The importance of nerve-derived signalling for correct regeneration has been the topic of research for more than a hundred years, but we are just beginning to identify the underlying molecular pathways of this process. Within the current review, we attempt to provide an extensive overview of the neural influences during early and late phases of both vertebrate and invertebrate regeneration. In general, denervation impairs limb regeneration, but the presence of nerves is not essential for the regeneration of aneurogenic extremities. This observation led to the “neurotrophic factor(s) hypothesis”, which states that certain trophic factors produced by the nerves are necessary for proper regeneration. Possible neuron-derived factors which regulate regeneration as well as the denervation-affected processes are discussed...
2. The importance of innervation in vertebrate regeneration
2.1. A brief description of vertebrate extremity regeneration
The general process of appendage regeneration (such as regeneration of limbs, tails and fins) proceeds in distinct phases (Fig. 1) (Simoes et al., 2014; Stocum, 2011; Kumar and Brockes, 2012). After amputation, epithelial cells first reorganise and migrate to the wound site in order to form the wound epidermis (WE) and close the wound. Via cell migration, the WE acquires additional cell layers and eventually establishes a specialized epidermis called the apical epithelial cap (AEC) (Simoes et al., 2014; Stocum, 2011; Kumar and Brockes, 2012). Next, in the mesenchymal tissue beneath the AEC the extracellular matrix of the tissues is degraded by proteases, liberating stem cells as well as mononucleate myofiber fragments, chondrocytes, fibroblasts and Schwann cells, which all start to dedifferentiate, migrate to the amputation plane and re-enter the cell cycle to give rise to the blastema (an undifferentiated cell mass, which will start to differentiate and in which the missing structures will be formed) (Simoes et al., 2014; Stocum, 2011).
In a last phase, interactions between the AEC and the blastema ensure growth and patterning of the regenerate until the formation of the missing structure is completed (Fig. 1) (Simoes et al., 2014; Stocum, 2011). The establishment and outgrowth of the regenerate are under the control of many factors, including the presence of nerves at the wound site. Due to the damage caused by the injury, nerves degrade, after which sensory neurons rapidly regenerate in the AEC, while motor neurons regenerate between the subjacent blastema cells (Stocum, 2011; Kumar and Brockes, 2012; Salpeter, 1965; Lentz, 1967). Both of these processes seem to be crucial for proper regeneration to proceed, since denervation results in various regeneration defaults depending on the extent and time of denervation (Brockes and Kumar, 2008; Carlson, 2007; Simoes et al., 2014; Stocum, 2011; Kumar and Brockes, 2012; Kumar et al., 2007). In the following section, the different aspects of the nerve dependence of the regeneration process are discussed.
2. The importance of innervation in vertebrate regeneration
2.1. A brief description of vertebrate extremity regeneration
The general process of appendage regeneration (such as regeneration of limbs, tails and fins) proceeds in distinct phases (Fig. 1) (Simoes et al., 2014; Stocum, 2011; Kumar and Brockes, 2012). After amputation, epithelial cells first reorganise and migrate to the wound site in order to form the wound epidermis (WE) and close the wound. Via cell migration, the WE acquires additional cell layers and eventually establishes a specialized epidermis called the apical epithelial cap (AEC) (Simoes et al., 2014; Stocum, 2011; Kumar and Brockes, 2012). Next, in the mesenchymal tissue beneath the AEC the extracellular matrix of the tissues is degraded by proteases, liberating stem cells as well as mononucleate myofiber fragments, chondrocytes, fibroblasts and Schwann cells, which all start to dedifferentiate, migrate to the amputation plane and re-enter the cell cycle to give rise to the blastema (an undifferentiated cell mass, which will start to differentiate and in which the missing structures will be formed) (Simoes et al., 2014; Stocum, 2011).
In a last phase, interactions between the AEC and the blastema ensure growth and patterning of the regenerate until the formation of the missing structure is completed (Fig. 1) (Simoes et al., 2014; Stocum, 2011). The establishment and outgrowth of the regenerate are under the control of many factors, including the presence of nerves at the wound site. Due to the damage caused by the injury, nerves degrade, after which sensory neurons rapidly regenerate in the AEC, while motor neurons regenerate between the subjacent blastema cells (Stocum, 2011; Kumar and Brockes, 2012; Salpeter, 1965; Lentz, 1967). Both of these processes seem to be crucial for proper regeneration to proceed, since denervation results in various regeneration defaults depending on the extent and time of denervation (Brockes and Kumar, 2008; Carlson, 2007; Simoes et al., 2014; Stocum, 2011; Kumar and Brockes, 2012; Kumar et al., 2007). In the following section, the different aspects of the nerve dependence of the regeneration process are discussed.
https://www.sciencedirect.com/science/article/pii/S0012160615300610
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