Early-Research Oral Care, Colgate-Palmolive Company, Piscataway, NJ 08854, USA.
Department of Oral & Maxillofacial Surgery & Pharmacology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Int J Mol Sci. 2022 Apr 6;23(7):4038. doi: 10.3390/ijms23074038.
Periodontal ligament derived stem cells (PDLSC) are adult multipotent mesenchymal-like stem cells (MSCs) that can induce a promising immunomodulation to interact with immune cells for disease treatment. Metabolic reconfiguration has been shown to be involved in the immunomodulatory activity of MSCs. However, the underlying mechanisms are largely unknown, and it remains a challenging to establish a therapeutic avenue to enhance immunomodulation of endogenous stem cells for disease management. In the present study, RNA-sequencing (RNA-seq) analysis explores that curcumin significantly promotes PDLSC function through activation of MSC-related markers and metabolic pathways. In vitro stem cell characterization further confirms that self-renewal and multipotent differentiation capabilities are largely elevated in curcumin treated PDLSCs. Mechanistically, RNA-seq reveals that curcumin activates ERK and mTOR cascades through upregulating growth factor pathways for metabolic reconfiguration toward glycolysis. Interestingly, PDLSCs immunomodulation is significantly increased after curcumin treatment through activation of prostaglandin E2-Indoleamine 2,3 dioxygenase (PGE2-IDO) signaling, whereas inhibition of glycolysis activity by 2-deoxyglucose (2-DG) largely blocked immunomodulatory capacity of PDLSCs. Taken together, this study provides a novel pharmacological approach to activate endogenous stem cells through metabolic reprogramming for immunomodulation and tissue regeneration.
牙周膜干细胞（PDLSC）是成体多能间充质样干细胞（MSCs），可诱导有希望的免疫调节作用，与免疫细胞相互作用以治疗疾病。代谢重编程已被证明参与了 MSC 的免疫调节活性。然而，其潜在机制在很大程度上尚不清楚，并且仍然具有挑战性，无法建立一种治疗途径来增强内源性干细胞的免疫调节作用，以进行疾病管理。在本研究中，RNA 测序（RNA-seq）分析表明姜黄素通过激活 MSC 相关标志物和代谢途径，显著促进 PDLSC 的功能。体外干细胞特征进一步证实，姜黄素处理后的 PDLSC 的自我更新和多能分化能力大大提高。在机制上，RNA-seq 表明姜黄素通过上调生长因子途径激活 ERK 和 mTOR 级联反应，使代谢重编程向糖酵解方向进行。有趣的是，姜黄素处理后 PDLSCs 的免疫调节作用显著增加，这是通过激活前列腺素 E2-吲哚胺 2,3 双加氧酶（PGE2-IDO）信号通路实现的，而 2-脱氧葡萄糖（2-DG）抑制糖酵解活性则大大阻断了 PDLSCs 的免疫调节能力。总之，这项研究提供了一种通过代谢重编程激活内源性干细胞以进行免疫调节和组织再生的新的药理学方法。
