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Integrative Analysis of Axolotl Gene Expression Data from Regenerative and Wound Healing Limb Tissues.

ABSTRACT: Axolotl (Ambystoma mexicanum) is a urodele amphibian endowed with remarkable regenerative capacities manifested in scarless wound healing and restoration of amputated limbs, which makes it a powerful experimental model for regenerative biology and medicine. Previous studies have utilized microarrays and RNA-Seq technologies for detecting differentially expressed (DE) genes in different phases of the axolotl limb regeneration. However, sufficient consistency may be lacking due to statistical limitations arising from intra-laboratory analyses. This study aims to bridge such gaps by performing an integrative analysis of publicly available microarray and RNA-Seq data from axolotl limb samples having comparable study designs using the "merging" method. A total of 351 genes were found DE in regenerative samples compared to the control in data of both technologies, showing an adjusted p-value?1. Downstream analyses illustrated consistent correlations of the directionality of DE genes within and between data of both technologies, as well as concordance with the literature on regeneration related biological processes. qRT-PCR analysis validated the observed expression level differences of five of the top DE genes. Future studies may benefit from the utilized concept and approach for enhanced statistical power and robust discovery of biomarkers of regeneration.

SUBMITTER: Sibai M

PROVIDER: S-EPMC6937273 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Integrative Analysis of Axolotl Gene Expression Data from Regenerative and Wound Healing Limb Tissues.

Sibai Mustafa M Parlayan Cüneyd C Tuğlu Pelin P Öztürk Gürkan G Demircan Turan T

Scientific reports 20191230 1

Axolotl (Ambystoma mexicanum) is a urodele amphibian endowed with remarkable regenerative capacities manifested in scarless wound healing and restoration of amputated limbs, which makes it a powerful experimental model for regenerative biology and medicine. Previous studies have utilized microarrays and RNA-Seq technologies for detecting differentially expressed (DE) genes in different phases of the axolotl limb regeneration. However, sufficient consistency may be lacking due to statistical limi ...[more]

PMID: 31889169

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Project description:BackgroundAlthough the sequence of events leading to wound repair has been described at the cellular and, to a limited extent, at the protein level this process has yet to be fully elucidated. Genome wide transcriptional analysis tools promise to further define the global picture of this complex progression of events.Study designThis study was part of a placebo-controlled double-blind clinical trial in which basal cell carcinomas were treated topically with an immunomodifier--toll-like receptor 7 agonist: imiquimod. The fourteen patients with basal cell carcinoma in the placebo arm of the trial received placebo treatment consisting solely of vehicle cream. A skin punch biopsy was obtained immediately before treatment and at the end of the placebo treatment (after 2, 4 or 8 days). 17.5K cDNA microarrays were utilized to profile the biopsy material.ResultsFour gene signatures whose expression changed relative to baseline (before wound induction by the pre-treatment biopsy) were identified. The largest group was comprised predominantly of inflammatory genes whose expression was increased throughout the study. Two additional signatures were observed which included preferentially pro-inflammatory genes in the early post-treatment biopsies (2 days after pre-treatment biopsies) and repair and angiogenesis genes in the later (4 to 8 days) biopsies. The fourth and smallest set of genes was down-regulated throughout the study. Early in wound healing the expression of markers of both M1 and M2 macrophages were increased, but later M2 markers predominated.ConclusionThe initial response to a cutaneous wound induces powerful transcriptional activation of pro-inflammatory stimuli which may alert the host defense. Subsequently and in the absence of infection, inflammation subsides and it is replaced by angiogenesis and remodeling. Understanding this transition which may be driven by a change from a mixed macrophage population to predominantly M2 macrophages, may help the interpretation of the cellular and molecular events occurring in the microenvironment of serially biopsied tissues.

Project description:Mouse fetuses up to 16 day of embryonic development and nude (Foxn1- deficient) mice are examples of animals that undergo regenerative (scar-free) skin healing. The expression of transcription factor Foxn1 in the epidermis of mouse fetuses begins at embryonic day 16.5 which coincides with the transition point from scar-free to scar-forming skin wound healing. In the present study, we tested the hypothesis that Foxn1 expression in the skin is an essential condition to establish the adult skin phenotype and that Foxn1 inactivity in nude mice keeps skin in the immature stage resembling the phenomena of neoteny.Uninjured skin of adult C57BL/6J (B6) mice, mouse fetuses at days 14 (E14) and 18 (E18) of embryonic development and B6.Cg-Foxn1 nu (nude) mice were characterized for their gene expression profiles by RNA sequencing that was validated through qRT-PCR, Western Blot and immunohistochemistry. Differentially regulated genes indicated that nude mice were more similar to E14 (model of regenerative healing) and B6 were more similar to E18 (model of reparative healing). The up-regulated genes in nude and E14 mice were associated with tissue remodeling, cytoskeletal rearrangement, wound healing and immune response, whereas the down-regulated genes were associated with differentiation. E14 and nude mice exhibit prominent up-regulation of keratin (Krt23, -73, -82, -16, -17), involucrin (Ivl) and filaggrin (Flg2) genes. The transcription factors associated with the Hox genes known to specify cell fate during embryonic development and promote embryonic stem cells differentiation were down-regulated in both nude and E14. Among the genes enriched in the nude skin but not shared with E14 fetuses were members of the Wnt and matrix metalloproteinases (Mmps) families whereas Bmp and Notch related genes were down-regulated.In summary, Foxn1 appears to be a pivotal control element of the developmental program and skin maturation. Nude mice may be considered as a model of neoteny among mammals. The resemblance of gene expression profiles in the skin of both nude and E14 mice are direct or indirect consequences of the Foxn1 deficiency. Foxn1 appears to regulate the balance between cell proliferation and differentiation and its inactivity creates a pro-regenerative environment.

Dataset Information

Integrative Analysis of Axolotl Gene Expression Data from Regenerative and Wound Healing Limb Tissues.

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Integrative Analysis of Axolotl Gene Expression Data from Regenerative and Wound Healing Limb Tissues.

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