Aging impairs the essential contributions of non-glial progenitors to neurorepair in the dorsal telencephalon of the KillifishN. furzeri

Abstract

The aging central nervous system (CNS) of mammals displays progressive limited regenerative abilities. Recovery after loss of neurons is extremely restricted in the aged brain. Many research models fall short in recapitulating mammalian aging hallmarks or have an impractically long lifespan. We established a traumatic brain injury model in the African turquoise killifish (Nothobranchius furzeri), a regeneration-competent vertebrate model that evolved to naturally age extremely fast. Stab-wound injury of the aged killifish dorsal telencephalon unveils an impaired and incomplete regeneration response when compared to young individuals. Remarkably, killifish brain regeneration is mainly supported by atypical non-glial progenitors, yet their proliferation capacity appears declined with age. We identified a high inflammatory response and glial scarring to also underlie the hampered generation of new neurons in aged fish. These primary results will pave the way for further research to unravel the factor age in relation to neurorepair, and to improve therapeutic strategies to restore the injured and/or diseased aged mammalian CNS.

Single-cell sequencing unravels the cellular diversity that shapes neuro- and gliogenesis in the fast aging killifish (N. furzeri) brain

“…To further refine the clustering, we performed iterative sub-clustering followed by lineage inference analyses of progenitor-like (PCs) and neuronal (NCs) cells separately and found 4 RG subtypes and novel cell types marking the transition between PCs and neurons. Our results elaborate previous research conducted on both juvenile and adult killifish discussing the expression of primary progenitors and glial markers in NGP and RG respectively 9,16 , and decode the relationship between these two progenitor classes. Extensive datasets like ours can be used for detailed investigations of the young adult killifish brain as well as act as an updated database for further research in the direction of neuroregenerative medicine.…”

“…Particularly, NGP and NE-RG3 together show exceptional stem-cell potential to transform into a multitude of cell types. Since radial glia do not seem to support neurogenesis as much as NGP do in the killifish telencephalon 9,16 , they might be contributing to astrocytic functions based on gene expression profiling. Thus, the presumptive central role of NGP within the diverse repertoire of radial glia is intriguing.…”

“…It is therefore extremely important to elucidate which regenerative strategies are used in vertebrate regeneration-competent animals, like urodeles and fish. Especially teleost fish have gained much attention in regenerative medicine since 70% of coding genes of zebrafish are conserved 8 , whilst killifish share 60% of genes with humans 9 . Similar to mammals, the teleost telencephalon is divided into a dorsal pallium and a ventral subpallium.…”

“…Both options hold merit but remain unexplored in adult killifish. Since the turquoise killifish is fast growing, reaching its full body size (~2.5 inches) in about 6 weeks 17 , it is of utmost importance to discover which progenitors types support such rapid neurogenesis and attain neuroregenerative ability at young adult age, yet lose this at old age 9 . This kind of CNS regenerative ability typically exhibited by teleosts is potentially of high clinical value, and cannot be easily studied using mammalian models 18 .…”

Differential Regenerative Capacity of the Optic Tectum of Adult Medaka and Zebrafish

“…In addition to zebrafish, goldfish ( Carassius auratus ) and brown ghost knifefish ( Apteronotus leptorhynchus ) are known to have high CNS regeneration potential ( Bernstein, 1964 ; Stevenson and Yoon, 1978 ; Zupanc, 1999 ; Sîrbulescu et al, 2009 ). In addition to these teleosts, recently, various other species including salmonoids (masu and chum salmon) ( Pushchina et al, 2017 , 2020 ) and killifish (mummichog, Aphaniops hormuzensis , and Nothobranchius furzeri ) ( Bisese et al, 2019 ; Soltani et al, 2020 ; Van houcke et al, 2021 ) have been explored as models to assess the mechanisms regulating the CNS regenerative potential. Previous studies showed that only medaka have low CNS regenerative potential, regardless of age and health condition ( Lust and Wittbrodt, 2018 ).…”