iiinova — where your digital self keeps evolving

Steven Sloan @sloanlab.bsky.social · 02/04/2026

Beautifully crafted by Nardos Kebede in the lab. Hope you enjoy!

Steven Sloan @sloanlab.bsky.social · 02/04/2026

We also discuss a bit about how these progenitors can be defined, and the molecular signatures that label them as well as drive their differentiation trajectories.

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Steven Sloan @sloanlab.bsky.social · 02/04/2026

This is particularly relevant for a newly defined class of cells that has garnered dozens (!!!) of names in recent years. We nominate a more unified nomenclature, and explain our view of how all of these populations represent overlapping cell states

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Steven Sloan @sloanlab.bsky.social · 02/04/2026

Neurodevelopment is such a fun field because so much is new to explore and define. But also that means it can be unclear. In our new review out this week @cp-trendsneuro.bsky.social, we try to synthesize the confusing field of neural intermediate progenitors authors.elsevier.com/a/1msKvbotqB...

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Steven Sloan @sloanlab.bsky.social · 30/03/2026

There's so much more packed into this work, so please check it out as we continue to investigate these questions!!! This is all possible because of an amazing scientific collaborative team @emorygenetics.bsky.social, @brainorganoidhub.bsky.social, and our funders.

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Steven Sloan @sloanlab.bsky.social · 30/03/2026

We think there are important implications here. Can astrocyte reactivity be reversed in the setting of neurologic disease? Why do astrocytes present peptides via MHCII? Is this pro- or anti-inflammatory for T-cells???

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Steven Sloan @sloanlab.bsky.social · 30/03/2026

And after all this, we wondered if it may be happening in adult human patient samples, too. We looked in biopsies of brain abscesses where chronic inflammation is likely, and found lots of MHCII positive astrocytes. We even saw examples in aged brains without other pathologies.

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Steven Sloan @sloanlab.bsky.social · 30/03/2026

Then we tried something fancier. We isolated peptides from human neurons and co-cultured with astrocytes in the presence of cytokines. After MHCII pulldown and MS we found lots of neuronal peptides associated with MHCII!!

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Steven Sloan @sloanlab.bsky.social · 30/03/2026

We found enrichment of proteins linked to MHCII processing (left heatmap) across nearly all pulldowns. We also identified unique peptide fragments in each sample (right), which were more likely to have endogenous cleavage rather than trypsin digestion during mass spec prep.

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Steven Sloan @sloanlab.bsky.social · 30/03/2026

What could astrocytes be presenting? This is really hard to figure out in human models, but we took a stab at it. We pulled down MHCII proteins in astrocytes and performed mass spec to see what peptide fragments came with it.

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Steven Sloan @sloanlab.bsky.social · 30/03/2026

We thought maybe this was some artifact related to organoids. But no! We see the same thing in primary human cortical slices. We see MHCII at the cell surface AND we see CD74 loaded onto MHCII only in the presence of inflammatory cytokines

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Steven Sloan @sloanlab.bsky.social · 30/03/2026

ok, but surprise! Remember those time-dependent genes that only turn on with prolonged inflammatory exposure? Almost all were related to MHCII presentation. We thought this must be a mistake. Astrocytes are not canonical antigen presenting cells! But we see this also by protein staining.

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Steven Sloan @sloanlab.bsky.social · 30/03/2026

More to come on that in a sec. But FIRST! We had another question. If you make astrocytes "reactive", can they reverse back to a "normal" state if you remove the inflammatory cue? Does it matter how long the initial inflammatory signal lasts before withdrawing it? The answer is generally, YES!

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Steven Sloan @sloanlab.bsky.social · 30/03/2026

Looking across transcriptomic and chromatin accessibility landscapes, we saw 3 clear patterns: some genes and loci react immediately to cytokines, while others emerge only with sustained exposure. A small group of genes also turn off quite quickly.

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Steven Sloan @sloanlab.bsky.social · 30/03/2026

So then we wondered whether it mattered how long astrocytes see an inflammatory environment. After all, some neurological injuries are very short-lasting, and others chronic. So, we exposed aged organoids with astrocytes to very short (1 day) or long (3 months) inflammatory periods.

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Steven Sloan @sloanlab.bsky.social · 30/03/2026

We started with a simple question. We know astrocytes form in human cortical organoids, but can we induce reactivity in 3D, and at more immature ages? Answer is yes. See C3 induction here in the setting of inflammatory cytokines. RNAseq shows robust reactive signatures, too!

