Regeneration in distantly related species: common strategies and pathways

Abstract

While almost all animals are able to at least partially replace some lost parts, regeneration abilities vary considerably across species. Here we study gene expression patterns in distantly related species to investigate conserved regeneration strategies. To this end, we collect from the literature transcriptomic data obtained during the regeneration of three species (Hydra magnipapillata, Schmidtea mediterranea, and Apostichopus japonicus), and compare them with gene expression during regeneration in vertebrates and mammals. This allows us to identify a common set of differentially expressed genes and relevant shared pathways that are conserved across species during the early stage of the regeneration process. We also find a set of differentially expressed genes that in mammals are associated to the presence of macrophages and to the epithelial-mesenchymal transition. This suggests that features of the sophisticated wound healing strategy of mammals are already observable in earlier emerging metazoans.

Fig. 1

Transcriptome annotation. Figure shows the number of genes and DE genes annotated against at least one human gene according to Swissprot database for H. magnipapillata, S. mediterranea, and A. japonicus. Functional annotation of DE genes was performed for each species, top enriched and depleted Panther go-slim biological processes and pathways is shown. Swissprot annotation of DE genes during mouse liver regeneration is shown for comparison. Symbols indicate corrected p-value ≤ 0.05

Fig. 2

Pattern of expression of DE genes. a Total number of DE genes and early/late upregulated (EU/LU) and downregulated (ED/LD) genes for the considered organisms. The expression profile of S. mediterranea head and tail regenerations is considered separately, as well as the DE genes shared between the two processes. b The expression profile of two illustrative human genes DE in all the considered regeneration processes. Calmodulin show a coherent expression profile among organisms, while Anoctamin-7 is differentially expressed in the organisms. Time is rescaled and normalized in order to make the timescales comparable. c Figure shows the average expression level as a function of time of exemplificative clusters of genes resulting transiently down/upregulated and continuously down/upregulated during the regeneration process for H. magnipapillata, S. mediterranea, A. japonicus, and rat

Fig. 3

Transcriptome co-annotation. a Human best-match of genes co-annotated between H. Magnipapillata (HM), S. Mediterranea (SM), and A. Japonicus (AJ). Most of these genes are also ortholog in mouse and annotated in axolotl. b The subset of human genes that are both co-annotated and differentially expressed in all the three considered organisms have a small superimposition with genes differentially expressed during mouse and axolotl regenerations. c Panther annotation of relevant biological processes, molecular function, and pathways of the 18 human best-match proteins that are both co-annotated and differentially expressed in H. Magnipapillata, S. Mediterranea, and A. Japonicus

Fig. 4

Macrophage-related and neutrophil-related genes. List of the 20 macrophage-related and neutrophil-related proteins present (green square) in the human best match annotation of at least one of the considered organisms. List match annotation of the same genes (half green square) is included for comparison. Filled rectangles indicate DE genes considering only human best match annotation, empty rectangles indicate DE genes when list-match annotation is considered. For a complete list-match annotation, see also Suppl. Figure 4

Fig. 5

Signature of masenchymal phenotype during regeneration process. Number of genes related to (a) EMT and (b) involved in adherens junction detected in H. magnipapillata (HM), S. mediterranea (SM), and A. japonicus (AJ) transcriptomes (left) and differentially expressed during regeneration process (right). Numbers reported close to the species label indicates the corresponding number of genes. (c) Biological processes annotation of the 76 EMT-related proteins represented in the considered organisms (right, violet bars) and the 54 not detected (left, purple). (d) Histogram shows the comparison between fraction of total DE genes and EMT-annotated genes that result in deregulated during regeneration process for the three organisms