Inhibition of Syk promotes chemical reprogramming of fibroblasts via metabolic rewiring and H ₂ S production

Abstract

Chemical compounds have recently been introduced as alternative and non-integrating inducers of pluripotent stem cell fate. However, chemical reprogramming is hampered by low efficiency and the molecular mechanisms remain poorly characterized. Here, we show that inhibition of spleen tyrosine kinase (Syk) by R406 significantly promotes mouse chemical reprogramming. Mechanistically, R406 alleviates Syk / calcineurin (Cn) / nuclear factor of activated T cells (NFAT) signaling-mediated suppression of glycine, serine, and threonine metabolic genes and dependent metabolites. Syk inhibition upregulates glycine level and downstream transsulfuration cysteine biosynthesis, promoting cysteine metabolism and cellular hydrogen sulfide (H 2 S) production. This metabolic rewiring decreased oxidative phosphorylation and ROS levels, enhancing chemical reprogramming. In sum, our study identifies Syk-Cn-NFAT signaling axis as a new barrier of chemical reprogramming and suggests metabolic rewiring and redox homeostasis as important opportunities for controlling cell fates.

Necroptosis Inhibition by Hydrogen Sulfide Alleviated Hypoxia-Induced Cardiac Fibroblasts Proliferation via Sirtuin 3

“…Secondly, some other fibroblast functions, such as migration and/or contraction, as well as the degree of cell death, were not examined, which is beneficial to comprehensively evaluate the growth of cardiac fibroblasts. Thirdly, H 2 S promoted the chemical reprogramming of fibroblasts via metabolic rewiring [37]. However, little was known about metabolic reprogramming in the fibroblasts with hypoxia by H 2 S, which might be further examined in further studies.…”

Human Dermal Fibroblast Subpopulations and Epithelial Mesenchymal Transition Signals in Hidradenitis Suppurativa Tunnels are Normalized by Spleen Tyrosine Kinase Antagonism in Vivo

“…These results clearly demonstrate EMT signals in tissue of HS, however the precise causative cascade leading to the development of EMT in HS remains unclear. The use of Fostamatinib partially ameliorates the gene expression signature of EMT in HS tissue, presumably indirectly through its action upon B cells, plasma cells and monocyte/macrophages (Frew., 2022; Wang et al, 2021). Wang demonstrates direct alteration of fibroblast function with the use of fostamatinib in vitro (Wang et al, 2021) and therefore fostamatinib may have potential as an adjuvant treatment alongside other targeted therapies such as Janus Kinase Inhibitors or Monoclonal antibodies (Frew et al, 2021b), particularly in the setting of epithelialised tunnels and/or significant fibrosis.…”

Endogenous hydrogen sulphide deficiency and exogenous hydrogen sulphide supplement regulate skin fibroblasts proliferation via necroptosis

“…On the other hand, H 2 S was also one of the potential pharmacological means to promote the growth of skin fibroblasts or inhibit excessive proliferation. What's more, H 2 S also promoted chemical reprogramming of fibroblasts to regulate proliferation via metabolic rewiring 47 . However, little was known about metabolic reprogramming in skin fibroblasts by H 2 S.…”

“…What's more, H 2 S also promoted chemical reprogramming of fibroblasts to regulate proliferation via metabolic rewiring. 47 However, little was known about metabolic reprogramming in skin fibroblasts by H 2 S.…”