After ten years of effort, researchers reporting in the May 14th issue of the journal Cell, a Cell Press publication, say they have found a way to coax embryonic stem cells as well as reprogrammed adult cells to develop into sensory cells that normally reside in the mammalian inner ear. Those mechanosensitive sensory hair cells are the linchpin of hearing and balance.
Assuming their recipe can be further perfected to reliably generate hair cells in the millions, it opens the door to detailed molecular studies on the cells and new insight into the molecular basis for hearing, according to the researchers. That's especially significant, says Stefan Heller of Stanford University School of Medicine, because the "inner ear shelters the last of our senses for which the molecular basis is unknown."
That understanding could also set researchers on a path to discovering new ways to prevent or correct hearing loss by encouraging hair cells' regeneration. After all, the researchers say, our inability to regenerate lost hair cells is the major reason for the permanence of hearing loss as well as certain balance disorders.
Scientists have been left in the dark on the molecular basis for hearing in large part because hair cells are relatively scarce by comparison to other sensory cells, Heller explains. Our inner ears harbor about 30,000 sensory hair cells in total in two different types, few of which can be dissected out of the inner ear and kept alive for study. (Compare that to the 120 million photoreceptors in the retina, all of which can be isolated rather easily.)
Heller's team long ago realized that one solution to this problem was to use stem cells as a source for generating new hair cells, and now they've got the recipe. They have devised what they refer to as a stepwise guidance protocol for making the hearing cells, starting with either mouse embryonic stem cells or induced pluripotent stem (iPS) cells, which are stem cell-like cells derived from adult mouse cells.
The researchers first directed the stem cells to become ectodermal cells capable of responding to ear-inducing growth factors. They then subjected those so-called otic progenitor cells to varying differentiation conditions until they found one that led to the formation of cell clusters displaying hair cell-like characteristics. The key ingredients were chemicals known as a fibroblast growth factors or FGFs, which others had shown to be both sufficient and necessary for ear development.
The hair cell-like cells display all the markers associated with bona fide hair cells, they report. Closer examination of the cells under a scanning electron microscope showed that they were developing bundled structures "highly reminiscent" of the hair-like tufts of stereocilia that lend hair cells their name.
Most importantly, further study showed that the hair cell-like cells also respond to mechanical stimulation by producing currents like hair cells should. (Fluid inside the ear moves in response to vibration, setting hair cells in motion. Those sensory cells then convert that mechanical signal into an electrical one that is ultimately sent to the brain.)
The reprogrammed cells acted like immature, as opposed to adult, hair cells, they found. For instance, the cells responded with currents regardless of whether they were pushed or pulled; mature hair cells only work in one direction.
In addition to its promise for further scientific study, the new protocol could have clinical implications.
"The fact that in vitro-generated hair cell-like cells display mechanosensitivity demonstrated that generation of replacement hair cells from pluripotent stem cells is feasible, a finding that justifies the development of stem cell-based treatment strategies for hearing and balance disorders," the researchers conclude.
Heller says that perhaps the most promising strategy for taking advantage of this new source for hair cells is high-throughput screening for drugs to awaken mammals' lost ability to regenerate hair cells in the way that other animals can.
"For some reason, we've lost this mechanism but it must still be there somehow," Heller says. "We need to find ways to activate it."
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