Regenerative loss in the animal kingdom as viewed from the mouse digit tip and heart

Abstract

The myriad regenerative abilities across the animal kingdom have fascinated us for centuries. Recent advances in developmental, molecular, and cellular biology have allowed us to unearth a surprising diversity of mechanisms through which these processes occur. Developing an all-encompassing theory of animal regeneration has thus proved a complex endeavor. In this chapter, we frame the evolution and loss of animal regeneration within the broad developmental constraints that may physiologically inhibit regenerative ability across animal phylogeny. We then examine the mouse as a model of regeneration loss, specifically the experimental systems of the digit tip and heart. We discuss the digit tip and heart as a positionally-limited system of regeneration and a temporally-limited system of regeneration, respectively. We delve into the physiological processes involved in both forms of regeneration, and how each phase of the healing and regenerative process may be affected by various molecular signals, systemic changes, or microenvironmental cues. Lastly, we also discuss the various approaches and interventions used to induce or improve the regenerative response in both contexts, and the implications they have for our understanding regenerative ability more broadly.

Figure 1:

Comparison of limb regeneration in the axolotl and the arthropod Parhyale showing distinct and similar stages. Limb amputation is followed by wound healing and the formation of the blastema. Pax7+ activated satellite progenitor cells are recruited to the wound site and proliferate, differentiating to undergo growth and morphogenesis to form the regenerated limb.

Figure 2.

(A) Second and terminal phalanges of the mouse digit. Amputations made within the distalmost third of the terminal phalanx (P3) is regenerative (area in green). Amputations that remove over 60% of P3 are non-regenerative (area in red). (B) A regenerative amputation through P3 (dotted line) at 0 days post amputation (0 dpa) and 28 dpa. By 28 dpa, the regenerated digit tip recapitulates the tapered morphology of P3, though it is structurally distinct as it is more porous than the original bone. (C) A non-regenerative amputation through P3 (dotted line). The post amputation response concludes at wound healing, with no regenerative response seen at 28 dpa. (D) Steps of mouse digit regeneration. Amputation is followed by a rapid immune response and histolysis of the bone prior to wound re-epithelialization. Blastema cells are recruited to the wound site and proliferate, then re-differentiate into specific cell types. Revascularization and reinnervation of the regenerating digit occur as it undergoes morphogenesis. Finally, the regenerated digit tip is formed through intramembranous ossification, preserving the shape but not the structure of the original digit tip.

Figure 3.

Diagram of the heart with structures derived from the cardiac neural crest labelled. Ao: Aorta P: Pulmonary artery.

Figure 4.

Differential heart regeneration ability in P1 and >P7 neonatal mice. At P1, cardiac injury results in regeneration of the injured tissue 21–28 days post injury. However, the same injury at >P7 concludes in a collagenous scar being deposited at the injury site. Some factors that change in the first week of neonatal development include increased cardiomyocyte polyploidy, differential activation of Hippo/YAP signaling, differing cardiac extracellular matrix (ECM) components and mechanical properties, and variation in the timing, duration, magnitude and signaling pathways involved in the immune response to injury.