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Sep 12, 2013

Stem Cells, No Petri Dish: Adult Cells Dedifferentiated in Vivo

  • Scientists have reprogrammed adult cells, generating induced pluripotent stem (iPS) cells within the tissues of mice. The scientists, from the Spanish National Cancer Research Centre (CNIO), also produced teratomas in multiple organs. Teratomas are tumors composed of multiple cell types. They are associated with cellular reprogramming, and their emergence in the study implies that full reprogramming can occur in vivo.

    Embryonic stem cells are the main focus for the future of regenerative medicine. They are the only ones capable of generating any cell type from the hundreds of cell types that make up an adult organism, so they are the first step toward curing illnesses such as Alzheimer’s Disease, Parkinson’s disease, or diabetes. Nevertheless, this type of cell has a very short lifespan, limited to the first days of embryonic development, and they do not exist in any part of an adult organism.

    Adult cells were reprogrammed in a biomedical breakthrough in 2006, when Shinya Yamanaka managed to create iPS cells via a cocktail of just four genes. Yamanaka’s discovery, for which he was awarded the Nobel Prize in Medicine in 2012, opened a new horizon in regenerative medicine. CNIO researchers have taken another step forward, by achieving the same feat as Yamanaka, but this time within the same organism, in mice, without the need to pass through in vitro culture dishes. Generating these cells within an organism brings this technology even closer to regenerative medicine.

    The research team, led by Manuel Serrano, Ph.D., the director of the CNIO’s molecular oncology program and head of the tumoral suppression laboratory, published their results yesterday in Nature. The authors of the paper said, “We demonstrate that the four factors Oct4, Sox2, Klf4, and c-Myc can induce dedifferentiation and pluripotency in a variety of cell types in vivo, including cells from the haematopoietic lineage, as well as epithelial cells from the stomach, intestine, pancreas, and kidney.”

    The first challenge for CNIO researchers was to reproduce the Yamanaka experiment in a living being. They chose a mouse as a model organism. Using genetic manipulation techniques, researchers created mice in which Yamanaka’s four genes could be activated at will. When these genes were activated, they observed that the adult cells were able to retreat in their evolutionary development to become embryonic stem cells.

    María Abad, Ph.D., the lead author of the article and a researcher in Serrano’s group, said: “This change of direction in development has never been observed in nature. We have demonstrated that we can also obtain embryonic stem cells in adult organisms and not only in the laboratory.”

    The researchers have also discovered that these embryonic stem cells, obtained directly from the inside of the organism, have a broader capacity for differentiation than those obtained via in vitro culture. Specifically, they have the characteristics of totipotent cells, a primitive state never before obtained in a laboratory.

    The authors were even able to induce the formation of pseudo-embryonic structures in the thoracic and abdominal cavities of the mice. They noted that “in vivo iPS cells have an unprecedented capacity to form embryo-like structures, including the three germ layers of the proper embryo and extraembryonic tissues, such as extraembryonic ectoderm and yolk sac like tissue with associated embryonic erythropoiesis. Together, we conclude that in vivo iPS cells represent a more primitive or plastic state than [embryonic stem] cells. Future work will explore the full capabilities of in vivo iPS cells.”

    The authors emphasize that the possible therapeutic applications of their work are still distant, but they venture that it might mean a change of direction for stem cell research, for regenerative medicine, or for tissue engineering.

    “Our stem cells also survive outside of mice, in a culture, so we can also manipulate them in a laboratory,” said Abad. “The next step is studying if these new stem cells are capable of efficiently generating different tissues such as that of the pancreas, liver, or kidney.”



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