Antonio Tomasso

All Publications

• Marvels of spiny mouse regeneration: cellular players and their interactions in restoring tissue architecture in mammals. Current opinion in genetics & development Tomasso, A., Disela, V., Longaker, M. T., Bartscherer, K. 2024; 87: 102228

  Abstract

  Understanding the cellular and molecular determinants of mammalian tissue regeneration and repair is crucial for developing effective therapies that restore tissue architecture and function. In this review, we focus on the cell types involved in scarless wound response and regeneration of spiny mice (Acomys). Comparative -omics approaches with scar-prone mammals have revealed species-specific peculiarities in cellular behavior during the divergent healing trajectories. We discuss the developing views on which cell types engage in restoring the architecture of spiny mouse tissues through a co-ordinated spatiotemporal response to injury. While yet at the beginning of understanding how cells interact in these fascinating animals to regenerate tissues, spiny mice hold great promise for scar prevention and anti-fibrotic treatments.

  View details for DOI 10.1016/j.gde.2024.102228

  View details for PubMedID 39047585

• Spatial transcriptomics reveals asymmetric cellular responses to injury in the regenerating spiny mouse (Acomys) ear. Genome research van Beijnum, H., Koopmans, T., Tomasso, A., Disela, V., Te Lindert, S., Bakkers, J., Alemany, A., Berezikov, E., Bartscherer, K. 2023; 33 (8): 1424-1437

  Abstract

  In contrast to other mammals, the spiny mouse (Acomys) regenerates skin and ear tissue, which includes hair follicles, glands, and cartilage, in a scar-free manner. Ear punch regeneration is asymmetric with only the proximal wound side participating in regeneration. Here, we show that cues originating from the proximal side are required for normal regeneration and use spatially resolved transcriptomics (tomo-seq) to understand the molecular and cellular events underlying this process. Analyzing gene expression across the ear and comparing expression modules between proximal and distal wound sides, we identify asymmetric gene expression patterns and pinpoint regenerative processes in space and time. Moreover, using a comparative approach with nonregenerative rodents (Mus, Meriones), we strengthen a hypothesis in which particularities in the injury-induced immune response may be one of the crucial determinants for why spiny mice regenerate whereas their relatives do not. Our data are available in SpinyMine, an easy-to-use and expandable web-based tool for exploring Acomys regeneration-associated gene expression.

  View details for DOI 10.1101/gr.277538.122

  View details for PubMedID 37726147

  View details for PubMedCentralID PMC10547259

• An ERK-dependent molecular switch antagonizes fibrosis and promotes regeneration in spiny mice (Acomys). Science advances Tomasso, A., Koopmans, T., Lijnzaad, P., Bartscherer, K., Seifert, A. W. 2023; 9 (17): eadf2331

  Abstract

  Although most mammals heal injured tissues and organs with scarring, spiny mice (Acomys) naturally regenerate skin and complex musculoskeletal tissues. Now, the core signaling pathways driving mammalian tissue regeneration are poorly characterized. Here, we show that, while immediate extracellular signal-regulated kinase (ERK) activation is a shared feature of scarring (Mus) and regenerating (Acomys) injuries, ERK activity is only sustained at high levels during complex tissue regeneration. Following ERK inhibition, ear punch regeneration in Acomys shifted toward fibrotic repair. Using single-cell RNA sequencing, we identified ERK-responsive cell types. Loss- and gain-of-function experiments prompted us to uncover fibroblast growth factor and ErbB signaling as upstream ERK regulators of regeneration. The ectopic activation of ERK in scar-prone injuries induced a pro-regenerative response, including cell proliferation, extracellular matrix remodeling, and hair follicle neogenesis. Our data detail an important distinction in ERK activity between regenerating and poorly regenerating adult mammals and open avenues to redirect fibrotic repair toward regenerative healing.

