Regeneration and mammalian auditory hair cells

tures of those labeled cells were similar to immature hair cells. The most parsimonious explanation of these findings is that the immature hair cells that appear after treatment in vivo develop from cells that have undergone proliferation, as had been suggested in the studies of organotypic cultures. The number of labeled cells that could be "putatively" identified as hair cells in the organotypic cultures was rather less than the number of cells with characteristics of immature hair cells that were identified from the in vivo morphological study, but this could be a result of differing capacities for proliferation and subsequent differentiation in vitro and in vivo. Alternatively, the apparent discrepancy could result because, in addition to proliferation, there are, as Rubel et al. suggest, other processes that lead to development of hair cells after damage, including self-repair of nonlethally damaged cells, or the direct conversion of some nonsensory cell type in the epithelium into a hair cell. Selfrepair through a process that involves redevelopment of their apical structures has never previously been recognized in the many, varied studies of hair cell injury in vivo. If such does occur, it seems unlikely that it is confined to the mammalian vestibular system, and this would have implications for studies of those sensory epithelia where recovery of hair cell numbers through proliferation has been reported. However, phenotypic conversion of supporting cells directly into hair cells has been suggested previously (5) as a supplementary mechanism for hair cell production, although at present the evidence is indirect and inconclusive. Rubel et al. however, appear to contend that in vivo most of the immature hair cells arise from some process other than from the proliferating nonsensory cells. None of the labeled cells in their study could be identified as hair cells. That they did not find any labeled hair cells is an unexpected and potentially significant result. However, the drug treatment protocol used by Rubel et al. appears to have induced extensive damage over prolonged periods, with marked interanimal variability in the amount of damage caused. The variability between animals in the pattern of damage could be reflected in a variability in the number and timing of appearance of immature hair cells. Some of the data do appear to show that the pattern of damage influences the pattern and extent of proliferation. In one of the two thymidine-exposed, drug-treated animals examined at 6 weeks after treatment, there are no labeled cells. The density of mature, remaining hair cells in the utricle in this animal is low, suggesting damage was extensive. The other animal examined at this time is the only sample showing pairs of labeled nuclei, and it is suggested that progression to cell division had occurred by this time. This animal is also the one that shows the highest density of hair cells after treatment, which suggests that it suffered the least damage. Furthermore, we have found significantly greater numbers of hair cells at 12 weeks than at 4 weeks after treatment, as assessed from SEM (6) and from thin sections (7). If this is correct, then it may be that the development of hair cells after injury to the epithelium continues over a period more prolonged than that examined by Rubel et al. It would be of interest to determine the developmental fate of those daughter cells that Rubel et al. found had been produced 6 weeks after drug exposure. It is difficult from the results presented by Rubel et al. to draw firm conclusions as to the extent to which proliferative regeneration is involved in the appearance of immature hair cells in the drug-damaged mammalian urtricles. Nevertheless, the results of their study indicate that proliferation might not be the only process involved. This raises important questions that need to be considered in future work. Andrew Forge Lin Li Graham Nevill Institute of Laryngology and Otology, University College London Medical School, 330-332, Gray's Inn Road, London WC1X 8EE, United Kingdom