Abstract
Purpose :
Zebrafish have the innate ability to regenerate lost or damaged retinal neurons. Recently, it has been shown that during the course of retina regeneration, a population of immune cells becomes senescent and contributes to the regenerative phenotype. These senescent cells are metabolically active through their senescence-associated secretory phenotype (SASP), which includes many cytokines, metalloproteases, and extracellular matrix factors. SASP factors influence the microenvironment, but their exact identity and expression pattern are not well established during retina regeneration.
Methods :
The most upregulated SASP factors were extracted from the soluble protein SASP Atlas under different conditions that induce senescence. Zebrafish orthologs of these factors were identified in the ZFIN database and then compared to RNAseq databases deposited by Kramer et al. 2021 (GSE180518) and Hoang et al. 2020 (GSE135406). This allowed for the identification of select inflammatory and senescence markers across long (Kramer) or short (Hoang) regeneration timelines.
Results :
Changes in transcript expression after light lesion (Kramer et al.) revealed that SASP factors and markers of senescent cells were enriched at early time points, followed by decreased enrichment out to 28 days post injury (dpi). Anti-inflammatory factors were generally downregulated throughout. After NMDA damage, SASP factors largely did not show differential expression between 4 and 36 hours post injury (hpi) (Hoang et al.). The SASP factors mmp9 and npm1a were highly upregulated between 24 and 36 hpi after both damage paradigms; psme1 was also highly upregulated after light damage only.
Conclusions :
SASP activity appears to be higher at early time points post light damage, coincident with the detection of senescent cells. mmp9 and npm1a are highly enriched SASP factors across both datasets and damage models. NMDA damage did not show significant enrichment of SASP factors before 36 hpi, which aligns with previous findings that senescent cells do not appear until around 48 hpi in this damage paradigm. Taken together, this data shows heterogeneity in the SASP response to different damage models, but agrees with the hypothesis that SASP activity is transient and decreases over the course of regeneration.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.