Fibrogenic fibroblast-selective near-infrared phototherapy to control scarring

Abstract

Rationale: Fibroblasts, the predominant cell type responsible for tissue fibrosis, are heterogeneous, and the targeting of unique fibrogenic population of fibroblasts is highly expected. Very recently, elevated glycolysis is demonstrated to play a pivotal role in the determination of fibrogenic phenotype of fibroblasts. However, it is lack of specific strategies for targeting and elimination of such fibrogenic populations. In this study, a novel strategy to use the a near-infrared (NIR) dye IR-780 for the targeting and elimination of a fibrogenic population of glycolytic fibroblasts to control the cutaneous scarring is developed.Methods: The identification and cell properties test of fibrogenic fibroblasts with IR-780 were conducted by using fluorescence activated cell sorting, transplantation experiments, in vivo imaging, RNA sequencing in human cell experiments and mouse and rat wound models. The uptake of IR-780 in fibroblasts mediated by HIF-1α/SLCO2A1 and the metabolic properties of IR-780H fibroblasts were investigated using RNA interference or signaling inhibitors. The fibrogenic fibroblast-selective near-infrared phototherapy of IR-780 were evaluated in human cell experiments and mouse wound models.Results: IR-780 is demonstrated to recognize a unique glycolytic fibroblast lineage, which is responsible for the bulk of connective tissue deposition during cutaneous wound healing and cancer stroma formation. Further results identified that SLCO2A1 is involved in the preferential uptake of IR-780 in fibrogenic fibroblasts, which is regulated by HIF-1α. Moreover, with intrinsic dual phototherapeutic activities, IR-780 significantly diminishes cutaneous scarring through the targeted ablation of the fibrogenic population by photothermal and photodynamic effects.Conclusion: This work provides a unique strategy for the targeted control of tissue scarring by fibrogenic fibroblast-selective near-infrared phototherapy. It is proposed that IR-780 based theranostic methodology holds promise for translational medicine aimed at regulation of fibrogenic behavior.

Pharmaceutical targeting of succinate dehydrogenase in fibroblasts controls bleomycin-induced lung fibrosis

“…Moreover, persistent myofibroblast activation distinguishes pathological fibrosis from physiological wound healing, suggesting that therapies selectively inducing myofibroblast apoptosis could prevent progression and potentially improve established lung fibrosis. Consistent with our previous research that IR-780 can characterize HIF-1/glycolysis hyperactive cell population [ 68 , 69 ], we also identify that glycolysis enhances cell retention of IR-780 and may lead to severe inhibition of SDHA and excessive ROS in myofibroblasts, this offers the opportunity to successfully improve pulmonary fibrosis with IR-780 by targeting myofibroblasts apoptosis. To our knowledge, this is the first study to realize the prevention and treatment of lung fibrosis by suppressing SDH or SDHA with varying degrees in fibroblasts and myofibroblasts, respectively.…”

“…7 C, glycolysis inhibitors significantly decreased the cellular uptake of IR-780, while fenofibrate did not, suggesting glycolysis enhanced cell retention of IR-780. We have reported that OATPs (organic-anion-transporting polypeptide), also known as solute carrier organic anion (SLCO), are the carriers of IR-780 [ 45 , 46 ], but the main OATP which induce IR-780 uptake varies in different tissues or cell types. Notably, the accumulation of IR-780 in myofibroblasts was significantly decreased when administered the OATPs inhibitor BSP (bromosulfophthalein) ( Fig.…”

ID1/ID3 Mediate the Contribution of Skin Fibroblasts to Local Nerve Regeneration Through Itga6 in Wound Repair

“…The isolation of neonatal mouse fibroblasts was described previously. 17 Previous isolated primary human skin fibroblasts were used, and the protocol was approved by the ethics committee of the AMU. Cells were cultured in DuIbecco’s modified eagIe’s medium (DMEM) with 10% fetal bovine serum (Gibco), 100 U/mL penicillin, and 0.1 mg/mL streptomycin (Beyotime).…”

Application of ADSCs and their Exosomes in Scar Prevention

“…Chen et al found that the hyperactive glycolytic fibroblast population is the main factor for ECM deposition during skin trauma, suggesting that glycolytic diversity is closely related to the heterogeneity of fibroblasts. Hyperactive glycolysis may be a functional phenotype in patients with fibrosis [ 10 ]. The enhancement of cellular glycolysis is usually caused by insufficient oxygen supply to the tissues, but the oxygen supply depends on the blood supply of the tissues.…”

“…Fibroblasts play an important role in wound healing and scar formation [ 8 ], which are essential for ECM production, but overproduction may be detrimental to the outcome of scarring [ 9 ]. Myofibroblasts are considered to be the main fibrogenic cells in wound healing [ 10 ]. The regulation of some signaling pathways in fibroblasts and myofibroblasts is beneficial to reduce scar formation.…”