Alex Genzelinakh

I'm so excited this episode of @MotionPod is finally out!! I had a blast chatting and diving deep into hot🔥 and cold❄️ #fibrosis in light of our recent @biorxivpreprint with @JACoates. Thanks for having me! biorxiv.org/content/10.110…

For more details feel free to reach out! In the following link, you can find a summarized, #stepbystep digest of our work by @Tzahore twitter.com/Tzahore/status…

I really want to acknowledge and thank the amazing collaborators in this project that made working on it so much fun! @YalinDivinsky @JacobElkahal, Kfir Umansky @genzelinakh @abingtonSA @LinglingZhang12 @DavidKain17 and Daria Lendengolts and Rachel Sarig from the @Tzahor_Lab>>

I'm ecstatic to announce that my first PhD paper is finally out!! Circuit to target approach defines an autocrine myofibroblast loop that drives cardiac fibrosis biorxiv.org/content/10.110… @Tzahore @UriAlonWeizmann @MiriAdler

We also thank @EladBassat And Jingkui Wang from the lab of @Tanaxolotl from @IMPvienna 🦾, Andrea Baehr, and Christian Kupatt @TU_Muenchen 🙏. Special Thanks to the amazing Dr. Avi Mayo from the @UriAlonWeizmann team, and to Danielle Kimchi for original illustrations 🖌️

Thanks to our wonderful co-authors and collaborators: @JacobElkahal, Kfir Umansky @YalinDivinsky @genzelinakh @abingtonSA @LinglingZhang12 @DavidKain17 and Daria Lendengolts and Rachel Sarig from the @Tzahor_Lab, Tali Shalit, Michael Gershovits from @WeizmannScience INCPM🦾🦾🦾

Here we show for the first time the utility of our circuit to target approach- relying on mechanistic yet simple mathematical models of complex #disease states and identifying new therapeutic targets!

Targeting of Timp1 using neutralizing antibodies reduced fibrosis after MI in adult mice 🐭13/

Using #NicheNet and in-vitro experiments we identified Timp1 as a novel autocrine growth factor for cardiac myofibroblasts 12/

We further asked which molecular interactions might be suitable targets for reducing cold❄️fibrosis. We suggest that inhibiting the myofibroblast autocrine growth-factor signaling could reduce cold❄️fibrosis 11/

We next asked whether cold❄️fibrosis is characterized by cell fate changes. Using #Pareto analysis, we find that #fibroblasts acquire a novel fibrotic function associated with ECM remodeling while macrophages return to baseline homeostatic functions 10/

Using RNAseq and histological analysis we show that cold❄️fibrosis is a conserved outcome in pigs🐖. We further show that administration of the ECM protein Agrin largely reverses cold❄️fibrosis into a healing state 9/

Using #Visium we show that macrophages are reduced specifically at the infarct zone between 7-14 days while myofibroblasts remain. Interestingly, we also find that the border zone is reduced when cold❄️fibrosis sets in 8/

Following MI, both macrophages and myofibroblasts rise together followed by a decline in macrophage numbers, while myofibroblasts persist- suggesting that MI leads to cold❄️fibrosis 7/

In this work, we explored these concepts in the context of a widely studied model for cardiac #fibrosis after acute #myocardialinfarction (MI)💔 6/ #heartattack

Recently, @MiriAdler @UriAlonWeizmann published a mathematical model for a macrophage-myofibroblasts cell circuit that predicts two types of #fibrosis- hot🔥fibrosis with both cell types supporting each other, and cold❄️fibrosis dominated by myofibroblasts 5/

#Fibrosis is a pathology of excessive #ECM deposition. It is immensely complex and involves multiple cell types, and molecules, and it continues to develop over time⏰. To develop new therapeutic approaches, it's crucial to simplify the underlying concepts 4/

This work was an immense synergistic effort led by the brilliant PhD student @MiyaraShoval co-mentored with my friend @UriAlonWeizmann, and the amazing @MiriAdler from @Rmedzhitov team 3/

🏃Briefly, here we combined mathematical #modeling and in-vivo studies to establish a new approach to determine the tissue fate after injury: fibrosis vs healing. We describe a new strategy to identify therapeutic targets to reduce #fibrosis 2/

Happy new year 🥂🎉🎇 Our first preprint for 2023 is now OUT in @BioRxiv! Circuit to target approach defines an autocrine myofibroblast loop that drives cardiac fibrosis 1/ biorxiv.org/content/10.110…