New Stem Cell Finding Bodes Well for Future Medical Use in Humans
New bone formation (stained bright green under ultra-violet light) was seen in monkeys given their own reprogrammed stem cells. Credit: Nature magazine
Stem cells are undifferentiated biological cells that can differentiate into specialized cells and can divide (through mitosis) to produce more stem cells. They are found in multicellular organisms. In mammals, there are two broad types of stem cells: embryonic stem cells, which are isolated from the inner cell mass of blastocysts, and adult stem cells, which are found in various tissues. In adult organisms, stem cells and progenitor cells act as a repair system for the 1) ___, replenishing adult tissues. In a developing embryo, stem cells can differentiate into all the specialized cells – ectoderm, endoderm and mesoderm but also maintain the normal turnover of regenerative organs, such as blood, skin, or intestinal tissues.
There are three known accessible sources of autologous adult stem cells in humans: bone marrow, lipid cells and 2) ___. Stem cells can also be taken from umbilical cord blood just after birth. Of all stem cell types, autologous harvesting involves the least risk. By definition, autologous cells are obtained from one’s own body, just as one may bank his or her own blood for elective surgical procedures.
Adult stem cells are frequently used in medical therapies, for example in bone 3) ___ transplantation. Stem cells can now be artificially grown and transformed (differentiated) into specialized cell types with characteristics consistent with cells of various tissues such as muscles or nerves. Embryonic cell lines and autologous embryonic stem cells generated through Somatic-cell nuclear transfer or dedifferentiation have also been proposed as promising candidates for future therapies. Induced pluripotent stem cells (also known as iPS cells or iPSCs) are a type of pluripotent stem cell that can be generated directly from adult cells. The iPSC technology was pioneered by Shinya Yamanaka’s lab in Kyoto, Japan, who showed in 2006 that the introduction of four specific genes could convert adult cells into pluripotent stem cells. He was awarded the 2012 Nobel Prize along with Sir John Gurdon for the discovery that mature cells can be reprogrammed to become pluripotent.
Pluripotent stem cells hold great promise in the field of 4) ___ medicine. Because they can propagate indefinitely, as well as give rise to every other cell type in the body (such as neurons, heart, pancreatic, and liver cells), they represent a single source of cells that could be used to replace those lost to damage or disease. The most well-known type of pluripotent stem cell is the embryonic stem cell. However, since the generation of embryonic stem cells involves destruction (or at least manipulation) of the pre-implantation stage embryo, there has been much controversy surrounding their use. Further, because embryonic stem cells can only be derived from embryos, it has so far not been feasible to create patient-matched embryonic stem cell lines. Since iPSCs can be derived directly from adult tissues, they not only bypass the need for 5) ___, but can be made in a patient-matched manner, which means that each individual could have their own pluripotent stem cell line. These unlimited supplies of autologous cells could be used to generate transplants without the risk of immune rejection. While the iPSC technology has not yet advanced to a stage where therapeutic transplants have been deemed safe, iPSCs are readily being used in personalized drug discovery efforts and understanding the patient-specific basis of disease. Depending on the methods used, reprogramming of adult cells to obtain iPSCs may pose significant risks that could limit their use in humans. For example, if viruses are used to genomically alter the cells, the expression of cancer-causing genes oncogenes may potentially be triggered.
In February 2008, scientists announced the discovery of a technique that could remove oncogenes after the induction of pluripotency, thereby increasing the potential use of iPS cells in human diseases. In April 2009, it was demonstrated that generation of iPS cells is possible without any genetic alteration of the adult cell: a repeated treatment of the cells with certain proteins channeled into the cells via poly-arginine anchors was sufficient to induce pluripotency. The acronym given for those iPSCs is piPSCs (protein-induced pluripotent stem cells).
A major concern over using stem cells is the risk of tumors: but now a new study shows that It takes a lot of effort to get induced pluripotent stem (iPS) cells to grow into 6) ___ after they have been transplanted into a monkey. The findings will bolster the prospects of one day using such cells clinically in humans. Making iPS cells from an animal’s own skin cells and then transplanting them back into the creature also does not trigger an inflammatory response as long as the cells have first been coaxed to 7) ___ towards a more specialized cell type. Both observations, published in May 2014, Cell Reports, bode well for potential cell therapies.
It’s important because the field is very controversial right now, says Ashleigh Boyd, a stem-cell researcher at University College London, who was not involved in the work. It is showing that the weight of evidence is pointing towards the fact that the cells won’t be rejected.
Pluripotent 8) ___ cells, can be differentiated into many different specialized cell types in culture – and so are touted for their potential as therapies to replace tissue lost in diseases such as Parkinson’s and some forms of diabetes and blindness. iPS cells, which are made by reprogramming adult cells, have an extra advantage because transplants made from them could be genetically matched to the recipient. Researchers all over the world are pursuing therapies based on iPS cells, and a group in Japan began enrolling patients for a human study last year. But work in mice has suggested controversially that even genetically matched iPS cells can trigger an immune 9) ____, and pluripotent stem cells can also form slow-growing tumors, another safety concern. Cynthia Dunbar, a stem-cell biologist at the National Institutes of Health in Bethesda, Maryland, who led the new study, decided to evaluate both concerns in healthy rhesus macaques. Human stem cells are normally only studied for their ability to form tumors in mice – as a test of pluripotency – if the animals’ immune systems are compromised, she says. We really wanted to set up a model that was closer to 10) ___. It was somewhat reassuring that in a normal monkey with a normal immune system you had to give a whole lot of immature cells to get any kind of tumor to grow, and they were very slow growing. Dunbar and her team made iPS cells from skin and white blood cells from two rhesus macaques, and transplanted the iPS cells back into the monkeys that provided them. It took 20 times as many iPS cells to form a tumor in a monkey, compared with the numbers needed in an immunocompromised mouse. Such information will be valuable for assessing safety risks of potential therapies, Dunbar says. And although the iPS cells did trigger a mild immune response – attracting white blood 11) ___ and causing local inflammation – iPS cells that had first been differentiated to a more mature state did not. Although this was the first study to look at undifferentiated iPS cells transplanted back into the 12) ___ they came from, it is not the first primate study to monitor how cells differentiated from iPS cells fare when transplanted. Scientists at Kyoto University in Japan found that monkey iPS cells that had been differentiated into dopaminergic neurons (the type of neuron that dies in Parkinson’s disease) and transplanted into the brain survived for months without forming tumors. Researchers at RIKEN in Kobe, Japan, got similar results when transplanting iPS cells first coaxed into forming retinal pigment epithelial cells, cells that support the photoreceptors at the back of the 13) ___. Neither study observed tumors forming, and both found that transplants are not rejected when animals receive their own cells. However, both of the sites involved normally have a fairly weak capacity to trigger immune responses.
Dunbar, by contrast, differentiated iPS cells into bone precursor cells and placed them into small scaffolds just under the skin, a location with a robust immune 14) ___. The transplants did not cause irritation or inflammation, probably because the differentiated cells do not express embryonic proteins absent in mature tissues. By eight weeks, new bone had formed. Almost a year later no tumors had formed, and bone formation persisted.
More work is needed because evidence from other studies suggests that the bone precursor cells themselves may damp down the immune system, says Dunbar. She is hoping to repeat these studies using iPS cells that have been coaxed into making heart and liver cells.
Sources: Nature.com, May 16, 2014; Wikipedia
ANSWERS: 1) body; 2) blood; 3) marrow; 4) regenerative; 5) embryos; 6) tumors; 7) differentiate; 8) stem; 9) response; 10) human; 11) cells; 12) monkey; 13) eye; 14) response