Reprogrammed skin cells can be turned into brain cells that may be highly effective in treating myelin disorders like multiple sclerosis and pediatric leukodystrophies, according to researchers at the University of Rochester Medical Center (URMC). The team says that their study is the first successful attempt to employ human induced pluripotent stem cells (hiPSC) to produce a population of cells that are critical to neural signaling in the brain. The scientists used cells crafted from human skin and transplanted them into animal models of myelin disease.
"This study strongly supports the utility of hiPSCs as a feasible and effective source of cells to treat myelin disorders," says URMC neurologist Steven Goldman, M.D., Ph.D., lead author of the study. "In fact, it appears that cells derived from this source are at least as effective as those created using embryonic or tissue-specific stem cells." The team adds that the discovery opens the door to potential new treatments using hiPSC-derived cells for a range of neurological diseases characterized by myelin loss.
Oligodendrocytes are the source of myelin in the brain and spinal cord. Oligodendrocytes themselves are the offspring of oligodendrocyte progenitor cells, or OPCs. Scientists have theorized that if healthy OPCs could be successfully transplanted into the diseased or injured brain, then these cells might be able to produce new oligodendrocytes capable of restoring lost myelin, thereby reversing the damage caused by these diseases. However, one of the key challenges is that OPCs are a mature cell in the central nervous system and appear late in development.
"Compared to neurons, which are among the first cells formed in human development, there are more stages and many more steps required to create glial cells such as OPCs," said Dr. Goldman. "This process requires that we understand the basic biology and the normal development of these cells and then reproduce this precise sequence in the lab."
Another challenge has been identifying the ideal source of these cells. While research using tissue-specific and embryonic stem cells has yielded critical insight into the biology of stem cells, these sources are not considered ideal to meet demand once stem cell-based therapies become more common. Induced pluripotent stem cells could be the key. Because these cells, created by using the recipient's own skin, would be a genetic match, the likelihood of rejection upon transplantation is significantly diminished. These cells also promise an abundant source of material from which to create the cells necessary for therapies.
From three hiPSC lines, as well as from human embryonic stem cells, Dr. Goldman's team was able to generate highly enriched OLIG2+/PDGFRα+/NKX2.2+/SOX10+ human OPCs, which could be further purified using fluorescence-activated cell sorting. Once they succeeded in OPC generation, they then assessed the ability of the cells to make new myelin when transplanted into mice with a hereditary leukodystrophy that rendered them genetically incapable of producing myelin.
They found that hiPSC OPCs efficiently differentiated into both myelinogenic oligodendrocytes and astrocytes, in vitro and in vivo. The OPCs spread throughout the animals' brains and began to produce myelin. They observed that hiPSC-derived cells did this even more quickly, efficiently, and effectively than cells created using tissue-derived OPCs. The animals were also free of any tumors, a dangerous potential side effect of some stem cell therapies, and survived significantly longer than untreated mice.
"The new population of OPCs and oligodendrocytes was dense, abundant, and complete," says Dr. Goldman. "In fact, the re-myelination process appeared more rapid and efficient than with other cell sources."
Now, Dr. Goldman along with a team of researchers and clinicians from Rochester, Syracuse, and Buffalo (dubbed the Upstate MS Consortium) are preparing to launch a clinical trial using OPCs to treat multiple sclerosis.
This work is detailed in yesterday's issue of Cell Stem Cell in a paper titled “Human iPSC-Derived Oligodendrocyte Progenitor Cells Can Myelinate and Rescue a Mouse Model of Congenital Hypomyelination”.