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A tremendous collaborative effort, spearheaded by my brilliant PhD student Shoval Miyara, co-mentored by my friend Uri Alon, and the amazing Miri Adler from @Rmedzhitov's team. (2/)

Miri Adler & Uri Alon developed a theoretical model based on a macrophage-myofibroblast circuit to predict injury outcomes. It predicts two fibrosis types: hot🔥fibrosis, where both cell types support each other, and myofibroblast-driven cold❄️fibrosis.

We decided to explore these theoretical concepts in the clinically relevant setting of acute (namely, a heart attack) and chronic (heart failure) cardiac pathologies

To do that we developed a macrophage-myofibroblast double reporter mouse line, named ‘MAMY’ (Sweetheart in Hebrew slang), based on the myofibroblast lineage reporter (Postn-MCM) (Kanisicak, et al. 2016), and the monocyte-macrophage reporter Cx3cr1-GFP (Jung, et al. 2003)

Using the MAMY mice, we find that acute myocardial infarction (MI) results in❄️cold fibrosis- a myofibroblast-dominated state, with low macrophage contribution

If acute MI leads to ❄️cold fibrosis? What kind of injuries would lead to hot fibrosis in the heart? Our model suggests that chronic or repetitive injuries can lead to 🔥hot fibrosis. doi.org/10.1016/j.isci…

28 days following chronic pressure overload (TAC) MAMY mice hearts showed increased macrophage-myofibroblast numbers- depending on the fibrotic degree. We conclude that chronic cardiac damage leads to 🔥hot fibrosis.

Anecdotally, we also find abundant macrophages & myofibroblasts around the LAD ligation suture in MI, resembling a foreign body response. This suggests that the local reaction to the suture aligns with 🔥hot fibrosis.

We focused MI induced ❄️cold fibrosis and showed that it is a conserved outcome in mice, pigs, and humans

Using ParTi (nature.com/articles/nmeth…), we show that in❄️cold fibrosis fibroblasts acquire a persistent fibrotic archetype (state), while macrophages return to homeostatic functions

we used the theoretical model to expose a vulnerability of ❄️cold fibrosis- the myofibroblast autocrine growth factor loop

We used NicheNet analysis on scRNAseq data (doi.org/10.1016/j.celr…), generously shared by Elvira Forte and team, to identify TIMP1 as a key post-myocardial infarction autocrine growth factor for myofibroblasts

In-vitro gain and loss of function experiments revealed that TIMP1 can act as a growth factor for cardiac myofibroblasts derived from mice and non-human-primate hearts

The in-vitro data was promising, but can TIMP1 act as a growth factor for cardiac myofibroblasts in-vivo?

Using MAMY mice we demonstrate that inhibition of TIMP1 following myocardial infarction by neutralizing antibodies can reduce myofibroblast proliferation and subsequent fibrosis.

A massive thank you to the most incredible collaborators—co-first author Miri Adler and Dr. Avi Mayo from the Uri Alon lab! You’ve made this journey truly unforgettable.

The story of our collaborative cardiac fibrosis paper with Uri Alon, Shoval Miyara, Miri Adler and many more. wis-wander.weizmann.ac.il/life-sciences/…

Our work made it to the cover of Cell Systems! 🥳 Cold and hot fibrosis define clinically distinct cardiac pathologies Check out our paper here: cell.com/cell-systems/f… Uri Alon Eldad Tzahor Miri Adler Weizmann Institute Hebrew University

Theory predicted two kinds of fibrosis, hot and cold. We show in vivo that hot and cold fibrosis describe heart failure, and heart attack, respectively, showing that they are very different disease states. Shoval Miyara Miri Adler Eldad Tzahor

Beyond excited to share our #NewPaper in Cell! Inflamed environments acidify intracellular pH. BRD4 senses this via transcriptional condensates, tuning #macrophage responses to match demand and consequences of inflammation. #inflammation #pH authors.elsevier.com/sd/article/S00…