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January 16, 2018

Stem Cells Made into Relay Cells for Sense of Touch

Sensory interneurons have been derived from human embryonic stem cells and from human induced pluripotent stem cells, marking progress in regenerative medicine toward restoring the sense of touch in paralyzed people. In these images, human embryonic stem cell–derived neurons are shown in green (nuclei are stained blue). (Left) Neurons treated with the signaling molecule retinoic acid. (Right) Neurons treated with retinoic acid and another signaling molecule, BMP4, creating proprioceptive sensory interneurons (pink). [UCLA Broad Stem Cell Research Center/Stem Cell Reports]

  • For the first time, human sensory interneurons—the cells that communicate the sense of touch in the central nervous system—have been derived from stem cells. In clinical applications, stem cell–derived sensory interneurons could restore feeling in paralyzed patients, potentially complementing stem cell–derived motor neurons, which are being developed to restore coordinated movement.

    "The field has for a long time focused on making people walk again," said Samantha J. Butler, Ph.D., a researcher at the University of California, Los Angeles. As the senior author of a new study describing the generation of stem cell–derived sensory interneurons, Dr. Butler took the opportunity to note that while significant progress has been made in the development of stem cell–derived motor neurons, protocols for generating stem cell–derived sensory interneurons have been lacking.

    “Making people feel again doesn't have quite the same ring,” she commented. “But to walk, you need to be able to feel and to sense your body in space; the two processes really go hand in glove.”

    Dr. Butler and colleagues have developed a protocol that can generate sensory interneurons from either human embryonic stem cells (hESCs) or human induced pluripotent stem cells (hiPSCs). Protocol details appeared January 11 in the journal Stem Cell Reports, in an article entitled “Deriving Dorsal Spinal Sensory Interneurons from Human Pluripotent Stem Cells.”

    “Two developmentally relevant factors, retinoic acid in combination with bone morphogenetic protein 4, can be used to generate three classes of sensory INs [interneurons]: the proprioceptive dI1s, the dI2s, and mechanosensory dI3s,” wrote the article’s authors. DI1 sensory interneurons give people proprioception—a sense of where their body is in space—and dI3 sensory interneurons enable them to feel a sense of pressure.

    Whether they tried reprogramming hESCs or hiPSCs, the researchers found that their protocol yielded the same mixture of sensory interneurons. This reprogramming method creates stem cells that can create any cell type while also maintaining the genetic code of the person from which they originated. The ability to create sensory interneurons with a patient's own reprogrammed cells—with hiPSCs derived from differentiated adult cells—holds significant potential for the creation of a cell-based treatment that restores the sense of touch without immune suppression.

    In the current study, which builds on work Dr. Butler’s team conducted with sensory interneurons from chicken embryos, the signaling molecules that were used worked only with neural progenitors in the correct competence state. The authors of the current study emphasized that the competence state of hESC-derived spinal progenitors changes over time.

    Dr. Butler hopes to be able to create one type of interneuron at a time, which would make it easier to define the separate roles of each cell type and allow scientists to start the process of using these cells in clinical applications for people who are paralyzed. However, her research group has not yet identified how to make stem cells yield entirely dI1 or entirely dI3 cells—perhaps because another signaling pathway is involved, she said.

    The researchers also have yet to determine the specific recipe of growth factors that would coax stem cells to create other types of sensory interneurons.

    The group is currently implanting the new dI1 and dI3 sensory interneurons into the spinal cords of mice to understand whether the cells integrate into the nervous system and become fully functional. This is a critical step toward defining the clinical potential of the cells.

    "This is a long path," Dr. Butler stated. "We haven't solved how to restore touch but we've made a major first step by working out some of these protocols to create sensory interneurons."

    In vitro–derived sensory INs can be used in drug testing platforms targeting diseased sensory INs as well as investigating the feasibility of using them in cellular replacement therapies,” the authors of the Stem Cell Reports paper concluded. “The ability to generate spinal INs in vitro will also accelerate studies examining the basis of debilitating spinal dysfunctions, such as congenital pain insensitivity and hereditary sensory and autonomic neuropathies.”

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