The author is professor of biology and dean of the School of Science, Indiana University-Purdue University, Indianapolis, IN, USA.
The annual cost of injured or failed human tissues and organs runs into billions of dollars, to say nothing of the loss of quality of life that often accompanies compromised tissue function. Over the past 50 years, we have made remarkable progress in restoring the structure and function of damaged and dysfunc tional tissues through bionic devices and organ transplants. Such replacement parts, however, still pose significant bio logical problems, and they are not useful in all situations. What we really want is a minor version of the Lazarus miracle--to regenerate damaged tissues in vivo. That wish is closer to becoming reality because of research in the emerg ing field of regenerative biology, several aspects of which are reviewed in this issue of Science.
In most vertebrates, the capacity for regeneration is limited to a few tissues, such as liver, bone, and skeletal muscle. Regeneration of these tissues partially recapitulates their embryonic differentiation from multipo tential stem cells. In mammalian bone and muscle, subpopulations of stem cells are set aside during embryonic and fetal life for use in juvenile growth stages and for regeneration throughout life. In the regenerating mammalian liver, cells undergo partial dedifferentiation, allowing them to reenter the cell cycle while maintaining all critical differenti ated functions. The divas of dedifferentiation are the urodele amphibians (salamanders and newts), which can regenerate many tissues by this mechanism, including the neural retina, cardiac muscle, limbs, and tails. Urodeles can also regen erate the spinal cord by a reversible epithelial-mesenchymal transformation that restores the ependyma while providing an environment favorable to the regrowth of severed axons.
The general approach of regenerative biology is to identify the cellular and molecular differences that distinguish tissue embryogenesis from wound repair (scarring) and then to recreate an embryonic (regenerative) environment in an injured adult tissue. Limited success in stimulating the regeneration of mammalian bone, skin, blood ves sels, and spinal cord has been achieved by bridging lesions with artificial or natural biomaterial scaffolds that promote the migration, proliferation, and differentiation of cells or the growth of severed axons. But achieving a wider range and greater degree of regeneration will require a deeper understanding of the cellular and molecular differences between wound repair and embryogenesis. There are two major reasons, not mutually exclusive, why our tissues might scar rather than regenerate. First, they might contain regeneration-competent cells but lack the stimulatory signals to effect regeneration and might also produce signals that suppress regeneration and favor repair. Thus, a major research direction in regenerative biology is to identify the signals that regulate the proliferation and differentiation of tissue precur sor cells during embryogenesis and in regenerating adult tissues as well as those that suppress these activities in nonregenerating adult tissues.
Alternatively, most of our tissues might lack stem or progenitor cells for regeneration. However, multipotential stem cells have now been identified in some nonregenerating adult tissues, such as the brain, and it has been postulated that stem cells might lie dormant in many or all tissues of the adult body. The function in vivo of these cells is unknown, but their presence could mean that converting repair to regeneration may be "simply" a matter of acti vating these cells by supplying the correct stimulatory signals or neutralizing suppressor signals, or both. If cells for regeneration are not ubiquitous in adult tissues, they could be provided in other ways, such as transplantation of embryonic stem cells into the body, either by themselves or after being seeded into polymer scaffolds that promote their dif ferentiation. A longer term but ultimately more satisfying approach would be to learn from the mammalian liver and from the urodeles how to induce regeneration via dedifferentiation. Many basic research and technical challenges remain to be addressed before tissue regeneration becomes a clinical reality, but the major approaches to solving the problem are now in place. I believe that, not too far into the next century, we will be able to regenerate a number of vital tissues. Regenerative biology promises not only to substantially reduce health care costs but to prevent potential losses in personal freedom, quality of life, and productiv ity. That will be miracle enough.
Complete spinal cord gaps in adult rats were bridged with multiple intercostal nerve grafts that redirected specific pathways from white to gray matter. The grafted area was stabilized with fibrin glue containing acidic fibroblast growth factor and by compressive wiring of posterior spinal processes. Hind limb function improved progressively during the first 6 months, as assessed by two scoring systems. The corticospinal tract regenerated through the grafted area to the lumbar enlargement, as did several bulbospinal pathways. These data suggest a possible repair strategy for spinal cord injury.
