Direct fibroblast reprogramming: an emerging strategy for treating organic fibrosis

Direct reprogramming has garnered considerable attention due to its capacity to directly convert differentiated cells into desired cells. Fibroblasts are frequently employed in reprogramming studies due to their abundance and accessibility. However, they are also the key drivers in the progression of fibrosis, a pathological condition characterized by excessive extracellular matrix deposition and tissue scarring. Furthermore, the initial stage of reprogramming typically involves deactivating fibrotic pathways. Hence, direct reprogramming offers a valuable method to regenerate target cells for tissue repair while simultaneously reducing fibrotic tendencies. Understanding the link between reprogramming and fibrosis could help develop effective strategies to treat damaged tissue with a potential risk of fibrosis. This review summarizes the advances in direct reprogramming and reveals their anti-fibrosis effects in various organs such as the heart, liver, and skin. Furthermore, we dissect the mechanisms of reprogramming influenced by fibrotic molecules including TGF-β signaling, mechanical signaling, inflammation signaling, epigenetic modifiers, and metabolic regulators. Innovative methods for fibroblast reprogramming like small molecules, CRISPRa, modified mRNA, and the challenges of cellular heterogeneity and senescence faced by in vivo direct reprogramming, are also discussed.