唤醒干细胞，诱导多个组织再生！长期运动可让身体脱胎换骨
再生医学，指通过生物学或生物工程技术，使人体组织自我修复、更新的医疗手段。减缓、制止甚至逆转衰老过程则便是再生医学的目的之一。
近20年来，随着老龄化的加重，再生医学受到了政府的高度重视与支持，成为我国医学研究的热点，干细胞、人造组织、基因治疗等新技术层出不穷[1,2]。
但是，有研究者告诉我们，除了这些高大上的技术，跑步、游泳等日常运动也可以促进人体组织再生，让我们越活越年轻。
今年5月，上海大学肖俊杰教授团队联合海外机构发表了综述[3]，阐述了长期运动对小鼠多个组织和系统再生的影响，并且通过对信号通路的研究，揭示了运动介导干细胞活化的机制。
肌肉
成人骨骼肌由肌细胞和少量肌肉干细胞组成，其中肌肉干细胞在成年后便处于静止状态，只有肌肉损伤或受到运动刺激时才会被激活[4]。
然而，在衰老等条件下，肌肉干细胞的调节因子被破坏，活化和再生能力被限制。例如钙结合蛋白异常表达，老化细胞外基质诱导肌肉干细胞转化为成纤维细胞，都损伤了肌肉干细胞的成肌能力[5]。
但是，运动能够改善衰老带来的肌肉萎缩，增加肌肉细胞增殖和活化，其机制包括AKT, MAPK等信号通路和代谢重编程。这些分子调节因子在年老和年轻小鼠体内发挥着不同作用。
例如，长期运动能够通过激活AKT通路、恢复细胞周期蛋白D1表达来促进老年小鼠肌肉干细胞增殖再生。而在年轻小鼠体内，运动则通过MAPK通路促进肌肉干细胞周期，还通过抑制AKT-mTOR活性和线粒体代谢、呼吸来保护肌肉干细胞增殖，增加干细胞更新能力[6-9]。
除了作用于肌肉干细胞外，运动还可以通过AMPK信号促进纤维成脂祖细胞(FAP)衰老，从而分泌促进肌肉干细胞增殖和分化的因子，引发“再生炎症”，激活肌肉再生[10]。
另外，抗阻训练也可提高蛋白质合成速率，增加肌肉质量和老年人肌纤维间干细胞数量[11,12]。
图注：运动介导肌肉再生的信号通路
神经
成年人大脑中，海马齿状回(DG)区域可以持续产生新神经元，调节学习、记忆和情绪[13]。研究表明，运动能够促进成人海马神经前体细胞（NPC）增殖和神经元分化[14,15]，修复阿尔茨海默导致的认知障碍[16]。
此外，运动还会让老年小鼠神经干细胞恢复到年轻时的水平[17]，改善小鼠痴呆[18]，同时促进脑部形成新的突触，起到提高小鼠记忆力，改善帕金森动物运动能力等作用[19-21]。
以往研究发现，运动会产生很多促进神经再生的因子，如BDNF[13]、VEGF[22]、IGF1[23，24]、GH[25]、神经递质5 -羟色胺[26]和RGS6[29]。
其中BDNF能够穿过血脑屏障[27]，即使产生于其它器官(如骨骼肌[28])也能诱导神经再生，并且可减轻阿尔茨海默病相关的脑内炎症[13]。
除了再生因子，运动还可以通过胞间作用来调节神经干细胞的增殖，例如通过血小板因子4 (PF4)激活血小板[11]，从而促进神经再生。
但是，运动会诱导鼻咽癌相关通路Notch1的活性[12]，目前机制尚不明确。
图注：运动介导神经再生的信号通路
心脏
到目前为止，研究者们还没有发现成年人心脏干细胞[30]，而胚胎干细胞诱导形成心脏细胞的技术尚不成熟，因此，心脏细胞的再生是亟待突破的难点。
研究表明，小鼠长期进行跑轮、游泳等运动可促进现有心肌细胞增殖，进而促进内源性心肌再生[31,32]。
运动还可以促进心肌梗死、心肌炎等心脏损伤后的修复[33,34]。目前，运动被认为是保护心血管健康和改善心血管疾病(CVD)的有效方式[35,36]。
目前发现运动介导心脏再生的途径有IGF-PI3K-Akt轴[37-39]、ADAR2 - mir -34a - cyclin D1轴[22]、非编码RNA[40,41]、小RNA [21,24,42]、长链非编码RNA LncCPhar和lncExACT1等[43,44]。
图注：运动介导心脏再生的信号通路
血管和淋巴管
内皮祖细胞(EPC)是血管生成的关键细胞。研究发现，游泳可以增加老年小鼠EPC数量，改善后肢缺血，同时，已经有研究证明适度的低氧运动可促进人类血管生成[45]。
最近的一项研究还表明，游泳等运动能够诱导小鼠的心脏淋巴管生成，促进心肌细胞增殖[46]。
虽然运动可以有效刺激组织再生，但是某些群体由于身体原因，不适合进行运动，运动的健康作用就被大大限制了。
为了解决这个问题，研究者们把目光放在了运动诱导再生的机制上，通过直接干预作用靶点，达到和运动一样的效果。目前，这类治疗方案已初见成效。
IGF1
在多个器官中，IGF1的表达随着运动而升高，对提高肌肉力量[47]、减少衰老导致的脑细胞凋亡[48]，以及心肌细胞生长[49]都起到重要作用。
研究发现，IGF1基因治疗能显著恢复脊髓损伤的成年大鼠神经功能[50]，还促进脊髓损伤小鼠的脊髓再生[51]。
由于IGF1治疗可能引发肿瘤，一些研究者开发了间接干预IGF1的小分子药物。例如，BGP-15可以提高IGF1磷酸化，改善心力衰竭小鼠的心脏功能[52]。
PI3K-Akt通路
在肌肉，大脑和心脏中，PI3K信号的激活都会促进组织再生，而且目前发现多种可以作用于PI3K的小分子药物。
例如，PTEN是PI3K信号通路的负调控因子[53]。Bisperoxovanadium可以通过抑制PTEN激活PI3K，进行肌肉修复[54]。
在神经系统中，芒柄花素可以通过激活PI3K通路来预防脑缺血；外源性FGF10则通过该信号，促进外周神经损伤后的轴突再生[55,56]。
磷脂酰肌醇3-激酶(caPI3K-p110α)是作用于心脏的靶向药物，目前发现可以通过刺激PI3K通路，改善小鼠心脏功能[57,58,59]，提示PI3K基因治疗在治疗心血管疾病方面具有临床潜力。
miRNA
小鼠的运动实验证明，miRNA介导多个器官的细胞增殖。例如，miR-23a/miR-27a可减轻慢性肾炎小鼠的肌肉损失[60]；miR-135a下调可增加神经前体细胞的增殖，促进轴突再生[61,62]；miR-17-3p有助于诱导的心肌细胞增殖。
这些观察结果表明，干预miRNA表达在组织再生方面有很大研究前景。
不用亲自运动，直接用药物就能达到同等效果，可能听起来很诱人，但是作者对这一研究提出了新的思考，那就是运动的调节分子对不同类型的细胞具有特异性作用，如果靶向精确性不够，则可能产生相反的效果。
另外，作者认为单纯的运动是不够的，需要结合其它因素一起治疗。我们期待研究能够近一步突破，早日发展新的再生医学。
—— TIMEPIE ——
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