rrust.bsky.social
Asst Prof at @keckmedicineusc.bsky.social with interest in the #brain, #BBB, #stemcells and what can go wrong following #stroke & #AD. 🧠 🔬 Alumni of @ethzurich.bsky.social
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Check out the preprint, we appreciate any feedback:
www.biorxiv.org/content/10.1...
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Since mouse pericytes have been shown to clear Aβ and tau from the brain, we showed that our iPSC-pericytes are also capable of clearing Aβ and tau, and that this clearance is dependent on the lipoprotein receptor LRP1, a major Aβ clearance receptor.
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Functionally, iPSC-pericyte transplantation locally restored BBB integrity and promoted neuronal survival in the hippocampus of pericyte-deficient mice
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To assess if the homing effect can be also seen in vivo, we next transplanted iPSC-pericytes into the hippocampi of pericyte-deficient mice. Similar to the ex vivo results, we confirmed that iPSC-pericytes can home to brain capillaries of mice in vivo
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Next, we confirmed a functional iPSC-pericyte–vasculature association using a proximity ligation assay (PLA) targeting two known pericyte–endothelium interactions: PDGF-BB/PDGFRB and vitronectin/ITGA5
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To assess the specificity of homing, we downregulated PDGFRB a key pericyte surface receptor involved in cell adhesion in iPSC-pericytes (using siRNA), which resulted in reduced homing.
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Then we asked whether iPSC-pericytes can home to brain capillaries in host brains with reduced pericyte coverage. We added our cells to live brain slices of pericyte-deficient mice
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Next we show iPSC-pericytes help with the formation of blood-brain barrier tight junction proteins in human brain endothelial cells.
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We first compared iPSC-pericytes and primary pericytes using proteomics/phosphoproteomics and found no major differences—iPSC-PC shared 96% of proteins and 98% of phosphopeptides, including key markers, adhesion proteins, and TFs.
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We also discuss few recent studies using e.g. gene and cell therapies to improve BBB integrity and neuronal function and much more!
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So how can we protect or modify BBB function in AD?
One option is to enhance the clerance function for neurotoxic proteins at the BBB e.g. targeting lipoprotein receptors (LRP)
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BBB breakdown can significantly affect neuronal and synaptic function and neurodegenerative processes.
We think that more attention should focus on therapeutics to preserve BBB functions when considering treatments of neurodegenerative diseases including AD.
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Very cool! Thanks for sharing ☺️
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@kevinbonham.com thanks Kevin! Did it myself, always happy to contribute to some work if you need similar illustrations! ☺️
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@profbrunt.bsky.social Please keep in mind for this study we did local transplantations. Here is an older one looking at systemic injections: pubmed.ncbi.nlm.nih.gov/19617198/
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@profbrunt.bsky.social great Q, a bit difficult to estimate for us because NPC also proliferate few times before maturation. But we estimate that we have a initial survival of 20-40%. We have a bit of experience with preconditioning so we can get probably >50% survival.
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We found that increased long-term graft survival was mainly due to higher NPC proliferation within days after transplantation. In both groups, most grafts differentiated into neurons or glia, with no pluripotent residuals at 6 weeks after stroke
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+ if a traditional paper gets rejected, often my reviews are kind of wasted time…since the authors just resubmit to the next journal…
Happy to chat more about it!
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the 150 USD in RSC is a great incentive imo; ofc for some of us it’s not a lot of money (for others it is though) but I personally love reviewing papers and learn a lot from it - and for all my reviews to high IF journals I got 0 USD.
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@david4096.bsky.social I was skeptical at first too; but started reviewing for them and now work as an editor.
I love the concept of preprint + open community review, imo, this is far better than the current publishing landscape.