Clear up This Stem-Cell Mess Confusion About Mesenchymal Stem Cells Is Making It Easier for People to Sell Unproven Treatments, Warn Douglas Sipp, Pamela G

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Scanning electron micrograph of what is called a human mesenchymal stem cell, which some say can develop into bone, cartilage or fat cells. Clear up this stem-cell mess Confusion about mesenchymal stem cells is making it easier for people to sell unproven treatments, warn Douglas Sipp, Pamela G. Robey and Leigh Turner.

arious populations of cells in the Several studies indicate that the variety have helped MSCs to acquire a near-magical, adult human body have been of cells currently dropped into the MSC all-things-to-all-people quality in the media the subject of controversy since bucket will turn out to be various tissue- and in the public mind3 — hype that has Vthe early 2000s. Contradictory findings specific cell types, including stem cells2. been easy to exploit. MSCs have become about these haphazardly termed ‘mesen- Yet the name persists despite the evidence the go-to cell type for many unproven stem- chymal stem cells’, including their ori- pointing to this, and almost two decades cell interventions. The confusion must be gins, developmental potential, biological after questions about the validity of MSCs cleared up. functions and possible therapeutic uses, were first raised. A literature search indi- What is needed is a coordinated global have prompted biologists, clinicians and cates that, over the past 5 years, more than effort to improve understanding of the scientific societies to recommend that the 3,000 research articles referring to MSCs have biology of the cells currently termed MSCs, term be revised or abandoned. Last year, been published every year (see ‘Tenacious and a commitment from researchers, jour- even the author of the paper that first used term’). And several national regulatory nal editors and others to use more-precise the term mesenchymal stem cells (MSCs) agencies have now licensed MSC-based labels. We must develop standardized called for a name change1. drugs, although most of these approvals analyses of gene expression, including on Tissue-specific stem cells, which have a have been provisional or are based on under a cell-by-cell basis, and rigorous assays limited ability to turn into other cell types, powered studies (see ‘Doubtful drugs’). to establish the precise products of cell are the norm in most of the adult body. In our view, the wildly varying reports differentiation in various tissues. Such