  View details for DOI 10.1126/sciadv.adf2331

  View details for PubMedID 37126559

  View details for PubMedCentralID PMC10132760

• Ischemic tolerance and cardiac repair in the spiny mouse (Acomys). NPJ Regenerative medicine Koopmans, T., van Beijnum, H., Roovers, E. F., Tomasso, A., Malhotra, D., Boeter, J., Psathaki, O. E., Versteeg, D., van Rooij, E., Bartscherer, K. 2021; 6 (1): 78

  Abstract

  Ischemic heart disease and by extension myocardial infarction is the primary cause of death worldwide, warranting regenerative therapies to restore heart function. Current models of natural heart regeneration are restricted in that they are not of adult mammalian origin, precluding the study of class-specific traits that have emerged throughout evolution, and reducing translatability of research findings to humans. Here, we present the spiny mouse (Acomys spp.), a murid rodent that exhibits bona fide regeneration of the back skin and ear pinna, as a model to study heart repair. By comparing them to ordinary mice (Mus musculus), we show that the acute injury response in spiny mice is similar, but with an associated tolerance to infarction through superior survivability, improved ventricular conduction, and near-absence of pathological remodeling. Critically, spiny mice display increased vascularization, altered scar organization, and a more immature phenotype of cardiomyocytes, with a corresponding improvement in heart function. These findings present new avenues for mammalian heart research by leveraging unique tissue properties of the spiny mouse.

  View details for DOI 10.1038/s41536-021-00188-2

  View details for PubMedID 34789755

  View details for PubMedCentralID PMC8599451

• Selective killing of spinal cord neural stem cells impairs locomotor recovery in a mouse model of spinal cord injury. Journal of neuroinflammation Cusimano, M., Brambilla, E., Capotondo, A., De Feo, D., Tomasso, A., Comi, G., D'Adamo, P., Muzio, L., Martino, G. 2018; 15 (1): 58

  Abstract

  Spinal cord injury (SCI) is a devastating condition mainly deriving from a traumatic damage of the spinal cord (SC). Immune cells and endogenous SC-neural stem cells (SC-NSCs) play a critical role in wound healing processes, although both are ineffective to completely restore tissue functioning. The role of SC-NSCs in SCI and, in particular, whether such cells can interplay with the immune response are poorly investigated issues, although mechanisms governing such interactions might open new avenues to develop novel therapeutic approaches.We used two transgenic mouse lines to trace as well as to kill SC-NSCs in mice receiving SCI. We used Nestin CreERT2 mice to trace SC-NSCs descendants in the spinal cord of mice subjected to SCI. While mice carrying the suicide gene thymidine kinase (TK) along with the GFP reporter, under the control of the Nestin promoter regions (NestinTK mice) were used to label and selectively kill SC-NSCs.We found that SC-NSCs are capable to self-activate after SCI. In addition, a significant worsening of clinical and pathological features of SCI was observed in the NestinTK mice, upon selective ablation of SC-NSCs before the injury induction. Finally, mice lacking in SC-NSCs and receiving SCI displayed reduced levels of different neurotrophic factors in the SC and significantly higher number of M1-like myeloid cells.Our data show that SC-NSCs undergo cell proliferation in response to traumatic spinal cord injury. Mice lacking SC-NSCs display overt microglia activation and exaggerate expression of pro-inflammatory cytokines. The absence of SC-NSCs impaired functional recovery as well as neuronal and oligodendrocyte cell survival. Collectively our data indicate that SC-NSCs can interact with microglia/macrophages modulating their activation/responses and that such interaction is importantly involved in mechanisms leading tissue recovery.

  View details for DOI 10.1186/s12974-018-1085-9

  View details for PubMedID 29475438

  View details for PubMedCentralID PMC5824446

• Generic wound signals initiate regeneration in missing-tissue contexts. Nature communications Owlarn, S., Klenner, F., Schmidt, D., Rabert, F., Tomasso, A., Reuter, H., Mulaw, M. A., Moritz, S., Gentile, L., Weidinger, G., Bartscherer, K. 2017; 8 (1): 2282

  Abstract

  Despite the identification of numerous regulators of regeneration in different animal models, a fundamental question remains: why do some wounds trigger the full regeneration of lost body parts, whereas others resolve by mere healing? By selectively inhibiting regeneration initiation, but not the formation of a wound epidermis, here we create headless planarians and finless zebrafish. Strikingly, in both missing-tissue contexts, injuries that normally do not trigger regeneration activate complete restoration of heads and fin rays. Our results demonstrate that generic wound signals have regeneration-inducing power. However, they are interpreted as regeneration triggers only in a permissive tissue context: when body parts are missing, or when tissue-resident polarity signals, such as Wnt activity in planarians, are modified. Hence, the ability to decode generic wound-induced signals as regeneration-initiating cues may be the crucial difference that distinguishes animals that regenerate from those that cannot.

