The preconditioning of lithium promotes mesenchymal stem cell-based therapy for the degenerated intervertebral disc via upregulating cellular ROS.
The preconditioning of lithium promotes mesenchymal stem cell-based therapy for the degenerated intervertebral disc via upregulating cellular ROS.
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DOI：
10.1186/s13287-021-02306-9
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发表时间：
2021-04-14
影响因子：
7.5
通讯作者：
Zhang N
中科院分区：
文献类型：
--
作者：
Zhu Z;Xing H;Tang R;Qian S;He S;Hu Q;Zhang N
脂肪源性干细胞（ADSC）是椎间盘退变相关疾病最广泛应用的候选细胞之一。然而，应激微环境下adsc的生存能力差、分化效率低，限制了其治疗效果。研究发现，预处理对不同病理条件下干细胞的增殖和功能有促进作用。锂是一种常见的抗抑郁药物，已被证明对增强干细胞功能有效。在本研究中，研究了使用LiCl预处理对ADSC细胞行为的影响，特别是在退行性ivd样条件下。通过检测不同浓度氯化锂（LiCl）处理大鼠ADSC后乳酸脱氢酶（LDH）的生成，评估其细胞毒性。通过检测Ki67的表达和ADSC的相对细胞数来检测ADSC的增殖能力。然后，预处理的ADSC受到退行性ivd样疾病的挑战。通过检测主要标志物的表达和细胞外基质（ECM）沉积，评价预处理ADSC的细胞活力和髓核（NP）细胞分化效果。采用IVD变性大鼠模型评价预处理ADSC的治疗效果，并观察其NP形态和ECM含量。在接下来的研究中，LiCl的浓度范围为1-10 mmol/L，因为较高的LiCl浓度会导致主要的细胞死亡（约40%）。预处理组与对照组预处理后的相对细胞数基本一致。预处理后Ki67表达升高。预处理后的ADSC具有更强的增殖能力。此外，NP细胞诱导后，预处理组NP标记物的表达高于对照组。此外，当受到退行性ivd样培养的挑战时，LiCl的预处理减少了细胞死亡并促进了ECM沉积。从机械上看，LiCl预处理诱导细胞活性氧（ROS）水平升高和ERK1/2活化，这与预处理后细胞存活率和ECM沉积的提高密切相关。预处理ADSC治疗效果优于对照ADSC移植，具有更好的NP保存和ECM沉积。上述结果表明，中等水平的LiCl预处理通过激活细胞ROS/ERK轴，提高了正常或不良培养条件下细胞的增殖和分化效率。它是一种很有前景的ADSC预处理方法，可以促进细胞功能和随后的再生能力，治疗效果优于未经处理的ADSC移植。
Adipose-derived stem cell (ADSC) is one of the most widely used candidate cell for intervertebral disc (IVD) degeneration-related disease. However, the poor survival and low differentiation efficacy in stressed host microenvironment limit the therapeutic effects of ADSC-based therapy. The preconditioning has been found effective to boost the proliferation and the functioning of stem cells in varying pathological condition. Lithium is a common anti-depression drug and has been proved effective to enhance stem cell functioning. In this study, the effects of preconditioning using LiCl on the cellular behavior of ADSC was investigated, and specially in a degenerative IVD-like condition. The cellular toxicity on rat ADSC was assessed by detecting lactate dehydrogenase (LDH) production after treatment with a varying concentration of lithium chloride (LiCl). The proliferative capacity of ADSC was determined by detecting Ki67 expression and the relative cell number of ADSC. Then, the preconditioned ADSC was challenged by a degenerative IVD-like condition. And the cell viability as well as the nucleus pulpous (NP) cell differentiation efficacy of preconditioned ADSC was evaluated by detecting the major marker expression and extracellular matrix (ECM) deposit. The therapeutic effects of preconditioned ADSC were evaluated using an IVD degeneration rat model, and the NP morphology and ECM content were assessed. A concentration range of 1–10 mmol/L of LiCl was applied in the following study, since a higher concentration of LiCl causes a major cell death (about 40%). The relative cell number was similar between preconditioned groups and the control group after preconditioning. The Ki67 expression was elevated after preconditioning. Consistently, the preconditioned ADSC showed stronger proliferation capacity. Besides, the preconditioned groups exhibit higher expression of NP markers than the control group after NP cell induction. Moreover, the preconditioning of LiCl reduced the cell death and promoted ECM deposits, when challenged with a degenerative IVD-like culture. Mechanically, the preconditioning of LiCl induced an increased cellular reactive oxidative species (ROS) level and activation of ERK1/2, which was found closely related to the enhanced cell survival and ECM deposits after preconditioning. The treatment with preconditioned ADSC showed better therapeutic effects than control ADSC transplantation, with better NP preservation and ECM deposits. These results suggest that the preconditioning with a medium level of LiCl boosts the cell proliferation and differentiation efficacy under a normal or hostile culture condition via the activation of cellular ROS/ERK axis. It is a promising pre-treatment of ADSC to promote the cell functioning and the following regenerative capacity, with superior therapeutic effects than untreated ADSC transplantation.
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影响因子：
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