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efforts could put an end to lingering of a subset of these — many hundreds over diseases and injuries, firms selectively high- questions about MSC identity and function, the past decade — suggests that the field light those articles suggesting that MSCs are once and for all. continues to be a mess. easy to harvest and can give rise to other cell According to the literature, MSCs are most types, or those indicating that the cells secrete A CONTROVERSIAL CELL often isolated from bone marrow and adipose all sorts of healing factors. (The large body of The MSC concept dates to a 1991 paper4 in tissue (fat). They have also been identified in research indicating that tissue-specific stem which US biologist Arnold Caplan described perinatal tissues — umbilical cord, Wharton’s cells have more limited roles is overlooked.) the isolation of a type of stem cell found in jelly (a gelatinous substance found in the Interestingly, some publicly traded com- bone marrow, building on reports by other umbilical cord), the amnion (the membrane panies have shown increasing reluctance groups (see, for example, ref. 5). Collec- surrounding the embryo) and the placenta to define their products as mesenchymal tively, this work showed that certain cells in — as well as in other sources, including baby stem cells. Cytori Therapeutics in San the supportive tissue of bone marrow (the teeth and menstrual blood. Some groups Diego, California, a developer of devices stroma) could differentiate into cartilage, report that MSCs are most common in fat. for harvesting and processing cells from bone and fat, and provide some of the sig- Others state that they are associated with patients, has begun to describe its target cell nals needed for haematopoietic stem cells blood vessels throughout the body’s connec- population as ‘adipose-derived regenerative (the immature precursors of all blood cells) tive tissues. Some note that MSCs are exceed- cells’ instead of calling them MSCs. to give rise to blood-cell types. ingly rare; others say they are abundant. Over the next decade, there was an Canonically, MSCs (including those from SOLUTIONS IN SCIENCE explosion in the number of tissue types in non-skeletal sources) are supposed to give rise What can be done to clear up the confusion? which MSCs were reported. And there was to cartilage, bone and fat. But reports exist of In our view, re-categorizing MSCs as a similar jump in the diversity of cell types their differentiation into muscle, endothelium ‘stromal’ or ‘signalling’ cells won’t help. that MSCs were reportedly able to differenti- and various cells of the heart, liver and kid- Some researchers are following the ISCT ate into. Yet by the early 2000s, it had become ney, as well as of the nervous and reproductive recommendations, but judging by the clear that separate labs were using different systems. Some researchers and clinical pro- thousands of papers on MSCs still being cell-surface markers to characterize MSCs. viders have even described MSCs as nearly published every year, many are not. Mean- In 2006, a working group of the International pluripotent, meaning that they can differen- while, Caplan’s proposal could introduce Society for Cellular Therapy (ISCT) acknowl- tiate into almost every cell type in the adult more problems than it solves. There is strong edged the “inconsistencies and ambiguities” body. Moreover, there are countless claims evidence for the existence of a tissue-specific and recommended a new designation: of therapeutic uses for these cells in multiple stem cell in bone-marrow stroma at least, multipotent mesenchymal stromal cells6. unrelated diseases, ranging from arthritis and albeit one with a limited ability to differen- Despite the ISCT’s recommendation, the diabetes to Parkinson’s disease and autism. tiate into other cell types. Also, the use of stem-cell designation has proved strangely ‘medicinal’ instead of ‘mesenchymal’ could durable. Assays commonly used to evaluate SALES PITCH encourage the assumption that MSCs have a cell’s ‘stemness’ are prone to misinterpre- All of the disagreement in the scientific broad therapeutic usefulness before robust tation. Many researchers have failed to take community about the nature of MSCs, and evidence for this has been obtained. into account the developmental origins of even about their existence, is almost cer- We think that answers will be found in the tissues they cite as sources of MSCs, or to tainly making it easier for businesses to sell better science. After all, many researchers observe the rigorous definition of a stem cell. treatments allegedly based on MSCs. now doubt that a single multipotent stem cell Also, the very commonness of the MSC term Direct-to-consumer marketing of (meaning one that can give rise to several seems to have consolidated its acceptance. unapproved stem-cell treatments for medi- other kinds of cell) is present throughout In the past few years, however, there cal conditions has exploded in the past five the adult body, thanks to the rigour and has been further questioning of the MSC years, particularly in the United States, Aus- persistence of some stem-cell biologists. as a valid biological entity. A 2014 study7 tralia and Japan. A 2016 report8 documented The reliable identification of tissue-spe- by researchers at the US Food and Drug 351 US companies selling putative stem-cell cific cells — stem cells or otherwise — should Administration found almost no agree- treatments direct to consumers; almost half involve omics approaches, such as those ment in the molecular characterization of refer to MSCs in their marketing materials. designed to analyse the gene-expression MSCs among the investigational new drug Businesses have been quick to capitalize patterns of a cell or its protein content, and applications submitted to the agency. A 2016 on the conflicting claims in the literature9. To rigorous assays to establish what a particu- study2 likewise found that various cell popu- convey that MSCs can treat a wide range of lar cell can differentiate into, either in vivo lations from different tissues, all classed as MSCs, actually differ drastically in their gene expression and in their ability to differenti- DOUBTFUL DRUGS ate. And last year, Caplan revealed that he no longer believes that MSCs are stem cells1. Clinical trials with MSCs fail to deliver In that article, Caplan implores the scientific community to adopt yet another A move towards translational studies According to that analysis, the studies moniker: medicinal signalling cells. (Accord- requires a robust understanding of the that scored better in terms of rigour were ing to Caplan, medicinal signalling cells, actual biological properties of the cell types more likely to report less efficacy for MSC identified on the basis of cell-surface proteins currently called mesenchymal stem cells treatments than were those judged to be and their ability to turn into other cell types (MSCs). less rigorous11. in vitro, home in on sites of injury. There they So far, both the results and the quality Clinical studies using MSCs (or any stem secrete cocktails of proteins that modulate the of MSC-based clinical trials have been cells) must adhere to the same standards immune response, reduce inflammation, pro- underwhelming. Take a 2014 meta-analysis of research design and oversight that mote wound healing and inhibit cell death.) of 49 trials using ‘bone-marrow stem cells’ apply to any responsible clinical trial Since 1991, more than 32,000 Medline- (in many cases, ‘bone-marrow MSCs’) to before the cells are administered to indexed articles referring to “mesenchymal treat cardiovascular disease, for instance. human participants. D.S., P.G.R. & L.T. stem cells” have been published. Our reading

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4,000 2017 Caplan recommends 3,739 term ‘medicinal TENACIOUS TERM signalling cells’5. Thousands of papers using the name ‘mesenchymal stem cells’ (MSCs) are published each year, despite calls for the 3,462 term to be revised or abandoned. 3,136 3,000

2014 2016 FDA† highlights the MSCs from di erent diversity of MSCs. tissues vary in their potential to give rise to other cells4. 2,062 2,000 2006 International Society for Cellular Therapy recommends name ‘multipotent mesenchymal stromal cells’. 2011 First MSC-based 1991 product is approved3. US biologist Arnold Caplan Number of papers published per year* 1,000 rst uses the term 2000 ‘mesenchymal stem cells’ Human MSCs from for a cell type derived from bone marrow reported 1 771 bone marrow . to form neurons2.

