Ca2+ Signaling and Regeneration

Abstract

Regeneration is the process by which lost or damaged tissue is replaced in adult organisms. Some organisms exhibit robust regenerative capabilities, while others, including humans, do not. Understanding the molecular principles governing the regenerative malleability of different organisms is of fundamental biological interest. Further, this problem has clear impact for the field of "regenerative medicine," which aspires to understand how human cells, tissues, and organs may be restored to normal function in scenarios of disease, damage, or age-related decline. This review will focus on the planarian flatworm as a powerful model system for studying the role of Ca²⁺ signals in regeneration. These invertebrate animals display an astounding innate regenerative capacity capable of regenerating complete organisms from tiny, excised fragments. New knowledge and methodological capabilities in this system highlight the potential for studying the role of Ca²⁺ signaling at multiple stages of the regenerative blueprint that controls stem cell behavior in vivo.

Figure 1.

Planarian morphology and classification. (A, Top), morphology of the planarian Dugesia japonica. Flatworms are bilaterally symmetrical and dorsoventrally flattened, displaying a clear head (anterior, “a”)-to-tail (posterior, “p”) polarity. (Bottom) Examples of D. japonica polarity defects after regeneration of trunk fragments (region illustrated by box in A) following RNAi of key patterning genes β-catenin-1 (yielding two-headed animals, eyespots shown by red arrows, and pharynx in green) or APC-1 (yielding two-tailed animals). (B) Systematic classification of free-living planaria and parasitic worms within the phylum Platyhelminthes.

Figure 2.

The diverse planarian ionotropic toolkit. Cladogram describing the Dugesia japonica voltage-gated-like ion channel superfamily. Dashed groupings indicated predicted gene loss in the parasitic flatworm Schistosoma mansoni. Channel topology is shown adjacent to the predicted groupings. Prediction of sequence number is intentionally conservative, encompassing only sequences with conservation of key motifs and architecture with human counterparts. Accessory ion channel subunits (nonpore forming) are not included in this figure. Sequence analysis supporting attribution and alignment is provided in Chan et al. (2017b), from which the figure has been modified.

Figure 3.

Praziquantel (PZQ) evoked bipolarity and Ca²⁺ signaling. (A) PZQ-evoked Ca²⁺ signals in dissociated planarian cells. (Inset) Structure of PZQ. Colored traces show fluo-4 fluorescence traces in dissociated single planarian cells on addition of vehicle (DMSO) and PZQ (100 µm). (Right) Images of fluorescence from cells at timepoints “1” and “2” during confocal imaging trace. (Figure modified from data in Zhang et al. 2011.) (B) Bipolar planarian produced by PZQ treatment of trunk fragment.