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Seth Blackshaw @sethblackshaw.bsky.social · 1d

Very proud to have Leah working with us.

Jane Coffin Childs Fund for Medical Research @jcchildsfund.bsky.social · 1d

Leah Elias, Ph.D., is our Featured Fellow! Elias' postdoctoral research in @sethblackshaw.bsky.social's lab is dissecting how the need for restorative sleep is encoded into our brains at the level of cellular circuits and molecular signals. Her findings may reveal novel therapeutic targets ...
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Reposted by Seth Blackshaw

Jane Coffin Childs Fund for Medical Research @jcchildsfund.bsky.social · 1d

Leah Elias, Ph.D., is our Featured Fellow! Elias' postdoctoral research in @sethblackshaw.bsky.social's lab is dissecting how the need for restorative sleep is encoded into our brains at the level of cellular circuits and molecular signals. Her findings may reveal novel therapeutic targets ...
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Seth Blackshaw @sethblackshaw.bsky.social · 8d

Exciting new study shows that organoid-derived human retinal ganglion cells survive when apoptosis is genetically inhibited.

Jingliang Simon Zhang @simonomisz.bsky.social · 8d

Excited to share my PhD work! We characterize waves of cell death during human retinal development, and show how blocking apoptosis promotes RGC long-term survival and alters their developmental dynamics in organoids. These findings will improve future organoid design for retinal disease modeling‼️

Bob Johnston @bobbyjeyeguy.bsky.social · 8d

Check this paper from @simonomisz.bsky.social in our lab!
www.biorxiv.org/cgi/content/...
Human retinas/organoids go through 2 apoptotic waves. Organoids also have a necrotic wave. Blocking apoptosis promotes RGC survival to day 200 (usually die!). Apoptosis promotes normal neurogenesis/maturation.

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Seth Blackshaw @sethblackshaw.bsky.social · 25d

Kudos to everyone who contributed to this, particularly Pin Lyu, Isabella Palazzo, Yang Jin, Leah Campbell, and co-corresponding authors David Hyde and Jiang Qian./end

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Seth Blackshaw @sethblackshaw.bsky.social · 25d

Muller glia-specific expression of Yamanaka factors induces modest but significantrejuvenative effects on rod and bipolar cells. Similar approaches may prove equally informative in humans./36

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Seth Blackshaw @sethblackshaw.bsky.social · 25d

Finally, spatial transcriptomics proved particularly informative in identifying prorejuvenative effects of mouse Muller glia and heterogeneity in aging rods./35

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Seth Blackshaw @sethblackshaw.bsky.social · 25d

Age-dependent changes in gene expression and regulation often unexpectedly (to us at least) represented homeostatic changes that potentially counteract the effects of inflammation and other deleterious aging-regulated processes. Reversing the age-dependent changes may prove counterproductive./34

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Seth Blackshaw @sethblackshaw.bsky.social · 25d

Mostly, though, if you want to study the translation relevance of aging, work in humans. These datasets will likely prove useful in evaluating organoid-based models of retinal aging, and help identify age-dependent mechanisms increasing risk for AMD and glaucoma progression./33

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Seth Blackshaw @sethblackshaw.bsky.social · 25d

Aging mouse and human retinas don’t have all that much in common with one another at the level of gene expression or regulation, or cell-cell signaling. although a few common and potentially useful homologies were identified./32

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Seth Blackshaw @sethblackshaw.bsky.social · 25d

So after all that, what are the take home messages. First, There’s a lot to take from this data, but I think that the main points are that age-dependent expression changes are _highly_ species, sex, and cell type-specific./31

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Seth Blackshaw @sethblackshaw.bsky.social · 25d

After one month of doxycycline treatment, Xenium and clock analysis showed rods and bipolars, though not Muller glia, were modestly but significantly rejuvenated. NicheNet confirmed rods shifted toward a young-like, photoreceptor-enriched state resembling Niche 8./30

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Seth Blackshaw @sethblackshaw.bsky.social · 25d

