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Exploring life-long tissue homeostasis through lineage tracing and cell transplantation

ABSTRACT: Using lineage tracing and fate mapping strategies to study vertebrate aging has lagged behind developmental studies, primarily due to of the relatively long lifespans of classical models. Here, we introduce the Killibow, an inducible transgenic model for in-vivo multicolor lineage tracing in the naturally short-lived turquoise killifish (N. furzeri). We demonstrate that Cre-mediated recombination in transgenic fish can generate robust and stochastic labeling that remains stable during aging and regeneration. In addition, to achieve inducible control of recombination, we either utilize in-vivo Cre electroporation or use the tamoxifen system in Killibow-derived cells. To further enable transplantation assays, we establish the first immunocompromised killifish model by mutating rag2. RNA sequencing reveals that rag2 mutants exhibit severely compromised expression of V(D)J recombination products, including immunoglobulins. Accordingly, we demonstrate that clearance of transplanted Killibow-derived cells is delayed in rag2 recipients, and present a proof-of-principle for a KRAS G12D cancer model that is compatible with lineage tracing. Our platform provides the opportunity to examine tissue homeostasis, stem cell function, cancer dynamics, and tissue regeneration at unprecedented temporal resolution during vertebrate aging and disease.

ORGANISM(S): Nothobranchius furzeri

PROVIDER: GSE226279 | GEO | 2026/04/10

REPOSITORIES: GEO

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Project description:In many vertebrate species, age at maturity is proportional to organismal lifespan. A number of theories have attempted to provide a conceptual framework for this fascinating apparent co-evolution. The ‘disposable soma’ theory predicts that costly resources that are invested in germline preservation come at the expense of repairing age-related somatic damage. On the other hand, classical experiments in C. elegans have reported that germline ablation promotes longevity via endocrine signals mediated by the somatic gonad. However, how these seemingly opposing mechanisms may affect vertebrate aging is largely unknown. Here, we use the naturally short-lived turquoise killifish (N. furzeri) to demonstrate that germline ablation can enhance damage repair and promote vertebrate longevity. This was achieved by producing a detailed single-cell atlas of the killifish ovary and testis, and generating a panel of genetic perturbations to manipulate the killifish reproductive state. Specifically, we either block costly stages of germline differentiation by mutating gonadotropins and their receptors, or alternatively, ablate the germline altogether by mutating the dnd1 gene (dead end). Interestingly, only germline ablation enhances somatic repair, particularly in females, by improving tail regeneration following genotoxic stress. To investigate the observed sexual dimorphism, we directly compare several somatic cell types from WT and dnd1 fish. We identify a surprising male-specific upregulation of pro-longevity pathways, including protein homeostasis and stress resistance. Accordingly, only germline-depleted males experience a significant extension in maximal lifespan. Together, dissecting distinct paradigms of germline manipulations, reveals a functional link between the reproductive state, damage repair, and longevity. The sex-specific effect further supports the concept that phenotypes are independent of resource allocation, and instead, could be the result of a possible endocrine effect. Our findings may therefore have exciting implications for uncoupling the reproductive state from vertebrate aging.

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Exploring life-long tissue homeostasis through lineage tracing and cell transplantation

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