H. Cheng, Department of Neuroscience, Karolinska Institute, S-171 77
Stockholm, Sweden, and Department of Neurosurgery, Neurologic Institute,
Veterans General Hospital-Taipei and Division of Surgery, National Yang-Ming
University, Taiwan. Y. Cao, Department of Cell and Molecular Biology, Karolinska
Institute, S-171 77 Stockholm, Sweden. L. Olson, Department of Neuroscience,
Karolinska Institute, S-171 77 Stockholm, Sweden. * To whom correspondence
should be addressed. E-mail: henrich.cheng@neuro.ki.se.
NEUROSCIENCE: Are Pushy Axons a Key to Spinal Cord Repair?
Science 1997 June 27; 276 (5321):1971 (in Research News)
Wade Roush
Unlike any higher vertebrate, a primitive fish called the sea lamprey can repair its spinal cord when it is severed. A new finding suggests that the regenerating axons owe their mobility to neurofilaments, rods of protein previously thought to play a purely supporting role in axon growth. While most axons are dragged to their destination by footlike extensions, the regenerating axons are apparently pushed forward by growing neurofilaments.
Neuron regeneration in culture
Science 1997 April 25; 276 (5312):505 (in This Week in Science)
Injuries to the spinal cord are particularly serious because damaged
neurons are not normally replaced. Kehl et al. have found that postnatal
rat spinal cord indeed contains cells with the capacity to proliferate
and dif ferentiate in vitro into functional neurons. The results suggest
new possibilities for therapeutic approaches to spinal cord injuries.
Spinal Cord Regeneration
Science 1996 July 26; 273 (5274):451 (in Perspectives) W. Young
Wise Young
A paper in this week's issue of Science (Cheng and Olson, p. 510) reports the first hint that truly functional regeneration of the adult spinal cord may be possible, at least in the rat. In his Perspective, Young describes why this demonstration of regeneration is so important but cautions that we have much more work to do before the procedure could be applied to humans.
The author is in the Department of Neurosurgery at New York University
Medical Center, New York, NY 10016, USA. E-mail: : wise.young@mcccm.med.nyu.edu
Neurogenesis in Postnatal Rat Spinal Cord: A Study in Primary Culture
Science 1997 April 25; 276 (5312):586 (in Reports)
Lois J. Kehl, Carolyn A. Fairbanks, Tinna M. Laughlin, George L. Wilcox
*
Spinal cord injuries result in paralysis, because when damaged neurons die they are not replaced. Neurogenesis of electrophysiologically functional neurons occurred in spinal cord cultured from postnatal rats. In these cultures, the numbers of immunocytochemically identified neurons increased over time. Additionally, neurons identified immunocytochemically or electrophysiologically incorporated bromodeoxyuridine, confirming they had differentiated from mitotic cells in vitro. These findings suggest that postnatal spinal cord retains the capacity to gen erate functional neurons. The presence of neuronal precursor cells in postnatal spinal cord may offer new thera peutic approaches for restoration of function to individuals with spinal cord injuries.
L. J. Kehl, Graduate Program in Neuroscience, University of Minnesota,
Minneapolis, MN 55455, USA. C. A. Fairbanks and T. M. Laughlin, Department
of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA. G.
L. Wilcox, Graduate Program in Neuroscience and Department of Pharmacology,
University of Minnesota, Minneapolis, MN 55455, USA. * To whom correspondence
should be addressed. E-mail: george@umn.edu
NEUROPHYSIOLOGY: Teaching the Spinal Cord to Walk
Science 1998 January 16; 279 (5349):319 (in Research News)
Ingrid Wickelgren
A flurry of recent work suggests that, with proper training, some patients with spinal cord injuries can regain at least a limited ability to walk. The idea is buttressed by a large and growing body of evidence in cats and now in humans showing that, contrary to dogma, the adult mammalian spinal cord can perform on its own, largely independent of the brain, many of the functions necessary for walking. What's more, recent data show that neural cir cuits governing locomotion in the spinal cord can "learn," by altering their connections. More work will be needed to confirm these encouraging, but early, results, and even supporters caution that no one knows how much improvement individual patients can expect from the treatment. Furthermore, many patients, including those whose spinal cords are completely severed and quadriplegics, will not benefit from the approach.