6 papers 54 0 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013 2015 2017

1. Caplan, A. I. J. Orthop. Res. 9, 641–650 (1991). 2. Woodbury, D. et al. J. Neurosci. Res. 61, 364–370 (2000). 3. Yang, H. Nature Biotechnol. 29, 857 (2011). 4. Sacchetti, B. et al. Stem Cell Rep. 6, 897–913 (2016). 5. Caplan, A. I. Stem Cells Transl. Med. 6, 1445–1451 (2017). *From PubMed search for “mesenchymal stem cells”. †US Food and Drug Administration.

or in vitro. (Historically, inconsistencies in rethink their choice of terms. Both bone Whatever the ultimate identity and surface markers and stains, or the use of marrow and fat, for example, contain stem- biological activity of the cells formerly unreliable morphological characteristics, cell populations that help to maintain these known as MSCs, the scientific principles have led to frequent errors when identifying tissues. And referring to these as skeletal or that guide their clinical development and cell types10.) adipose stem cells could help to vanquish use must be the same as those for other new Ongoing initiatives such as the Human Cell the myth of a near-ubiquitous, all-powerful therapies: precision, validation, characteri- Atlas, an effort to characterize all cells in the adult MSC2. Certainly, studies of poorly zation, objectivity and the abandonment of body, could shed light on the cellular com- characterized cellular miscellanies should terms and conceptual models that mislead ponents of specific tissues. But, ultimately, not be accepted without rigorous evidence more than they illuminate. ■ resolving the MSC identity crisis is likely to of multipotency require a focused undertaking by stem-cell and self-renewal. “In most cases, Douglas Sipp is a researcher at RIKEN and biologists — similar to a series of projects Journal editors, rigorous project professor at Keio University School conducted in the 2000s by the International editorial boards preclinical of Medicine and Global Research Institute, Stem Cell Forum to characterize pluripotent and reviewers studies of Tokyo, Japan. Pamela G. Robey is a senior stem cells. (The forum is a collaboration should similarly these cells investigator at the National Institute of designed to support stem-cell research.) be more exacting are limited or Dental and Craniofacial Research, National As part of the push for better science, when accepting or non-existent.” Institutes of Health, Department of Health regulatory agencies and editors of influen- approving MSC and Human Services, Bethesda, Maryland, tial stem-cell and general scientific journals reports for publication in journals. And USA. Leigh Turner is associate professor will need to develop and enforce rigorous funding bodies must consider whether stud- at the Centre for Bioethics, University of methodological standards. ies using MSCs qualify for funds earmarked Minnesota, Minneapolis, USA. for stem-cell research. e-mail: [email protected] DISPEL THE MSC MYTH Journalists can also play an important part 1. Caplan, A. I. Stem Cells Transl. Med. 6, Meanwhile, the community needs to stop in combating MSC misconceptions. When 1445–1451 (2017). subsuming multiple cell types under one reporters write stories about clinics selling 2. Sacchetti, B. et al. Stem Cell Rep. 6, 897–913 (2016). catch-all phrase. ‘mesenchymal stem-cell treatments’ and 3. Caulfield, T., Sipp, D., Murry, C. E., Daley, G. Q. & Scientific societies, such as the Inter other purported stem-cell therapies, they Kimmelman, J. Science 352, 776–777 (2016). national Society for Stem Cell Research should inform their audiences that scientists 4. Caplan, A. I. J. Orthop. Res. 9, 641–650 (1991). 5. Owen, M. & Friedenstein, A. J. Ciba Found. Symp. (ISSCR) and national stem-cell organiza- debate whether such cells are, in fact, stem 136, 42–60 (1988). tions, should consider whether MSC studies cells. They should also make it clear that, in 6. Dominici, M. et al. Cytotherapy 8, 315–317 (2006). ought to be presented at stem-cell confer- most cases, rigorous preclinical studies of 7. Mendicino, M., Bailey, A. M., Wonnacott, K., Puri, R. K. & Bauer, S. R. Cell Stem Cell 14, ences under the MSC umbrella. Clinical-trial these cells are limited or non-existent. 141–145 (2014). registries, such as clinicaltrials.gov, should Meanwhile, organizations such as the 8. Turner, L. & Knoepfler, P. Cell Stem Cell 19, also exercise heightened scrutiny over studies ISSCR, the ISCT and national stem-cell 154–157 (2016). 9. Sipp, D. et al. Sci. Transl. Med. 9, eaag0426 (2017). in which MSCs are described as the investi- societies should ensure that guidebooks, 10. Bianco, P., Robey, P. G. & Simmons, P. J. Cell Stem gational product. (Hundreds of such studies educational videos and other communica- Cell 2, 313–319 (2008). are already listed on international clinical- tion tools designed for people receiving ‘adult 11. Nowbar, A. N. et al. Br. Med. J. 348, g2688 (2014). research databases.) Groups studying tissue- stem-cell therapies’ are updated to reflect the L.T. declares competing non-financial interests; specific stem cells should be encouraged to demise of the MSC as a viable concept. see go.nature.com/2pjhdai for details.