Toeing the line between regeneration and fibrosis

Abstract

Understanding the remarkable capacity of vertebrates to naturally regenerate injured body parts has great importance for potential translation into human therapeutic applications. As compared to other vertebrates, mammals have low regenerative capacity for composite tissues like the limb. However, some primates and rodents can regenerate the distal tips of their digits following amputation, indicating that at least very distal mammalian limb tissues are competent for innate regeneration. It follows that successful digit tip regenerative outcome is highly dependent on the location of the amputation; those proximal to the position of the nail organ do not regenerate and result in fibrosis. This distal regeneration versus proximal fibrosis duality of the mouse digit tip serves as a powerful model to investigate the driving factors in determining each process. In this review, we present the current understanding of distal digit tip regeneration in the context of cellular heterogeneity and the potential for different cell types to function as progenitor cells, in pro-regenerative signaling, or in moderating fibrosis. We then go on to discuss these themes in the context of what is known about proximal digit fibrosis, towards generating hypotheses for these distinct healing processes in the distal and proximal mouse digit.

Keywords: blastema; digit tip regeneration; fibrosis; finger; limb regeneration.

FIGURE 1

Mouse digit anatomy in relation to amputations resulting in regeneration or fibrosis (LEFT) Schematic of a longitudinal section through an adult mouse digit. Tissues depicted include: epithelium (orange), connective tissue (off-white), nail (dark grey), phalangeal bones P1, P2, and P3 (grey), bone marrow (white), sweat glands (brown), blood vessels (red), and nerves (green). Distal amputations (ex. dashed line through P3) undergo regeneration; proximal amputations (ex. dashed line through P2) undergo fibrosis. (TOP) Digit amputations that are permissive for regeneration will form a blastema (light grey) which will differentiate into the new digit tip. (BOTTOM) Digit amputations that are not permissive for regeneration will undergo wound healing and form a fibrotic scar (brown).

FIGURE 2

Schematic of the mouse digit tip during the regenerative and fibrotic processes. (A) The regenerative blastema forms distal to the amputated bone with established cellular signals (blue) from their source tissue into target tissue (arrows), extracellular matrix (maroon), and a heterogeneous mix of cells. (B) The digit amputated at the mid-P2 level forms a fibrotic scar distal to the wound site composed of myofibroblasts (pink) and unidirectional extracellular matrix fibers while chondro- and osteo-progenitors from the P2 bone contribute to bone repair. Cellular signalling is relatively understudied in the fibrotic model. Tissue colors are as described in Figure 1.

FIGURE 3

Efforts to induce regeneration in nonregenerative mouse digit amputation models. Studies utilizing the P2 amputation model (TOP) and nonregenerative proximal P3 model (BOTTOM) with post-amputation treatment with exogenous factors yield varying degrees of regenerative success as indicated by the black dashed lines for each factor. Induced regeneration of the chondrogenic joint is shown in teal. Thicker light grey dashed lines within the phalangeal bones indicate original amputation plane. No study has yet to identify factors that overcome the roadblock(s) to regenerating the full mouse digit tip, as shown on the right. Tissue colors are as described in Figure 1.