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Stem cells generated in live mice

A team of scientists in Spain has reprogrammed adult cells in live mice to revert to stem cells that appear as potent as embryonic stem cells.

The team reports its findings online this week in the journal Nature. The study is the first to achieve in living tissue what so far has only been possible in a petri dish.

Embryonic stem cells represent the "gold standard" in stem cell research and regenerative medicine, since they are the only stem cells capable of differentiating into any of the hundreds of cell types in the body.

The hope is that harnessing this ability to differentiate into any cell type will lead to treatments that can cure diseases like Alzheimer's, Parkinson's and diabetes.

However, there are ethical problems about sourcing embryonic stem cells, as well as practical difficulties, since they have a very short lifespan during the early development of the embryo.

Thus, there is a need to find alternative ways to make stem cells that are as good as embryonic stem cells.

One possibility that has been hotly pursued is to try and "reverse engineer" adult cells - that is, cells that once used to be stem cells but have fully differentiated into a particular type of cell - back to their undifferentiated, primitive state.

In 2006, a Japanese team led by Shinya Yamanaka showed it was possible, in cell culture using just four genes, to reprogram adult cells to behave almost like embryonic stem cells. They named the cells induced pluripotent stem cells (iPSCs).

Yamanaka was awarded the Nobel Prize in Medicine in 2012 in recognition of the importance of this work to regenerative medicine.

"Totipotent" stem cells generated without petri dish

In this latest study, scientists led by Dr. Manuel Serrano, a cancer researcher at the Spanish National Cancer Research Centre (CNIO), managed to generate directly in live mice what Yamanaka and colleagues achieved, but without the need to pass through the petri dish stage.

The team also found the stem cells they generated were even more like embryonic stem cells than those made using cultured cells. They say their cells' ability to differentiate is more than pluripotent, it is "totipotent," a primitive state that has never before been generated in the lab.

They say the state of undifferentiation they achieved in the totipotent stem cells is equivalent to that found in human embryos at the 72-hour stage of development, when they comprise only 16 cells.

This represents a much earlier embryonic state than that shown by iPSCs, with greater capacity for differentiation, and potentially placing the totipotent stem cells closer to the gold standard.

Regenerating tissue in place of damaged tissue
Researchers managed to manipulate cells in live mice by activating four genes, resulting in embryonic stem cells in adult tissues and organs.

The team believes the achievement brings the potential to use stem cell technology in regenerative medicine a step closer.

They managed to genetically manipulate adult cells in living mice by activating the four genes from the Yamanaka experiment and make the cells regress to an earlier evolutionary state. In effect, the cells became embryonic stem cells in multiple adult tissues and organs.

This has never been seen before in nature, says lead author María Abad.

Dr. Serrano, who is director of the Molecular Oncology Program and head of the Tumoral Suppression Laboratory at CNIO, adds:

"We can now start to think about methods for inducing regeneration locally and in a transitory manner for a particular damaged tissue."

Totipotent stem cells are more versatile

The totipotent stem cells even produced (in the chest and abdominal cavities of the mice) tissue structures that occur in the early stages of a new embryo.

These included the three types of tissue (ectoderm, mesoderm and endoderm) that develop in embryos and external structures, like the Vitelline membrane, as well as early signs of blood cells.

Serrano says this suggests their stem cells are more versatile than iPSCs produced in the lab, "whose potency generates the different layers of the embryo but never tissues that sustain the development of a new embryo, like the placenta."

He and his colleagues were also able to make the stem cells survive outside of mice, in a culture. This makes it easier to manipulate them and carry out further experiments.

While the step they have taken is a huge one and sends regenerative medicine and tissue engineering research in a new direction, the researchers say they still have far to go before their stem cells are ready for any kind of clinical use.

They now plan to find out if their new stem cells can produce different tissue types, such as that of organs like the pancreas, liver and kidney.

The Spanish Ministry of Economy & Competitiveness, the European Research Council, the Madrid regional government, and the AXA, Botín, and Ramón Areces Foundations funded the team's work.

In another paper published recently, scientists in China reported how they found a safe and easy way to make stem cells.

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