Propranolol accelerates adipogenesis and inhibits endothelium differentiation of HemSCs via suppressing HK2 mediated glycolysis.

Abstract

As the first-line treatment for hemangioma (IH), the mechanism of propranolol (PRN) remains unclear. In clinical practice, challenges such as PRN resistance and rebound after discontinuation of PRN are frequently encountered. Hence, this research seeks to investigate the mechanisms underlying PRN-induced regression of IH. Hexokinase 2 (HK2) expression was assessed via immunohistochemistry and double-labeling staining. Glycolysis in hemangioma-derived stem cells (HemSCs) was evaluated by measuring glucose uptake, lactate, and ATP production. Peroxisome proliferator-activated receptor Gamma (PPARγ) and vascular endothelial cadherin (VE-cadherin) levels were analyzed using Western blot and qPCR. PRN-treated HemSCs were examined for adipogenic differentiation via Oil Red O and BODIPY staining. Our results demonstrate that PRN inhibits HemSCs proliferation and endothelial differentiation while promoting adipogenesis by suppressing glycolysis. This effect occurs through HK2 downregulation, likely mediated by PI3K-Akt pathway inhibition. Notably, HK2 expression was significantly lower in CD133⁺ cells from involutive hemangiomas versus proliferative lesions. This study presents the first evidence for the essential role of glycolysis in regulating the proliferation and differentiation of HemSCs, while the efficiency of PRN may be associated with the inhibition of HK2-mediated glycolysis in HemSCs by suppressing the activities of PI3K-Akt pathway. Glycolysis level is high in HemSCs. Glycolysis is required in propranolol perturbated the HemSCs differentiation. PRN could inhibit glycolysis of HemSCs through down-regulation of HK2 expression. PRN suppressed endothelial differentiation and accelerated adipogenesis of HemSCs. PRN down-regulated HK2 expression through restrained the PI3k-Akt pathway. Schematic of treatment mechanism of PRN in IH. HK2 is highly expressed in HemSCs. PRN may be associated with the inhibition of HK2-mediated glycolysis in HemSCs by suppressing the activities of PI3K-Akt pathway which finally promotes regression of IH.