The U.S. Census Bureau reports in its results from the 2006 American Community Survey that 7 million Americans older than five years possess a severe sensory disability. According to the National Eye Institute, 1.75 million Americans are losing vision, owing to age-related macular degeneration. In the year 2020, their ranks will swell to roughly 3 million. Gallaudet University suggests in informative, well-documented data analyses that about 1 million Americans are functionally deaf. Recent breakthroughs in regenerative medicine have decisively progressed toward promising treatments.
|Carassius auratus (courtesy G. Blakemore)|
Retinal ganglion cells constitute the nerve cells that convey visual information from the retina to the optic tectum in the midbrain where their endings terminate in a topographic map of the retina. Because of this retinotopy, an image of the surrounding world cast on the retina retains its spatial relations when it is represented by nerve cell activity in the tectum. As the retina grows, retinotectal nerve fibers are added and new tectal terminations are formed, while old ones continue to process visual information. In our mature visual system nothing like this happens. Once our brain matured, the retinal nerve cells and their connections with the brain remain by and large unchanged.
In addition, the goldfish visual system is capable of an achievement even greater than the continuous addition of functionality. Maier and Wolburg (1979) discovered that goldfish retinae deprived of almost all cells by metabolic poisoning were able to reconstitute themselves from scratch within a few months. As we know now, surviving Müller glia cells and photoreceptor cells convert into multipotent stem cells that serve as dividing progenitors from whose offspring retinal cells differentiate (Bernardos and others, 2007). The new ganglion cells innervate the optic rectum in roughly topographic fashion. My project was to examine with a functional imaging method whether the newly formed connections with the tectum were functional. Indeed, my colleagues and I found compelling evidence that the novel retinotectal inputs could be activated by visual stimulation.
|Destruction & Renewal (Melzer & Powers, 2001)|
Alas, the terminally differentiated cells in our mature retina do not possess the goldfish's power of spontaneous regeneration. However, much progress has been made since I conducted my research, unraveling the molecular mechanisms and identifying the genes that reconvert differentiated cells into multipotent stem cells or conditioned pluripotent embryonic stem cells to become progenitors. Recently, Advanced Cell Technology developed the first gene therapy for people with Stargard's macular dystrophy that will soon be tested in clinical trials, aiming to replace dysfunctional pigment epithelium cells in the retina with healthy ones generated from human stem cells.
By contrast, the effort to restore hearing in deaf people has not advanced to clinical trials yet, though stem cells have also shown promise. Oshima and others (2010) successfully directed induced pluripotent stem cells and embryonic stem cells from mice to change into skin cells. The skin cells were subsequently converted into progenitor cells. The researchers were then able to promote these progenitors' offspring to differentiate into hair cell-like cells with stereocilial bundles that exhibited stimulus transduction currents resembling those of immature sensory hair cells in the organ of Corti of the cochlea, that is the inner ear.
|Schematic crossection through the organ of Corti showing the hair cells topped by the basilar membrane surrounded by support cells (courtesy Madhero88).|
Only about 14,000 hair cells populate the human organ of Corti. Because of the inability of our hair cells in the inner ear to repair or replace themselves, drug- or sound volume-induced damage irreversibly leads to the persistent loss of hearing in the range of pitch associated with the location of the damage on the organ of Corti. In offering one possible resolution of this predicament, Oshima and others (2010) recently developed a three-step hair cell generation procedure, manipulating molecular signaling pathways that regulate cell fate and proliferation in tissue culture. In the first step, inhibition of the Wnt/TGF-beta pathways commits the stem cells to ectoderm. In the second step, FGF signaling promotes the ectodermal cells into otic progenitors. In the third step, the progenitors divide and differentiate into immature hair cell-like cells in a culture system with stromal cell-derived activity. The findings constitute a proof of concept, demonstrating that the replacement of hair cells from stem cells is possible. Whether the newly generated cells can be implanted in inner ears and form functional connections with nerve cells remains to be established.
Alternatives to the implantation of stem cells may exist. In vertebrates other than mammals lost hair cells are replaced by regeneration from support cells in the surrounding skin, known as phalangeal cells and Deiters' cells. The support cells convert into dividing pluripotent otic progenitor cells. In analogy, methods that may help de- or transdifferentiate support cells into dividing progenitor cells in vivo are being pursued (Izumikawa and others, 2005; Löwenheim and others, 1999).
Regardless of the obstacles that still need to be overcome, there is now a good chance that stem cell therapies or regenerative medical procedures derived from this research may be able to help people with sensory disabilities regain function.
- Bernardos RL, Barthel LK, Meyers JR, Raymond PA (2007) Late-stage neuronal progenitors in the retina are radial Müller glia that function as retinal stem cells. J Neurosci 27:7028-7040.
- Izumikawa M, Minoda R, Kawamoto K, Abrashkin KA, Swiderski DL, Dolan DF, Brough DE, Raphael Y (2005) Auditory hair cell replacement and hearing improvement by Atoh1 gene therapy in deaf mammals. Nat Med 11:271–276
- Löwenheim H, Furness DN, Kil J, Zinn C, Gültig K, Fero ML, Frost D, Gummer AW, Roberts JM, Rubel EW, Hackney CM, Zenner HP (1999) Gene disruption of p27(Kip1) allows cell proliferation in the postnatal and adult organ of corti. Proc Natl Acad Sci USA 96:4084-4088.
- Maier W, Wolburg H (1979) Regeneration of the goldfish retina after exposure to different doses of ouabain. Cell Tissue Res 202:99-118.
- Melzer P, Powers MK (2001) Metabolic activity in optic tectum during regeneration of retina in adult goldfish. Vis Neurosci 18:599-604.
- Oshima K, Shin K, Diensthuber M, Peng AW, Ricci AJ, Heller S (2010) Mechanosensitive hair cell-like cells from embryonic and induced pluripotent stem cells. Cell 141:704-716.
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- The picture of the retina mentioned above and other astounding renderings of the brain can found in Carl Schoonover's recent book with the title "Portraits of the Mind: Visualizing the Brain from Antiquity to the 21st Century" (11/07/10).
- Today the Swedish Royal Academy awarded this year's Nobel Prize in Physiology or Medicine to John B. Gurdon from Great Britain and Shinya Yamanaka from Japan for their successes in converting differentiated cells into pluripotent stem cells (10/08/2012).