ScienceWeek

NEUROBIOLOGY: ON REGENERATION OF SENSORY EPITHELIA

The following points are made by Hernan Lopez-Schier (Current Biology 2004 14:R127):

1) The inner ear is a complex sensory organ responsible for our senses of hearing and balance. The sensory elements of the inner ear are the hair cells, which are exclusive to vertebrates and organized with exquisite precision in the auditory epithelium. In the cochlea, hair cells serve in sound detection, and in the vestibular system -- the semicircular canals, saccule and utricle -- they are dedicated to sensing balance, head movements and acceleration. Hair cells are able to transduce mechanical stimulation into changes in electrical potential, which are interpreted by neuronal terminals reporting to the brain [1]. In humans, hair cells develop during the first trimester of gestation and are expected to survive for the whole life of the individual. Hair cell death is the most prominent cause of non-hereditary deafness.

2) Because the inner ear of mammals shows very limited regenerative capacity, deafness due to hair cell loss is normally irreversible [2]. Unlike mammals, however, other vertebrates are able to replace damaged hair cells throughout their entire lifetime. Inherited deafness affects one child in every thousand born worldwide, and hearing dysfunction afflicts more than 10% of the population in industrialized countries. Therefore, understanding the mechanisms that allow hair cell regeneration in some animals, or what prevents mammals from doing so, is of major biological and clinical relevance. The ultimate goal, of course, is to coach damaged human ears to regenerate hair cells. Recent results from Li and co-workers [3,4] are a major step forward towards this aim.

3) Some 15 years ago, two groups [5] independently reported that adult birds are able to generate new hair cells after acoustic trauma, the reports provoking vigorous research on the subject. To date, however, one important question remains unanswered: where do these newly formed hair cells come from? Some results suggest that hair cells regenerate from neighboring supporting cells by transdifferentiation. But others indicate that some supporting cells re-enter mitosis before producing new hair cells. Although the transdifferentiation of supporting cells is a well-documented and perhaps simpler way to replace dead hair cells, the amplification of supporting cells may also be required. Because these animals need to replenish hair cells over a period of several years, it is likely that the two processes act in parallel to maintain auditory tissue homeostasis without depleting the supporting cell population.

References (abridged):

1. Hudspeth, A.J. (1989). How the ear's works work. Nature 341, 397-404.

2. Walshe, P., Walsh, M., and McConn Walsh, R. (2003). Hair cell regeneration in the inner ear: a review. Clin. Otolaryngol. 28, 5-13.

3. Li, H., Liu, H., and Heller, S. (2003). Pluripotent stem cells from the adult mouse inner ear. Nat. Med. 9, 1293-1299.

4. Li, H., Roblin, G., Liu, H., and Heller, S. (2003). Generation of hair cells by stepwise differentiation of embryonic stem cells. Proc. Natl. Acad. Sci. USA 100, 13495-13500.

5. Corwin, J.T. and D.A. Cotanche, D.A. (1988). Regeneration of sensory hair cells after acoustic trauma. Science 240, 1772-1774

Current Biology http://www.current-biology.com

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HEART TISSUE REGENERATION IN ADULT MICE

The following points are made by J.M. Leferovich et al (Proc. Nat. Acad. Sci. 2001 98: 9830):

1) Wound healing of mammalian tissue is an essential process in the maintenance of body integrity. The general mechanism of wound healing usually studied in adult mammals is repair, in contrast to the regeneration seen in more primitive vertebrates. There are, however, mammalian tissues that can regenerate, such as adult mammalian skeletal muscle, which recruits a population of mitotically active satellite cells that contribute to the resultant stable population of myonuclei. In contrast, amphibian skeletal muscle myonuclei undergo division concurrent with satellite cell activation and proliferation.

2) It is widely believed that mammalian myocardium does not contain reserve cells and that terminally differentiated adult cardiomyocytes generally do not proliferate and therefore cannot regenerate. In this case, scar formation is the predominant response to injury. Amphibians again stand out in terms of their ability to display cardiac regeneration and cardiomyocyte division, a phenomenon only rarely seen in mammals, including humans, and only to a minimal degree.

3) In 1998, the authors reported that a particular mouse strain (MRL strain) is unique in its capacity for regenerative wound healing, as demonstrated by the closure of ear punches with normal tissue architecture and cartilage replacement reminiscent of amphibian regeneration as opposed to scarring. Furthermore, the authors reported that they had mapped the genes involved, identified a minimum of 6 different loci on 5 chromosomes, with a demonstration that a complex multigenic trait was involved. Now the authors report that in this mouse strain, the heart, when injured with a cryoprobe, is capable of growing and replacing wounded tissue without scarring (without fibrosis) and with apparent recovery of myocardial function.

Proc. Nat. Acad. Sci. http://www.pnas.org

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REGENERATION OF CARDIAC MUSCLE CELLS

In general, an "infarct" is an area of necrosis caused by a sudden insufficiency of blood supply, and a "myocardial infarction" (cardiac infarction) is such damage of an area of heart muscle, usually as a result of occlusion of a coronary artery.

The following points are made by A.P. Beltrami et al (New Engl. J. Med. 2001 344:1750):

1) The authors report evidence that human cardiac muscle cells (myocytes) divide after myocardial infarction. The scarring of the heart that results from myocardial infarction has been interpreted as evidence that the heart is composed of myocytes that are unable to divide. Recent observations, however, have provided some evidence of proliferation of myocytes in the adult heart.

2) The authors studied the extent of mitosis among myocytes after myocardial infarction in humans, and they suggest that their results challenge the dogma that the adult heart is a postmitotic organ, and that their results raise the possibility that the regeneration of myocytes may contribute to the increase in muscle mass of the myocardium. The adult heart apparently has a subpopulation of myocytes that are not terminally differentiated, and these myocytes evidently reenter the cell cycle and undergo nuclear mitotic division early after infarction. The number of cell-cycling myocytes is significantly larger in the zone bordering the infarct than in the distant myocardium.

New Engl. J. Med. http://www.nejm.org

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