In 2017, scientific journals published more than 3,500 papers using the words “mesenchymal stem cells,” according to an op-ed that appears in Nature today (September 26). The term initially described cells from bone marrow, but its usage has expanded to encompass many types of cells from diverse tissues with varying levels of multipotency. The problem is what a mesenchymal stem cell (MSCs) is isn’t always clearly defined, which has led to confusion in the scientific community, as well as public misunderstandings exploited by businesses marketing questionable cell-based treatments, the authors argue.
“The name mesenchymal stem cells should not be used for anything. It’s just a completely bogus name,” commentary coauthor Pamela Robey, a stem cell biologist at the National Institute of Dental and Craniofacial Research in Bethesda, Maryland, tells The Scientist. “There are tissue-specific stem progenitor cells, which are wonderful things [and] get tossed into the MSC bucket, but using that term implies that they’re identical . . . and they just really are not.”
Robey and two coauthors call on scientists to stop using this term, as they say it perpetuates confusion in the scientific community and allows companies marketing unproven stem-cell therapies to take advantage of consumers.
As Robey and colleagues recount in their commentary, Arnold Caplan, a biologist at Case Western Reserve University, popularized the term MSC in 1991 to describe cells isolated from bone marrow stroma that could give rise to bone and cartilage. Since then, they write, researchers have reportedly isolated mesenchymal stem cells from many other tissues and differentiated them to kidney, liver, heart, and nerve cells in vitro.
By the late 1990s, researchers were using the term MSC to describe any manner of cells isolated from the stromal compartments of bone, fat, and other tissues able to stick to plastic culture dishes and differentiate into other cell types in vitro. But scientists had trouble getting the cells to differentiate in vivo, raising questions about their therapeutic capacity.
In 2006, a working group at the meeting of the International Society for Cellular Therapy released a position statement proposing that the scientific community use the phrase multipotent mesenchymal stromal cell instead of mesenchymal stem cell, unless the cells were specifically capable of self renewal and differentiating into specific cell types in vivo, then the accepted criteria for defining stem cells. The advice didn’t stick.
Robey and colleagues found in a literature search that, despite the 2006 recommendation, the number of studies using the name mesenchymal stem cells rose from 771 in 2006 to 3,739 in 2017. Plus, a 2014 study released by the US Food and Drug Administration revealed that, while many mesenchymal stem cell–based products had been submitted to the agency for regulatory approval, these applications rarely agreed about what an MSC is, in terms of both shared molecular markers and tissue of origin.
The commentary authors also point to problems with marketing scientifically unsupported MSC-based therapies directly to consumers. They highlight a 2016 study, coauthored by University of Minnesota bioethicist Leigh Turner, who also cowrote the current commentary, showing that 351 companies offer stem-cell treatments at 570 clinics across the United States. And nearly half of the marketing materials of those businesses mention MSCs.
“One of the things that makes this industry so successful and makes its arguments so compelling to patients is that they’ve been very good at couching their marketing in this science-y language that is probably convincing to people who are not intimately familiar with the field,” explains commentary coauthor Douglas Sipp of the RIKEN research institute in Japan. “The problem is that it’s now begun to pollute the literature. If you decide to search for . . . what mesenchymal stem cells are capable of, you can find a paper that’s been published and is searchable using Medline to superficially back up your claims.”
Robey, Turner, and Sipp recommend that stem cell societies and individual scientists reassess their use of the term. They also say that funders and journal editors should consider whether or not publishing or financing studies that use MSCs is appropriate.
“I agree with many of the [authors’] sentiments,” says Christine Mummery, a stem cell biologist at Leiden University in the Netherlands who was not involved in the commentary. “People really want to believe [cell therapy] will work, and there’s a lot of money to be made in it,” she adds.
Mummery says that gaining a better understanding of the cells that have been called MSCs, perhaps with single-cell sequencing to probe the identity of all the cells in an organ or tissue, could help address the confusion. “The [cells] shouldn’t be called MSCs because they’re not stem cells. The difficult question is really to sort out what’s really true and not true about these cells,” she explains.
“The solution is in science,” agrees Massimo Dominici, a stem cell biologist at the University of Modena and Reggio Emilia in Italy who coauthored the 2006 call for an MSC name change. “The majority of the scientists dealing with these cell types are aware of the limitations,” he says, adding that, while it couldn’t hurt to more clearly define the cells, it would not be appropriate for funding bodies to cut resources for MSC-related projects. “Good research would clear up [our understanding of] the stemness and the stromal capacity of the cells,” he explains.
Indeed, the cells known as MSCs may have some utility in the clinic. “One of the things they do seem to do is stabilize blood vessels, and that could be a mechanism [by] which they have a bona fide effect on regenerative medicine. I don’t think that’s been really decided for sure,” says Mummery. The cells’ capacity to modulate the immune system is also open for discussion. “There’s been very little done about actually measuring immune cells in the blood system after these cells have been infused, but of the few studies that have been done, there seem to be some effects,” she adds.
Robey tells The Scientist that the bottom line is that using the term is “scientifically unsound” and doesn’t reflect the development or function of these cells. While genomics and transcriptomics could help clarify the role of these cells, “what is really important is demonstrating their functionality in rigorous assays,” she says.
D. Sipp et al., “Clear up this stem cell mess,” Nature, doi:10.1038/d41586-018-06756-9, 2018.