  View details for DOI 10.1038/s41467-017-02338-x

  View details for PubMedID 29273738

  View details for PubMedCentralID PMC5741630

• The H3K9 dimethyltransferases EHMT1/2 protect against pathological cardiac hypertrophy. The Journal of clinical investigation Thienpont, B., Aronsen, J. M., Robinson, E. L., Okkenhaug, H., Loche, E., Ferrini, A., Brien, P., Alkass, K., Tomasso, A., Agrawal, A., Bergmann, O., Sjaastad, I., Reik, W., Roderick, H. L. 2017; 127 (1): 335-348

  Abstract

  Cardiac hypertrophic growth in response to pathological cues is associated with reexpression of fetal genes and decreased cardiac function and is often a precursor to heart failure. In contrast, physiologically induced hypertrophy is adaptive, resulting in improved cardiac function. The processes that selectively induce these hypertrophic states are poorly understood. Here, we have profiled 2 repressive epigenetic marks, H3K9me2 and H3K27me3, which are involved in stable cellular differentiation, specifically in cardiomyocytes from physiologically and pathologically hypertrophied rat hearts, and correlated these marks with their associated transcriptomes. This analysis revealed the pervasive loss of euchromatic H3K9me2 as a conserved feature of pathological hypertrophy that was associated with reexpression of fetal genes. In hypertrophy, H3K9me2 was reduced following a miR-217-mediated decrease in expression of the H3K9 dimethyltransferases EHMT1 and EHMT2 (EHMT1/2). miR-217-mediated, genetic, or pharmacological inactivation of EHMT1/2 was sufficient to promote pathological hypertrophy and fetal gene reexpression, while suppression of this pathway protected against pathological hypertrophy both in vitro and in mice. Thus, we have established a conserved mechanism involving a departure of the cardiomyocyte epigenome from its adult cellular identity to a reprogrammed state that is accompanied by reexpression of fetal genes and pathological hypertrophy. These results suggest that targeting miR-217 and EHMT1/2 to prevent H3K9 methylation loss is a viable therapeutic approach for the treatment of heart disease.

  View details for DOI 10.1172/JCI88353

  View details for PubMedID 27893464

  View details for PubMedCentralID PMC5199699

• What makes y family pols potential candidates for molecular targeted therapies and novel biotechnological applications. Current molecular medicine Tomasso, A., Casari, G., Maga, G. 2014; 14 (1): 96-114

  Abstract

  Nature has evolved DNA polymerases (Pols) with different replication fidelity with the purpose of maintaining and faithfully propagating the genetic information. Besides the four classical Pols (Pol α, δ, ε, γ), mammalian cells contain at least twelve specialized Pols whose functions have been discovered recently and are still not completely elucidated. Among them, Pols belonging to the Y family contribute to cell survival by promoting DNA damage tolerance. They are primarily involved in the translesion synthesis (TLS) pathway, incorporating dNTPs in an error-free or error-prone manner, depending on the nature of the DNA lesion. From an evolutionary point of view, their high mutagenic potential seems to guarantee the proper flexibility of vital importance for both adaptation to a changeable environment and evolution of the species. These Pols are subjected to a complex network of regulation, since their uncontrolled access to DNA might promote mutagenesis and neoplastic transformation. Altered expression of Y family is a hallmark of several tumor types. In recent years, the unique structure and properties of Y family Pols have been exploited to design molecules that selectively interfere with the Pol of interest with minimal effect on normal cells. In addition, their distinctive properties have been applied to innovative techniques, such as compartmentalized self-replication (CSR), short-patch CSR, phage display and molecular breeding. These approaches are based on mutant Pols provided with novel and ameliorated features and find applications in various fields, from biotechnology to diagnostics, paleontology and forensic analysis.

  View details for DOI 10.2174/15665240113136660080

  View details for PubMedID 24160487