Adult stem cell figure retracted

Nature has retracted a figure in a highly cited study that found some adult stem cells in mouse bone marrow could form most other tissues in the body. The flawed data do not affect the main finding of the paper, according to an inquiry launched by the journal.

The authors of the 2002 study, led by Catherine Verfaillie at the University of Minnesota, issued a corrigendum of the figure, which described the cell surface phenotypes of the relatively rare multipotent adult progenitor cells (MAPCs).

The 2002 paper, which triggered international headlines, claimed that MAPCs could be an ideal source for stem cell therapy. But the results proved difficult to replicate, and scientists debated the paper after its release.

A University of Minnesota inquiry into the paper concluded earlier this year that the Nature figure was "significantly flawed," but there was no evidence that the mistakes were intentional. One outside adult stem cell researcher asked by the university to review the data believed the flawed data might weaken the conclusion of the paper somewhat, while another believed the findings were not affected.

"We're pleased that Nature did such a thorough job of evaluating the key issue," which was whether the overall findings still stood, Tim Mulcahy, vice president for research at the University of Minnesota, told The Scientist.

Data in the Nature figure was "found to be flawed in that corresponding [antibody] isotype tracings for several of the plots differ by 1 log in fluorescence intensity," the authors wrote in the corrigendum. Nature concluded that the cell surface profiles had no bearing on the ability of these multipotent cells to proliferate.

"I believe that, despite the hype over the mistake, a mistake for which I take responsibility and which I fully regret we made and should not have happened, we and the editors of Nature conclude that the final findings of the paper still [stand]," Verfaillie wrote in an Email to The Scientist.

Verfaillie was director of the University of Minnesota's stem cell center from 1999-2006. She now holds a part-time appointment at the University of Minnesota but lives in Belgium, where she runs a stem cell institute at the Catholic University of Leuven in Belgium.

Meanwhile, the New Scientist (which first raised questions about the 2002 Nature study) has now prompted the investigation of additional findings from Verfaillie and her colleagues. In March, the magazine reported that two Western blot figures within a 2001 study in Blood journal resembled each other, despite the fact that they were describing different proteins. The magazine reported that the blots were similar to a blot used to describe yet a third protein type in a patent submitted by Verfaillie and others. The patent covers the methods used to isolate and use MAPCs.

Morayma Reyes, an inventor listed on the patent, first author of the Blood study and now an assistant professor at University of Washington in Seattle, acknowledged that the paper contains mistakes. "As far as the Blood paper is concerned, although errors were made, which Dr. Verfaillie and I regret very much, we do not believe that the conclusion of the paper is affected, similar to what is true for the Nature paper," she told The Scientist in an Email. She declined to discuss details of the errors while the paper is under review.

Verfaillie did not respond to requests via phone and Email to address the New Scientist's allegations about the Blood paper.

The University of Minnesota is launching an investigation into the Blood study, Mulcahy said, declining to comment on details of the inquiry. The editor-in-chief of Blood, Sanford Shattil from the University of California, San Diego, confirmed that an investigation is underway, but also declined to comment on the details.

"The errors [in the Nature paper] are minor, but that's the sort of thing that damages the field and that's unfortunate. It takes the focus off the important issues," Darwin Prockop at Tulane University Medical School in New Orleans, La., who works with adult stem cells but has not collaborated with Verfaillie, told The Scientist.

Last week, a series of papers illustrated how to transform mouse fibroblasts into pluripotent cells, an achievement scientists have hailed as strong support for adult stem cell research.

Adult stem cell researchers are currently either planning or conducting clinical trials that inject multipotent cells into patients who have a variety of conditions, such as heart attack and stroke.

Irving Weissman, director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine in California, co-authored a 2007 study with Verfaillie, and said he believes Verfaillie is innocent of any foul play. Verfaillie "has a long record of solid, reproducible work. I can't conceive that, if there is a systematic error, she participated in it," he said.

"Nevertheless at the very least, the markers associated with the cells [in the Nature study] can't be taken as gospel," Weissman continued. In the case of Verfaillie's MAPCs, he said, "it is conceivable that [Verfaillie] found a way of tissue culture isolation of pluripotent cells that was difficult to reproduce."

The New Scientist also raised questions about flow cytometry data in a 2002 Experimental Hematology paper, also by Verfaillie's group, noting that some of the data looked the same as data printed in the now-retracted Nature figure. Experimental Hematology issued an errata in June of last year, stating that the bone marrow flow cytometry plots in the paper were also published in the Nature paper, and some of the Experimental Hematology figure also contained flaws. Again, the journal concluded that those errors did not affect the paper's conclusion, that bone marrow-derived MAPCs were similar to MAPCs derived from muscle and brain.

The Nature paper has been cited 1,290 times, and the Experimental Hematology paper 235 times. The Blood paper has been cited 405 times.

Felipe Prosper, a postdoctoral researcher in Verfaillie's lab from 2004 to 2007, said he thinks the flawed data published by Verfaillie in Nature was a mistake. "During the years I trained with her, she was a great mentor and regarding the quality of the work, I have never had any doubt about her work which is completely sound," he wrote in an Email to The Scientist.

Kelly Rae Chi
mail@the-scientist.com

Links within this article:

Jiang, Y. et al., "Pluripotency of mesenchymal stem cells derived from adult marrow," Nature, June 20, 2002.
http://www.the-scientist.com/pubmed/12077603

Catherine Verfaillie
http://www.stemcell.umn.edu/stemcell/faculty/Verfaillie/home.html

Jiang, Y. et al., "Corrigendum," Nature, June 14, 2007.
http://www.nature.com/nature

S. Pincock, "Adult stem cell report questioned," The Scientist, Feb. 26, 2007.
http://www.the-scientist.com/news/display/52892/

P. Aldhous and E. Reich, "Flawed stem cell data withdrawn," New Scientist, Feb. 15, 2007.
'http://www.newscientist.com/

P. Aldhous, "Fresh questions on stem cell findings," New Scientist, March 21, 2007.
http://www.newscientist.com/

Patent for isolation and use of MAPCs
http://patft.uspto.gov/

Darwin Prockop
http://www.som.tulane.edu/neurograd/prockhm.htm

K. Okita et al., "Generation of germline-competent induced pluripotent stem cells," Nature, June 6, 2007.
http://www.the-scientist.com/pubmed/17554338

C. T. Scott. "Trials of the heart," The Scientist, July 4, 2005.
http://www.the-scientist.com/article/display/15594/

I.Oransky, "Trial of the heart," The Scientist, October 2006.
http://www.the-scientist.com/article/display/24908

K. Chien, "Making a play at regrowing hearts," The Scientist, August 1, 2006.
http://www.the-scientist.com/article/display/24104

Irving Weissman
'http://med.stanford.edu/profiles/Irving_Weissman

M. Serafini et al., "Hematopoietic reconstitution by multipotent adult progenitor cells: precursors to long-term hematopoietic stem cells," J Exp Med, Jan. 16, 2007.
http://www.the-scientist.com/pubmed/17227908

I.Weissman and M. Clarke, "Leukemia and cancer stem cells," The Scientist, April 1, 2006.
http://www.the-scientist.com/article/display/23273/

Jiang, Y. et al., "Multipotent progenitor cells can be isolated from postnatal murine bone marrow, muscle, and brain," Exp Hematol, 2002.
http://www.the-scientist.com/pubmed/12160841