HA-DA/AD-RAPA缓释体系通过mTORC2上调内源性滑膜干细胞旁分泌作用促进肩袖修复的机制研究

肩袖损伤作为退变疾病，发病率逐年升高。氧化应激增强和肌腱修复能力下降是其预后不良的重要原因。本课题组前期构建了HA-DA/AD支架，可通过精氨酸（AD）对抗氧化应激。但仍需进一步改进以提高肌腱修复能力。结合我们前期基础：雷帕霉素（RAPA）可激活内源性滑膜干细胞（SMSCs）的自噬水平，抑制其凋亡，从而保护SMSCs的肌腱修复能力。我们合成了HA-DA/AD-RAPA缓释体系，发现其可提高肌腱细胞（TCs）成肌腱能力，但机制不清。预实验提示缓释体可促进SMSCs旁分泌CTGF作用于TCs，提高其成肌腱能力。进一步研究发现激活内源性SMSCs自噬水平，继而上调mTORC2，可能为促进其旁分泌CTGF的关键机制。本研究拟以此为切入点，深入探讨HA-DA/AD-RAPA缓释体调控内源性SMSCs旁分泌CTGF的机制。本缓释体着眼于调控肌腱内环境，有望为改善肩袖损伤预后提供新思路。

As a degenerative disease, the rotator cuff tear has been more and more common. The increase in oxidative stress and the decrease of tendon repair ability are considered as the most important causes for the poor prognosis. In our previous research, we have created the HA-DA/AD scaffold which can resist oxidative stress through arginine (AD). However, further improvement is needed to enhance the tendon repair ability. Based on our previous foundation: rapamycin (RAPA) can protect the repair ability of endogenous synovial stem cells (SMSCs) by activating their autophagy and inhibiting their apoptosis, we further constructed HA-DA/AD-RAPA sustained release system and found that it can also improve the tendon repair ability of tenocytes (TCs) with unclear mechanism. The preliminary results implied that the sustained release system could promote the CTGF paracrine of SMSCs which acts on TCs and improve their tendon repair ability. Further study showed that the up-regulated mTORC2 by the autophagy of SMSCs might be the key mechanism for modulating CTGF paracrine. In this study, we intend to explore the mechanism of how HA-DA/AD-RAPA sustained release system affecting CTGF paracrine of endogenous SMSCs. The sustained release system can simultaneously suppress oxidative stress and improve the tendon repair ability, providing a new choice for improving the prognosis of rotator cuff tear.