Setback for New Stem Cell Treatment
In an unexpected setback to efforts to harness a promising new type of stem cell to treat diseases, researchers reported on 5/13/11; that tissues made from those stem cells might be rejected by a patient’s immune system — even though the tissues would be derived from that very same patient.
The research involved so-called induced pluripotent stem cells, or iPS cells, which can be made from skin cells and which appear to have the characteristics of embryonic stem cells. That means they can theoretically be turned into nerve, heart, liver or other types of cells and transplanted to repair damaged organs.
The initial creation of human iPS cells in 2007 electrified scientists because the cells seemed to have two big advantages over embryonic stem cells. They were not controversial, because their creation did not entail the destruction of human embryos. And since the stem cells could be made from a particular patient’s skin cells, they could be used to make tissues that presumably would not be rejected by that patient’s immune system.
But that latter assumption was never really tested, until now. When Yang Xu, a biologist at the University of California, San Diego, and colleagues did so, they found that iPS cells made from mouse skin cells were nonetheless rejected by genetically identical mice.
Other scientists said the results, published online on Friday in the journal Nature, were surprising.
- “The path to the clinic has just gotten a lot murkier,” said Dr. Robert Lanza, chief scientific officer of Advanced Cell Technology, a company trying to develop medical treatments using both embryonic stem cells and induced pluripotent stem cells. He said it was not clear that the results in mice would hold true for humans, though some other scientists said they assumed they would. “This reopens the whole need for S.C.N.T, which will be controversial,” said Dr. Lanza referring to somatic cell nuclear transfer, the scientific term for cloning. “We had thought we had put that aside with this technology.”
The new report is just the latest to take some of the shine off iPS cells. In recent months other researchers have reported that the cells are prone to various types of genetic abnormalities.
- “As with any new technology, there is always this initial phase of infatuation, and then the reality sets in,” said Dr. George Q. Daley, director of the stem cell transplantation program at Children’s Hospital Boston. “I think it goes to the heart of the issue of how ignorant we really are in understanding these cells.” Dr. Daley said the finding about the immune reactions “happened to be a particularly startling result that I wasn’t anticipating;” Still, he added, years of work lie ahead before iPS cells would be ready to use in treating people, so it is too early to be discouraged. Many scientists say iPS cells for now will be used to create cells — like brain cells from someone with Alzheimer’s disease — that can be used to study diseases in the laboratory;
- Dr. Rudolf Jaenisch, a professor of biology at the Massachusetts Institute of Technology and a founding member of the Whitehead Institute, said that in practice, iPS cells themselves would not be implanted into people. Rather, the stem cells would first be turned into specific types of cells, like brain cells or heart cells. He said it was unclear whether such differentiated cells would elicit the same immune response as the stem cells did in the mice;
- Jeanne F. Loring, director of the center for regenerative medicine at the Scripps Research Institute, said the new findings would not preclude use of the iPS cells for therapy because immune-suppressing drugs could always be used. But the potential problem with iPS cells might make some scientists take another look at making patient-specific tissues by creating an embryo from a patient’s cell through so-called therapeutic cloning. That approach, which is not known to have been accomplished using human cells, is controversial because the same technique might also be used to create a baby. (HWM and A Pollack, NYT)
Nature Extract: Immunogenicity of induced pluripotent stem cells
Induced pluripotent stem cells (iPSCs), reprogrammed from somatic cells with defined factors, hold great promise for regenerative medicine as the renewable source of autologous cells. Whereas it has been generally assumed that these autologous cells should be immune-tolerated by the recipient from whom the iPSCs are derived, their immunogenicity has not been vigorously examined. We show here that, whereas embryonic stem cells (ESCs) derived from inbred C57BL/6 (B6) mice can efficiently form teratomas in B6 mice without any evident immune rejection, the allogeneic ESCs from 129/SvJ mice fail to form teratomas in B6 mice due to rapid rejection by recipients. B6 mouse embryonic fibroblasts (MEFs) were reprogrammed into iPSCs by either retroviral approach (ViPSCs) or a novel episomal approach (EiPSCs) that causes no genomic integration. In contrast to B6 ESCs, teratomas formed by B6 ViPSCs were mostly immune-rejected by B6 recipients. In addition, the majority of teratomas formed by B6 EiPSCs were immunogenic in B6 mice with T cell infiltration, and apparent tissue damage and regression were observed in a small fraction of teratomas. Global gene expression analysis of teratomas formed by B6 ESCs and EiPSCs revealed a number of genes frequently overexpressed in teratomas derived from EiPSCs, and several such gene products were shown to contribute directly to the immunogenicity of the B6 EiPSC-derived cells in B6 mice. These findings indicate that, in contrast to derivatives of ESCs, abnormal gene expression in some cells differentiated from iPSCs can induce T-cell-dependent immune response in syngeneic recipients. Therefore, the immunogenicity of therapeutically valuable cells derived from patient-specific iPSCs should be evaluated before any clinic application of these autologous cells into the patients.
The Bottom Line: Dr. Xu, whose research was paid for by the National Institutes of Health and by California’s stem cell program, created both embryonic stem cells and iPS cells from an inbred strain of mice and implanted those stem cells into other mice of the same strain. The mice did not have an immune response to the implanted embryonic stem cells. But their immune systems attacked the implanted iPS cells. Further experiments suggested that the reaction was caused by the abnormal activation of certain genes in the iPS cells, resulting in the production of proteins that seemed foreign to the immune systems of the mice. The degree of immune response depended on how the iPS cells were made. The strongest response was to cells made by incorporating genes for certain growth factors into the DNA of the skin cells. Cells made that way are not likely to be used for medical treatments anyway because at least one of the inserted genes can cause cancer. But Dr. Xu also found an immune response, though not as strong, when the iPS cells were made in a way that did not involve the permanent incorporation of the genes into the cell’s genome.