Can laboratory model systems instruct human limb regeneration?

Abstract

Regeneration has fascinated scientists since well before the 20th century revolutions in genetics and molecular biology. The field of regenerative biology has grown steadily over the past decade, incorporating advances in imaging, genomics and genome editing to identify key cell types and molecules involved across many model organisms. Yet for many or most tissues, it can be difficult to predict when and how findings from these studies will advance regenerative medicine. Establishing technologies to stimulate regrowth of a lost or amputated limb with a patterned replicate, as salamanders do routinely, is one of the most challenging directives of tissue regeneration research. Here, we speculate upon what research avenues the field must explore to move closer to this capstone achievement.

A conserved strategy for inducing appendage regeneration

“…In this view of regeneration, before tissue-specific morphogenesis commences, a more upstream regulation is hypothesized that controls the broadly shared processes of growth, proliferation, and differentiation. In support of this idea, regeneration across species and organs relies one way or another on the presence of stem cells or differentiated cells re-entering cell cycle and re-differentiating (Cox et al, 2019). We propose that in animals that poorly regenerate, high nutrient input turns on growth and anabolic states that promote tissue rebuilding upon injury.…”

Establishing the pattern of the vertebrate limb

“…We have presented a current view of how the vertebrate limb is patterned. This knowledge is crucial to our understanding of how a myriad of genetic disorders affect human limb development, and to the ultimate goal of designing regenerative therapies to enable the replacement of missing limb structures (Cox et al, 2019). However, many challenges remain and we will outline three.…”

Immunity in salamander regeneration: Where are we standing and where are we headed?

“…For example, targeting osteoclasts in murine digit tip regeneration more selectively (using free clodronate) results in delays to wound closure, blastema formation and regeneration. 62 It is important to note that transgenic and CRISPR approaches have recently become available in the axolotl [4]. Therefore, whereas experiments using Clo-Lipo have been indispensable in highlighting macrophages as major players in regenerative processes, additional genetic analysis may be required to determine the exact roles of and requirement for this critical cell type.…”

“…the new structure. [1][2][3][4] Similarly, during dorsal pallium regeneration in the brain, wound closure takes place by remodeling of pre-existing tissues, after which cell proliferation and differentiation of progenitor cells occurs. 5 In contrast, during organ regeneration such as the heart after puncture or resection, cell proliferation of the epicardium takes place.…”

“…In salamanders, after a limb has been severed, wound closure ensues through contraction and wound epithelium migration. This is followed by the induction of dedifferentiation of mature cell types in the stump, yielding a population of proliferating cells (termed “blastema”) that subsequently expands and re‐differentiates into the tissues of origin, giving rise to the new structure 1‐4 . Similarly, during dorsal pallium regeneration in the brain, wound closure takes place by remodeling of pre‐existing tissues, after which cell proliferation and differentiation of progenitor cells occurs 5 .…”