Less Deformable Erythrocyte Subpopulations Biomechanically Induce Endothelial Inflammation in Sickle Cell Disease (Caruso et al 2024)

Emory University School of Medicine, Atlanta, Georgia, United States.



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. 2024 Aug 23

• DOI: 10.1182/blood.2024024608

Abstract
Sickle cell disease (SCD) is canonically characterized by reduced red blood cell (RBC) deformability leading to microvascular obstruction and inflammation. While the biophysical properties of sickle RBCs are known to influence SCD vasculopathy, the contribution of poor RBC deformability to endothelial dysfunction has yet to be fully explored.

Leveraging interrelated in vitro and in silico approaches, we introduce a new paradigm of SCD vasculopathy in which poorly deformable sickle RBCs directly cause endothelial dysfunction via mechanotransduction, where endothelial cells sense and pathophysiologically respond to aberrant physical forces independently of microvascular obstruction, adhesion, or hemolysis. We demonstrate that perfusion of sickle RBCs or pharmacologically-dehydrated healthy RBCs into small venule-sized "endothelialized" microfluidics leads to pathologic physical interactions with endothelial cells that directly induce inflammatory pathways.

Using a combination of computational simulations and large venule-sized endothelialized microfluidics, we observed that perfusion of heterogeneous sickle RBC subpopulations of varying deformability, as well as suspensions of dehydrated normal RBCs admixed with normal RBCs leads to aberrant margination of the less-deformable RBC subpopulations towards the vessel walls, causing localized, increased shear stress.

Increased wall stress is dependent on the degree of subpopulation heterogeneity and oxygen tension and leads to inflammatory endothelial gene expression via mechanotransductive pathways. Our multifaceted approach demonstrates that the presence of sickle RBCs with reduced deformability leads directly to pathological physical (i.e., direct collisions and/or compressive forces) and shear-mediated interactions with endothelial cells and induces an inflammatory response, thereby elucidating the ubiquity of vascular dysfunction in SCD.

 

I don't think this is likely to be a primary cause of trouble in me/cfs. But, there were those provisional findings from Stanford that RBC deformability was reduced in mecfs. If that is true - and i'm not sure what the status of replication of that is - it could be in the mix of reasons endothelial immune responses are ongoing.

 

I can't remember any details, but I believe Hohberger in collaboration with Martin Kräter (from the Max Planck Institute/Guck Lab) had been looking at exactly this in both LC and ME/CFS (here is a small press release:https://mpl.mpg.de/de/news-events/n...]=1118&cHash=068921c21e14a71624aa57b25d4ecde5, for acute Covid they had already published on this subject: https://www.cell.com/biophysj/fulltext/S0006-3495(21)00454-9).

 

This is the other mechinism, aside from GPCR autoantibodies, by which it's theorised BC007 could work. The drug apparently affects/corrects RBC deformability. I believe Hohberger is running the UK Erlangen LC study on this and would have done the cancelled ME study.

Still, we'll see in October whether there's anything to it.

 

Yes. I know that the study in cooperation with the MPI that studies RBC deformability is part of the BC007 reCOVer study at Erlangen (where they are giving BC007, testing for aabs via rat hearts, taking MRIs, OCTAs, testing for RBC deformability etc), and which from what I've heard won't be done before mid 2025 (a patient part of the study mentioned something along the lines of recuitment not being done at least till the beginning of 2025). I also think there was an additional study where Erlangen/Hohberger where cooperating with the MPI and studying RBC deformability, maybe as part of disCOVer, but I may be misremembering.

That is of course independent of BC007s own study called BLOC, which is also recruiting in Erlangen as well as other places and which should be done sooner. But that will anyways tell us nothing about RBC deformability...

 

Hopefully the BLOC study will tell us whether or not BC007 has a significant effect in long covid. Results in October last I heard.

I will never cease to be mad at Berlin Cures for postponing the LC Erlangen trial and cancelling the ME one (although there are whispers it will happen eventually). We could have had a clear answer by now.