Georgetown Team Discovers New Type of Stem Cell

A research group a Georgetown Lombardi Comprehensive Cancer Center has developed a new and powerful stem cell in the laboratory that grows in sheets and has many characteristics desirable for regenerative medicine.

The senior author of this paper, Richard Schlegel, M.D., Ph.D., chairman of the department of pathology at Georgetown Lombardi, a part of Georgetown University Medical Center, said of these new stem cells: “These seem to be exactly the kind of cells that we need to make regenerative medicine a reality.”

The results of his lab’s research has been published in the November 19 online early edition of the Proceedings of the National Academy of Sciences (PNAS). In this publication, they report that their new stem-like cells do not express the same genes as embryonic stem cells and induced pluripotent stem cells (iPSCs). Thus, they do not produce tumors when injected into laboratory animals. Also, these cells are stable, since they differentiate into the cell types desired by researchers.

This publication is a continuation of a study published in December 2011, when Schlegel and his colleagues invented a laboratory technique that could maintain both normal and cancer cells alive indefinitely. Previously such a technique did not exist and it was simply not possible to keep such cells alive in the laboratory indefinitely.

Schlegel and others showed that if they added two different substances to their cells in culture – fibroblast feeder cells and a chemical that inhibits the Rho kinase – they could push the cells to assume a kind of stem-like state. While in this stem cell-like state, the cells would stay alive indefinitely. Once the feeder cells and the inhibitor were withdrawn, the cells reverted back to their original state. In this paper, Schlegel and his team called these laboratory-derived cells “conditionally reprogrammed cells” or CRCs. See Liu X et al. Am J Pathol. 2012 Feb;180(2):599-607.

Could CRCs be used for personalized medicine? A follow-up study suggested that they could. Published in the New England Journal of Medicine in September 2012, they found a patient who had a 20-year history of recurrent respiratory “papillomatosis” (a type of tumor) that had invaded the lung tissue in both lungs. The tumor was difficult to treat and slow-growing, but it stubbornly resisted treatment. Schlegel and his team made CRCs from this patient’s normal and tumorous lung tissue. By utilizing this technique, they discovered that the tumor cells were infected the same virus that causes warts; the human papillomavirus. They then used these cultured tumor CRCs to determine which cancer drug would work the best. They identified a drug called vorinostat as the best candidate, and 3 months after starting treatment, the tumors stopped growing and the prognosis looked substantially better for this patient (see Yuan H, et al. N Engl J Med. 2012 Sep 27;367(13):1220-7).

Of this paper, Schlegel said, “Our first clinical application utilizing this technique represents a powerful example of individualized medicine. It will take an army of researchers and solid science to figure out if this technique will be the advance we need to usher in a new era of personalized medicine.”

The present study is study was published in PNAS compared CRCs to embryonic stem cells and iPSCs. Both embryonic stem cells and iPSCs have been investigated for use in regenerative medicine, but both cells have the drawback to potentially producing tumors when injected into mice and “it is difficult to control what kind of cells these cells differentiate into,” Schlegel says. “You may want them to be a lung cell, but they could form a skin cell instead.”

In contrast, if lung cells are treated to make lung-specific CRCs, they can be expanded in culture to make a huge quantity of lung-specific cells, but when these conditions are withdrawn, the lung-specific CRCs will revert to mature lung cells. This transformation is rather rapid, since the cells become CRCs within three days of adding the inhibitor and the feeder cells. Once the cells lose their stem-like properties and potentially can be safely implanted into tissue.

A comparison of gene expression patterns from CRCs and embryonic stem cells (ESCs) or iPSCs showed that CRCs do not overexpress the same critical genes that embryonic stem cells and iPSCs express. “Because they don’t express those genes, they don’t form tumors and they are lineage committed, unlike the other cells,” Schlegel says. “That shows us that CRCs are a different kind of stem-like cell.”

In this study, Schlegel’s team used cervical cells and made CRCs from them. However, then they placed the cervical cell-derived CRCs on a three-dimensional platform, they grew into a canal-like structure that looked startlingly like a cervix. A very similar result was seen with cells extracted from the trachea. When the trachea-derived CRCs were grown on a 3-D platform, they begin to look like a trachea.

If and when use of CRCs are perfected for the clinic, which will require considerably more work, they have the potential to be used in a wide variety of novel ways. “Perhaps they could be used more broadly for chemosensitivity, as we demonstrated in the NEJM study, for regenerative medicine to replace organ tissue that is damaged, for diabetes — we could remove remaining islet ells in the pancreas, expand them, and implant them back into the pancreas —and to treat the many storage diseases caused by lack of liver enzymes. In those cases, we can take liver cells out, expand them and insert normal genes in them, and put them back in patients,” Schlegel says.

Schlegel added: “The potential of these cells are vast, and exciting research to help define their ability is ongoing.”