Fibrin, Bone Marrow Cells and Macrophages Interactively Modulate Cardiomyoblast Fate

Abstract

Interactions between macrophages, cardiac cells and the extracellular matrix are crucial for cardiac repair following myocardial infarction (MI). We hypothesized that cell-based treatments might modulate these interactions. After validating that bone marrow cells (BMC) associated with fibrin lowered the infarct extent and improved cardiac function, we interrogated the influence of fibrin, as a biologically active scaffold, on the secretome of BMC and the impact of their association on macrophage fate and cardiomyoblast proliferation. In vitro, BMC were primed with fibrin (F-BMC). RT-PCR and proteomic analyses showed that fibrin profoundly influenced the gene expression and the secretome of BMCs. Consequently, the secretome of F-BMC increased the spreading of cardiomyoblasts and showed an alleviated immunomodulatory capacity. Indeed, the proliferation of anti-inflammatory macrophages was augmented, and the phenotype of pro-inflammatory switched as shown by downregulated Nos2, Il6 and IL1b and upregulated Arg1, CD163, Tgfb and IL10. Interestingly, the secretome of F-BMC educated-macrophages stimulated the incorporation of EdU in cardiomyoblasts. In conclusion, our study provides evidence that BMC/fibrin-based treatment improved cardiac structure and function following MI. In vitro proofs-of-concept reveal that the F-BMC secretome increases cardiac cell size and promotes an anti-inflammatory response. Thenceforward, the F-BMC educated macrophages sequentially stimulated cardiac cell proliferation.

Live-imaging studies reveal how microclots and the associated inflammatory response enhance cancer cell extravasation

“…Here, we suggest a mechanism by which fibrin might drive metastasis by recruiting innate immune cells but preventing their pro-inflammatory polarisation. This speculation is bolstered by prior works showing that fibrin has an anti-inflammatory influence on macrophages ( Borrego et al, 2022 ; Hsieh et al, 2017 ; Zhang et al, 2020 ).…”

“…Recently, fibrin has been shown to drive the pro-resolution, M2-like phenotype in macrophages and to dampen the effects of pro-inflammatory signals that might drive them towards the pro-inflammatory, M1-like phenotype ( Borrego et al, 2022 ; Hsieh et al, 2017 ; Tanaka et al, 2019 ; Zhang et al, 2020 ). To test whether loss of fibrin might drive an increase in pro-inflammatory phenotypes and an increase of tnfa expression, we used a splice-site-disrupting morpholino against fibrinogen subunit α ( fga ) injected at the one-cell stage, which has been shown to lead to a loss of functional fibrinogen in zebrafish larvae, causing clotting defects ( Vilar et al, 2021 ; Vo et al, 2013 ).…”

The Tissue Engineering Revolution: From Bench Research to Clinical Reality

“…Similarly, research revealing the interplay between fatty hepatocytes and skeletal muscle cells, as well as albumin's protective role, offers hope for more effective treatments for fatty liver disease and it related muscle atrophy [11]. Complementing these works, a study probing the synergistic potential of fibrin, bone marrow cells, and macrophages in cardiac repair opens new avenues for therapeutic strategies in heart disease, indicative of the intricate dance between cellular components and therapeutic outcomes [12].…”