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Steven Sloan @sloanlab.bsky.social · 30/03/2026

New work from our team, led by the incredible @emily-hill.bsky.social out today @cp-neuron.bsky.social. Including some exciting additions from our prepint. Thread below! authors.elsevier.com/a/1ms0u3BtfH...

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Steven Sloan @sloanlab.bsky.social · 30/03/2026

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Steven Sloan @sloanlab.bsky.social · 30/03/2026

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Steven Sloan @sloanlab.bsky.social · 30/03/2026

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Steven Sloan @sloanlab.bsky.social · 30/03/2026

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Steven Sloan @sloanlab.bsky.social · 30/03/2026

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Steven Sloan @sloanlab.bsky.social · 30/03/2026

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Steven Sloan @sloanlab.bsky.social · 30/03/2026

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Steven Sloan @sloanlab.bsky.social · 30/03/2026

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Steven Sloan @sloanlab.bsky.social · 30/03/2026

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Steven Sloan @sloanlab.bsky.social · 30/03/2026

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Steven Sloan @sloanlab.bsky.social · 30/03/2026

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Steven Sloan @sloanlab.bsky.social · 21/08/2025

This wouldn’t have been possible without our amazing collaborators and support (Emory HERCULES, @emorygenetics.bsky.social) and the bold and fearless ambition of @maureenbiologies.bsky.social

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Steven Sloan @sloanlab.bsky.social · 21/08/2025

There is so much more packed into the pre-print, including some evidence on how this is all working via PRC2 disruption, so please take a look!

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Steven Sloan @sloanlab.bsky.social · 21/08/2025

Then came one of our most astonishing observations. We exposed human progenitors to a 10-day pulse of Pb before xenografting. We left the cells for 7 weeks (!) without any more Pb in the mouse at all. THEN, we isolated these human cells and saw robust evidence of metal response genes STILL active!!

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Steven Sloan @sloanlab.bsky.social · 21/08/2025

But maybe again this is an artifact of in vitro culture conditions? So, we worked closely with our amazing collaborators Ye Zhang and @bhadurilab.bsky.social to perform xenograft experiments into the mouse cortex. Human progenitors exposed to Pb engrafted readily throughout the mouse brain.

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Steven Sloan @sloanlab.bsky.social · 21/08/2025

When we look at the composition of clone families, we again saw an increase in neuronal progenitor populations at the expense of glial progenitors.

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Steven Sloan @sloanlab.bsky.social · 21/08/2025

But we wanted a more sophisticated approach for verifying this cell fate change. We used genetic lineage tracing approaches in cultured human progenitors where we could identify individual clone families as they differentiate in the presence or absence of Pb.

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Steven Sloan @sloanlab.bsky.social · 21/08/2025

Turns out, we saw the same striking shift of cell fate away from astrocyte lineages. Sometimes by as much as a 50% decrease!

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Steven Sloan @sloanlab.bsky.social · 21/08/2025

Maybe this was some artifact of working with organoids? We optimized protocols for isolating primary human neural progenitors so we could find out.

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Steven Sloan @sloanlab.bsky.social · 21/08/2025

Once we knew Pb was getting into cells, we next wanted to know how it affected neural differentiation. One of the most striking observations we saw across multiple hiPSC lines was a shift in cell fate away from astrocytes and towards excitatory neurons.

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Steven Sloan @sloanlab.bsky.social · 21/08/2025

Could we then observe Pb being actively taken up by human neural cells? Yes! A human Pb sensor (leadmium) let us literally watch Pb uptake over the course of several hours into human neurons and astrocytes.

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Steven Sloan @sloanlab.bsky.social · 21/08/2025

One of the first challenges we had was figuring out how much Pb to give to human cells to reflect true exposure levels. We dug through the literature for relevant Pb levels in brain and then empirically correlated this with exposure paradigms that resulted in similar tissue levels in human organoids

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Steven Sloan @sloanlab.bsky.social · 21/08/2025

We decided to investigate one of the most infamous and widely prevalent neurotoxicants—Lead (Pb). In the US, approximately 2.5% of pregnant women exhibit high blood Pb levels (!!!) What is the consequence of this on the developing human brain?

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Steven Sloan @sloanlab.bsky.social · 21/08/2025

Excited to share an important new pre-print from the lab led by incredibly talented postdoc @maureenbiologies.bsky.social, a neurotoxicologist who came to the lab with an ambitious goal of understanding the consequences of toxicant exposure in human neurodevelopment. www.biorxiv.org/content/10.1...