Inspired by this, we tested rejuvenation strategies. We selectively expressed Yamanaka factors Oct4, Sox2, and Klf4 in Muller glia using a tamoxifen-inducible GlastCreER system with tetON control, driving low-level, sustained expression in adult mouse retina./29

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Seth Blackshaw @sethblackshaw.bsky.social · 25d

Using NicheNet, we identified rod-specific age-dependent niches: Niche 8, enriched in young rods with photoreceptor genes, and Niche 11, enriched in aged rods with Col4a3 and proinflammatory Ly75. These niches highlight distinct pro-youth vs. pro-aging states./28

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Seth Blackshaw @sethblackshaw.bsky.social · 25d

Xenium spatial data also revealed some surprising aging-related cell-cell interactions. Muller glia exerted broad pro-rejuvenative effects on neighboring cells, especially rod photoreceptors, bipolar cells, and amacrine interneurons, suggesting they help buffer against aging-related decline./27

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Seth Blackshaw @sethblackshaw.bsky.social · 25d

Gene expression changes observed using snRNA-Seq generally replicated in Xenium analysis. This shows plots of several aging-regulated genes in Muller glia./27

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Seth Blackshaw @sethblackshaw.bsky.social · 25d

To further examine aging-dependent changes in situ, we performed Xenium5k analysis in mouse retina, simultaneously measuring ~5,000 genes at 1 μm resolution. This mapped all major retinal cell types and enabled construction of cell-type-specific aging clocks across the tissue./26

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Seth Blackshaw @sethblackshaw.bsky.social · 25d

But as with gene expression and regulation, we detected few evolutionarily conserved patterns of cell-cell signaling./25

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Seth Blackshaw @sethblackshaw.bsky.social · 25d

In all three species, aged cells showed more complex patterns of cell-cell signaling, with Muller glia acting as signaling hubs, particularly in zebrafish and mouse./24

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Seth Blackshaw @sethblackshaw.bsky.social · 25d

In mouse Muller glia, we saw upregulation of gliogenesis-related TFs such as Nfix, Hes5, and Sox9 in aged cells. This may reflect compensatory gliogenic activity. Interestingly, this pattern was absent in humans, which showed weaker age-linked inflammatory shifts./23

Seth Blackshaw @sethblackshaw.bsky.social · 25d

Photoreceptor-specific TFs such as Crx, Neurod1, and Nrl also changed with age, in both young and old cells. This likely reflects homeostatic compensation, as inflammation and stress suppress photoreceptor gene programs, forcing ongoing regulatory adjustments./22

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Seth Blackshaw @sethblackshaw.bsky.social · 25d

In rod photoreceptors, stress- and metabolism-related transcription factors, including FoxO3, Esrrg, Stat1, and the glucocorticoid receptor Nr3c1, became more active with age. These factors align with known stress response and inflammatory signaling pathways./21

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Seth Blackshaw @sethblackshaw.bsky.social · 25d

By integrating scRNA-Seq with scATAC-Seq, we mapped transcription factor activity in young vs. aged cells. This revealed robust age-dependent regulatory shifts, though again with strong dependence on species and cell type, and limited evolutionary conservation./20

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Seth Blackshaw @sethblackshaw.bsky.social · 26d

Still, a few broad regulators emerged: fat4, an atypical cadherin, was age-regulated in zebrafish; Stat1, an inflammatory signal transducer, in mice; and metallothionein 1F, a stress response gene, in humans. These may represent conserved functional stress axes./19

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Seth Blackshaw @sethblackshaw.bsky.social · 26d

Gene regulation with aging is also highly cell-type specific. Very few genes showed consistent aging patterns across more than two or three retinal cell types. Each population ages in a distinct transcriptional trajectory, with limited overlap across lineages./18

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Seth Blackshaw @sethblackshaw.bsky.social · 26d

Pairwise conservation was not higher between human and mouse than between either species and zebrafish. This is notable because mouse is often assumed to better model human aging, but our data suggest zebrafish may be equally informative for some comparisons./17

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