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ScienceWeek
DEVELOPMENT: ON APPENDAGE REGENERATION IN VERTEBRATES
The following points are made by J.P. Brockes and A. Kumar (science 2005 310:1919):
1) The goal of regenerative medicine is to restore cells, tissues, and structures that are lost or damaged after disease, injury, or aging. The current approaches are influenced by our understanding of embryonic development, of tissue turnover and replacement in adult animals [1-3], and by tissue engineering and stem cell biology [4]. The regeneration of organs and appendages after injury occurs in diverse animal groups and provides another important viewpoint, in addition to the demonstration that complex adult tissues can be rebuilt. The lessons of biological regeneration have not been extensively assimilated, in part because this attribute appears remote and exceptional from a mammalian perspective.[5]
2) Regenerative medicine currently uses three approaches [4]: the implantation of stem cells to build new structures, the implantation of cells pre-primed to develop in a given direction, and the stimulation of endogenous cells to replace missing structures. Each of the different aspects identified in the first two examples -- the generation of an appropriate cohort of regenerative cells, their regulated division and differentiation, and the restoration of the appropriate part of the structure --must be evoked from endogenous cells in the third approach. These processes operate in adult animals that regenerate, and in addition, the regenerative response must be initiated by signals responsive to tissue injury or removal. One candidate signal in salamanders is the local activation of thrombin, a regulator of hemostasis and other aspects of the response to injury, as well as an activator of S phase (the phase of chromosome replication) reentry in differentiated cells.
3) A salamander can regenerate its limbs and tail, upper and lower jaws, ocular tissues such as the lens and retina, the intestine, and small sections of the heart. The various contexts for regeneration do not present an equivalent degree of difficulty. To restore the intricate and discontinuous pattern of the vertebrate limb is a different proposition from replacing a patch of cardiac tissue in the ventricle. Nonetheless, recent efforts at tissue engineering of heart muscle have underlined that even in the heart, it is quite challenging to achieve an appropriate vascular and electromechanical integration after implantation. The salamanders are unusual among adult vertebrates in their ability to regenerate an entire limb from a blastema. Regeneration of the digit tip in fetal mammals does not proceed from a blastema but rather from progenitor cells in the nail bed. The limb blastema consists of a mound of mesenchymal stem cells at the end of the stump. The critical questions for research into limb regeneration are concerned with the blastema, and its properties offer a distinct perspective for regenerative medicine.
4) In summary: The regeneration of complex structures in adult salamanders depends on mechanisms that offer pointers for regenerative medicine. These include the plasticity of differentiated cells and the retention in regenerative cells of local cues such as positional identity. Limb regeneration proceeds by the local formation of a blastema, a growth zone of mesenchymal stem cells on the stump. The blastema can regenerate autonomously as a self-organizing system over variable linear dimensions.
References (abridged):
1. L. Alonso, E. Fuchs, Proc. Natl. Acad. Sci. U.S.A. 100, 11830 (2003)
2. S. Harada, G. A. Rodan, Nature 423, 349 (2003)
3. F. Radtke, H. Clevers, Science 307, 1904 (2005)
4. D. L. Stocum, Adv. Anat. Embryol. Cell Biol. 176, 1 (2004)
5. J. P. Brockes, Science 276, 81 (1997)
Science http://www.sciencemag.org
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Related Material:
ON REGENERATING THE DAMAGED CENTRAL NERVOUS SYSTEM
Notes by ScienceWeek:
The ability to regenerate at least certain parts of the organism is found in all living systems, including plants and animals, unicellular and multicellular. With higher organisms, however, for example with mammals, the process of regeneration involves many constraints. Of great concern in clinical medicine are injuries to the nervous system, injuries which are often permanently debilitating because of poor or absent regeneration of neural tissue. Important advances have recently been made in our understanding of nervous system injury and regeneration, and there are now indications that significant breakthroughs will occur in the near future.
What happens when a nerve cell is injured? Consider the case when the *axon of the nerve cell is severed. When a *peripheral nerve fiber is cut, certain events follow in different parts of the neuron. The distal segment of the nerve fiber, the part on the far end of the cut, undergoes degeneration, which begins slowly, requiring days to be completed, and involves the separate parts of the nerve fiber differently. The axon gradually breaks up and the segments are digested and absorbed. If there is a *myelin sheath, it is gradually transformed into a chain of lipid droplets, the larger of which may in the early stages contain degenerating fragments of the axon. The fragments of the axon disappear in a few days; parts of the degenerating myelin sheath, in the form of droplets, may persist for six months or more.
When a nerve fiber is cut, the parts of the neuron from the break toward the cell body (the proximal parts) also show characteristic changes. The cell body undergoes evident changes in *endoplasmic reticulum and *ribosomes (chromatic changes in Nissl substance). These changes reach their peak in 7 to 15 days, after which there may be recovery, or complete degeneration if there is too much damage. If the cell body completely degenerates, the nerve fiber between the cell body and the cut undergoes degeneration (Wallerian degeneration) just as the distal segment does.
But if the cell body survives, only a small amount of destruction of the proximal segment occurs, and that near the cut. Since this is a peripheral nerve, what happen then is that from each axon near its cut end a number of small sprouts grow out in all directions. Some of the sprouts grow in the direction of the former distal axon segment and grow into the connective tissue matrix that has formed scar tissue. The haphazard arrangement of connective tissue fibers influences the amoeboid growing tips of the nerve sprouts. Not all of the fibers get across the scar, but a few do, and even fewer manage to regain the original neural pathway.
