomson Reuters has indexed more than 190,000 papers containing “stem cell” among the title, abstract, or keywords. The phrase “regenerative medicine,” meanwhile, occurs in only about 5,700 reports during the same period.

Imbalance in Research Fronts

Another measure can be found in the current population of “Research Fronts” in Essential Science Indicators. These Research Fronts represent discrete areas of related research identified through citation analysis—specifically, analysis of papers that are frequently cited together, or “co-cited.” Each Front consists of a “core” of co-cited foundational papers along with the subsequent reports that have cited the core.

As of the late summer of 2012, the number of Research Fronts devoted to stem cells exceeds 120, while only four Fronts expressly specify “regenerative medicine.”

Clinicians and patients will be hoping to see these ratios turning round.
For a sense of the emergent face of regenerative medicine, ScienceWatch has compiled the accompanying table (below), which collects the four pertinent Research Fronts and lists their respective core papers.

“Stem cell” is an umbrella term, encompassing embryonic and cord-blood-derived cells and adult cells derived from bone marrow, adipose tissue and blood, for example, and they are variously classed as totipotent, multipotent, pluripotent and even unipotent, depending on how many of the body’s 200 or so cell types they have the potential to produce.

Four Research Fronts Expressly Addressing Regenerative Medicine
Research Front Title
Adipose tissue-derived stromal cells; Adipose-derived stem cells; Novel cell-based therapies; Regenerative medicine
Core Papers Citations
1 J.M. Gimble, et al., “Adipose-derived stem cells for regenerative medicine,” Circ. Res., 100(9): 1249-60, 2007. 288
2 A. Schaffler, C. Buchler, “Concise review: Adipose tissue-derived stromal cells – Basic and clinical implications for novel therapies,” Stem Cells, 25(4): 818-27, 2007. 227
Research Front Title
Tissue engineering applications; Natural-origin biodegradable systems; Natural-origin polymers; Regenerative medicine
Core Papers Citations
1 P.B. Malafaya, G.A. Silva, R.L. Reis, “Natural-origin polymers and scaffolds for biomolecules and cell delivery in tissue engineering applications,” Advan. Drug. Delivery Rev., 59(4-5): 207-33, 2007. 142
2 J.F. Mano, et al., Natural origin biodegradable systems in tissue engineering and regenerative medicine: Present status and some moving trends,” J. R. Soc. Interface, 4(17): 999-1030, 2007. 137
Research Front Title
Mesenchymal stem cells; Residing stem cells; Human immature permanent teeth; Dental tissues; Regenerative medicine
Core Papers Citations
1 G.T.J. Huang, S. Gronthos, S. Shi, “Mesenchymal stem cells derived from dental tissues vs. those from other sources: Their biology and role in regenerative medicine,” J. Dent. Res., 88(9): 792-806, 2009. 100
2 W. Sonoyama, et al., “Characterization of the apical papilla and its residing stem cells from human immature permanent teeth: A pilot study,” J. Endodont., 34(2): 166-71, 2008. 85
Research Front Title
Superparamagnetic iron oxide nanoparticles (SPIONS); Multifunctional nanoparticles; Magnetic fluid hyperthermia; Clinical regenerative medicine
Core Papers Citations
1 M. Mahmoudi, et al., “Magnetic resonance imaging tracking of stem cells in vivo using iron oxide nanoparticles as a tool for the advancement of clinical regenerative medicine,” Chem. Rev., 111(2): 253-80, 2011. 35
2 Y.D. Jin, et al., “Multifunctional nanoparticles as coupled contrast agents,” Nat. Commun., 1: art. no.-41, 2010. 35
3 M. Mahmoudi, et al., “Superparamagnetic iron oxide nanoparticles (SPIONS): Development, surface modification and applications in chemotherapy,” Advan. Drug Delivery Rev., 63(1-2): 24-46, 2011. 26
4 S. Laurent, et al., “Magnetic fluid hyperthermia: Focus on superparamagnetic iron oxide nanoparticles,” Advan. Colloid. Interface Sci., 166(1-2): 8-23, 2011 15
5 M. Mahmoudi, et al., “Effect of nanoparticles on the cell life cycle,” Chem. Rev., 111(5): 3407-32, 2011. 15
SOURCE: Thomson Reuters Web of Science

Suited to Clinical Medicine

In previous years, when ScienceWatch covered highly cited papers systematically six times a year, articles on stem cells published in Science, Nature and Cell did appear from time to time among the Hot Papers in Clinical Medicine, but they then seemed more suited to Biology. No longer. Of course, making use of stem cells to treat patients is not new, as this approach is well established for certain hematopoietic disorders. However, it is still very early days for the many other applications now being talked of — so much so that one commentary earlier this year concluded that “the transplantation of stem cells from bone marrow, umbilical cord blood, or peripheral blood for treatment of haemopoietic diseases is probably the only safe and controlled stem cell based therapy in use today” (D. Ilic, J. Polak, Lancet, 379[9819]: 877-78, 2012).

Since 2002, Thomson Reuters has indexed more than 190,000 papers containing “stem cell” among the title, abstract, or keywords. The phrase “regenerative medicine,” meanwhile, occurs in only about 5,700 reports during the same period.

Others might include burns and corneal conditions, but desperate patients trawling the internet for relief can be forgiven for thinking that stem-cell therapy has arrived for a swathe of diseases. There is a lot at stake. Progress has been impeded by legal and ethical controversies (most notably in the United States, where challenges to government funding of research using embryonic stem cells and to the status of peripheral blood cells obtained by apheresis under the National Organ Transplant Act now seem close to resolution), by safety issues, by more technical questions such as the yields of induced pluripotent cells — and, not least, by exaggerated claims. Four years ago the International Society for Stem Cell Research was already so concerned about the exploitation of patients’ hopes that it issued guidelines (I. Hyun, et al., Cell Stem Cell,3[6]: 607-09, 2008) and its website provides hints about how to spot possibly unreliable providers of stem cell treatments.

Of the scores of Research Fronts on stem cells, the largest in terms of core papers (48) and total citations to the core literature (almost 23,000) is the one covering the induction of pluripotent stem cells, reflecting the excitement generated by papers in Cell and other journals six years ago, in work that ultimately resulted in the recent Nobel Prize for Shinya Yamanaka and Sir John Gurdon  (e.g., K. Takahashi, S. Yamanaka, Cell, 126[4]: 663-76, 2006). But the caution currently being urged by several commentators is supported by the specific titles for these Fronts (reflective of the constituent papers themselves), which weigh much more toward important and promising laboratory findings rather than persuasive clinical evidence. For the moment, fascinating single cases constituting “proof of principle” outnumber randomized trials.

Mr. David W. Sharp, M.A. (Cambridge), formerly deputy editor of The Lancet, is a freelance writer in Minchinhampton, U.K.

The data and citation records included in this report are from Thomson Reuters Web of ScienceTM. Web of ScienceTM is a registered trademark of Thomson Reuters. All rights reserved.