Public release date: 24-Jul-2013 [ | E-mail | Share ]

Contact: Mary Beth O'Leary moleary@cell.com 617-397-2802 Cell Press

Scientists have reported that very small embryonic-like stem cells (VSELs), which can be isolated from blood or bone marrow rather than embryos, could represent an alternative to mouse and human embryonic stem cells for research and medicine. But their very existence is hotly debated, and a study appearing online on July 24th in the ISSCR's journal Stem Cell Reports, published by Cell Press, provides strong evidence against the existence of VSELs capable of turning into different cell types. The findings call into question current plans to launch a clinical trial aimed at testing whether VSELs can be used for regenerative medicine in humans.

"To know when a stem cell discovery is true, it must meet several criteria," says senior study author Irving Weissman of Stanford University School of Medicine. "First, the work must be published in a peer-reviewed journal; second, other labs in the field should be able to repeat the findings; third, the phenomenon should be so robust that other experimental methods must reveal it; and fourth, in the stem cell field, the regeneration that occurs must be rapid, robust, and lifelong. In our study, we did not find evidence supporting the second, third, and fourth requirements."

In 2006, a group of researchers first reported the presence of VSELs in mice. Subsequent studies have provided evidence that these cells also exist in human blood and bone marrow and could turn into specialized cells such as lung cells, a finding which may be useful for replacing damaged tissue. But other labs have failed to replicate these findings. Nonetheless, a biopharmaceutical company called Neostem, which acquired the exclusive license to VSEL technology, plans to apply for Food and Drug Administration approval to carry out a first-in-man trial to test whether VSELs can regenerate bone.

In light of these conflicting results, Weissman and his team made the most rigorous effort yet to replicate the original VSEL findings. Although they used a variety of protocols, they failed to find VSELs derived from mouse bone marrow that could turn into specialized blood cells. Instead, the "VSELs" appeared to be artifacts such as cell debris and fragments from dying cells. "Our findings clearly refute the basis in mouse studies that VSELs have the potentials claimed, and therefore call into question claims that these cells have potential for clinical application in humans," Weissman says.

Another article that will be published on the same day in the journal Cell Stem Cell reviews the controversy surrounding VSELs and includes wide-ranging commentary from experts in the field.

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Stem Cell Reports, Miyanishi et al.: "Do pluripotent stem cells exist in adult mice as very small embryonic stem cells?."

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New study refutes existence and clinical potential of very small embryonic-like stem cells

Mariusz Ratajczak first reported finding very small embryonic-like stem cells in 2006.

University of Louisville Health Sciences Center

Does a rare and minuscule cell type with the potential to repair almost any tissue in the body really exist?

Proponents of very small embryonic-like cells (VSELs) extracted from bone marrow say that the cells have the potential to transform regenerative medicine. A trial has begun in Poland, and cell-therapy company Neostem in New York is planning another in Michigan.

But in a major blow to the field, a paper published on 24 July in Stem Cell Reports suggests that the diminutive stem cells are not real1. Led by Irving Weissman, a prominent stem-cell researcher at Stanford University in California, the study is the fourth to refute the cells existence and the most thorough yet.

Weissmans evidence is a clincher it is the end of the road for VSELs, believes Rdiger Alt, head of research at Vita 34, a private bank for umbilical cord blood in Leipzig, Germany, who last year published the first failure to replicate claims for the cells2.

Robin Smith, chief executive at Neostem, disagrees. She compares the attacks on VSELs to those suffered by Charles Darwin and Nicolaus Copernicus when they proposed their world-changing scientific theories.

The battle over VSELs has been raging for more than two years, and has covered ground from the United States to Vatican City and Poland. The cells were first described3 in mouse bone marrow in 2006, by a team led by Mariusz Ratajczak at the University of Louisville in Kentucky. His group and a few others have since generated a literature that characterizes VSELs as rare components of bone marrow and other tissues, less than 6micrometres in diameter and able to turn into a diverse range of cell types, including blood, bone, muscle and nerve.

Ratajczak was given a joint position at the Pomeranian Medical University in Szczecin, Poland, in 2006. From there, he obtained 10.6million (US$14 million) from European Union sources for a VSEL research network involving five institutions. The network last year registered the first human trial of a VSEL preparation, which aims to treat 60 people who have severe angina. Around one-quarter of the participants have already been injected with the preparation.

But the network became rattled after one collaborator, Jzef Dulak at the Jagiellonian University in Krakow, failed to find traces of VSELs in his experiments. When he published his findings in May4, Ratajczak tried to force him out of the consortium. Dulak, like Weissman, found no molecular signatures associated with pluripotency in any mouse bone-marrow cells smaller than 7micrometres across. Weissmans more extensive analysis now also reports that in his experiments, the small cells did not aggregate into spheres in vitro, as pluripotent cells do; nor could they differentiate into blood cells, the adult tissues that such cells are most likely to become.

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Doubt cast over tiny stem cells

A US company that promoted its stem cell discovery in partnership with the Vatican has come under fresh scrutiny by independent scientists who said Wednesday the cells do not exist.

Scientists at Stanford University said in the journal Stem Cell Reports they could not replicate NeoStem's findings of very small embryonic-like cells (VSELs) in the bone marrow of lab mice.

These cells have been touted by the New York-based company as an ethical alternative to stem cells requiring the destruction of human embryos, with the same regenerative ability to transform into other cell types in the body.

Earlier this year, NeoStem announced plans to launch the first human trials of the cells for bone growth.

"We tried as hard as we could to replicate the original published results using the methods described and were unable to detect these cells in either the bone marrow or the blood of laboratory mice," said lead author Irving Weissman, who directs Stanford's Institute for Stem Cell Biology and Regenerative Medicine.

Weissman's study is the first to evaluate the biological potency of the cells, and it found they could not transform into blood cells and contained very little DNA.

Instead, researchers found that what purported to be VSELs -- about five micrometers in diameter -- were either debris or dead cells.

"A true pluripotent cell would be able to differentiate into any tissue type," said Weissman. "But we couldn't confirm that cells of that size or phenotype could generate hematopoietic cells with any reliability."

In response, NeoStem chairman and CEO Robin Smith said the company has studies in progress that will "confirm whether or not VSEL(s) have characteristics of a pluripotent stem cell."

"We acknowledge that there is controversy in the VSEL field but this is not unusual for most new scientific discoveries and theories (Darwin and evolution, Copernicus and earth orbiting the sun as examples)," Smith said in a statement emailed to AFP.

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'Embryonic-like' stem cells can't be found: US study