The above is a description of mammalian peripheral nerve degeneration and regeneration, the process first described at the beginning of the 20th century. For most of the 20th century, there was a clear dogma in neurobiology: It was believed that in the mammalian central nervous system, including in humans, the nerve fibers of the brain and spinal cord were incapable of regeneration sufficient to restore function. A most important corollary of this dogma was that this incapability of sufficient regeneration (or any regeneration at all) was intrinsic to central nervous system nerve cells.
In 1980, that corollary dogma was overturned, and it is now understood that the regenerative capacity of the central nervous system is not intrinsic to central nervous system nerve cells, but depends on the circumstances of damage and the immediate environment of the nerve cells. Regeneration can occur in the damaged central nervous system, and this new understanding has caused considerable excitement in the neurobiological and medical communities.
The following points are made by P.J. Horner and F.H. Gage (Nature 2000 407:963):
1) In contrast to fish, amphibia, and the mammalian peripheral nerves and developing central nerves, adult central mammalian neurons do not regrow functional axons after damage. This inability of adult central nervous system neurons to regrow after injury cannot be entirely attributed to intrinsic differences between adult central nervous system neurons and all other neurons, since it has been known since the early years of the 20th century that adult central nervous system neurons could regrow in a permissive environment. In 1980, P.M Richardson et al replicated the early studies with new methods that definitely confirmed that adult central nervous system neurons have regenerative capabilities. This finding revealed that the failure of central nervous system neurons to regenerate was not an intrinsic deficit of the neuron, but rather a characteristic feature of the damaged environment that either did not support or prevented regeneration. In the past 20 years, progress has been made in identifying the elements that are responsible for the differences between the adult central nervous system and peripheral nervous system environments, and in the past few years the molecular and cellular bases of regenerative compared with non-regenerative responses are beginning to be revealed.
2) Regeneration strategies developed from these new discoveries will be applicable to many central nervous system disorders. Spinal cord injury could be the most approachable, owing to the well-defined loss of cells and axons and the relative lack of consequent chronic pathology. Genetic disorders that result in aberrant axonal pathfinding or neuronal cell loss may also be amenable to regeneration. Degenerative diseases where a defined cell type is lost (e.g., Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis) are also good targets, but may be more challenging because of the potential for continued cell loss or axonal degeneration. Finally, regeneration strategies may also be applied to less well-defined disorders where diffuse cell and axonal loss can occur, such as cerebrovascular disease, tumor, and infection of the central nervous system.
3) Concerning recent work, an increasing number of studies have demonstrated that an adult cut axon in the central nervous system can be induced to regrow by either increasing the permissive cues or decreasing the non-permissive cues of the existing environment. Furthermore, a growing list of reports indicate that one strategy or another can induce some level of functional recovery following damage. The authors (Horner and Gage), however, point out that it is not sufficient to demonstrate axon elongation and behavioral improvement after injury to conclude that authentic functional regeneration is responsible for the outcome. There are many mechanisms that may account for observed functional recovery that do not require regeneration, and these non-regenerative mechanisms are common in most experimental models of traumatic injury and need to be excluded before invoking functional regeneration as the cause of repair and recovery. The reason for sorting out the authentic mechanisms of functional recovery is that without understanding the underlying basis of regeneration, little progress can be made beyond the phenomenological observation of recovery from injury.
4) The authors conclude: "Despite the progress in the last century of research on regeneration... *Cajal's [1928] flowery decree, as translated by Raoul May, still resonates: 'Once the development was ended, the founts of growth and regeneration of the axons and *dendrites dried up irrevocably. In the adult centers the nerve paths are something fixed, ended, and immutable. Everything may die, nothing may be regenerated. It is for the science of the future to change, if possible, this harsh decree.' The decree is lifted; the solution remains elusive."
Nature http://www.nature.com/nature
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Notes by ScienceWeek:
*axon: In general, nerve cells have a single long extension (the "axon") that propagates the electrical output (the action potential) of the cell. In some types of nerve cells, axons are extensively branched into a multitude of fine fibers that make contact (synapses) with other nerve cells.
*peripheral nerve fiber: In mammals, neural tissue comprising the brain and spinal cord is called the "central nervous system", while neural tissue outside the brain and spinal cord is called the "peripheral nervous system". The dichotomy is more than formal, since anatomical, functional, and in this context regeneration differences are significant.
*myelin sheath: High signal propagation velocities in motor and sensory neurons in vertebrates are achieved by association of the nerve fiber with an enfolding "myelin sheath". The myelin sheath consists of concentric layers of electrically insulating lipid material (myelin), but the sheath is periodically interrupted, and at the points where the sheath is interrupted so is the electrical insulation interrupted. The result, predictable from the classical physics of electrical transmission lines and the electrical parameters of nerve fibers, is that the propagation of an electrical pulse along such nerve fibers occurs at a velocity much higher than that found in unmyelinated fibers.
*endoplasmic reticulum: The term "endoplasmic reticulum" refers to a complex system of intracellular flattened sacs, and it is the site of many important syntheses, including the production of new surface membrane and the intracellular transport of various biochemical entities.
*ribosomes: A ribosome (not to be confused with riboZYME) is a small particle, a complex of various ribonucleic acid component subunits and proteins that functions as the site of protein synthesis.
*Cajal: Santiago Ramon y Cajal (1852-1934), one of the founders of microscopic neuroanatomy, was awarded the 1906 Nobel Prize in Physiology or Medicine for establishing the neuron as the fundamental unit of the nervous system.
*dendrites: The general input extensions of nerve cells are called "dendrites", and they may be extensively branched. In general, dendrites are considered to receive input and axons to propagate output, but the electrical architecture of most neurons is complicated, and in many types of nerve cells activation of the axon produces electrical activity that not only propagates down the axon but also propagates backward through the cell body and dendrites.
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