再生醫(yī)學(xué)，指通過(guò)生物學(xué)或生物工程技術(shù)，使人體組織自我修復(fù)、更新的醫(yī)療手段。減緩、制止甚至逆轉(zhuǎn)衰老過(guò)程則便是再生醫(yī)學(xué)的目的之一。

近20年來(lái)，隨著老齡化的加重，再生醫(yī)學(xué)受到了政府的高度重視與支持，成為我國(guó)醫(yī)學(xué)研究的熱點(diǎn)，干細(xì)胞、人造組織、基因治療等新技術(shù)層出不窮[1,2]。

但是，有研究者告訴我們，除了這些高大上的技術(shù)，跑步、游泳等日常運(yùn)動(dòng)也可以促進(jìn)人體組織再生，讓我們?cè)交钤侥贻p。

今年5月，上海大學(xué)肖俊杰教授團(tuán)隊(duì)聯(lián)合海外機(jī)構(gòu)發(fā)表了綜述[3]，闡述了長(zhǎng)期運(yùn)動(dòng)對(duì)小鼠多個(gè)組織和系統(tǒng)再生的影響，并且通過(guò)對(duì)信號(hào)通路的研究，揭示了運(yùn)動(dòng)介導(dǎo)干細(xì)胞活化的機(jī)制。

肌肉

成人骨骼肌由肌細(xì)胞和少量肌肉干細(xì)胞組成，其中肌肉干細(xì)胞在成年后便處于靜止?fàn)顟B(tài)，只有肌肉損傷或受到運(yùn)動(dòng)刺激時(shí)才會(huì)被激活[4]。

然而，在衰老等條件下，肌肉干細(xì)胞的調(diào)節(jié)因子被破壞，活化和再生能力被限制。例如鈣結(jié)合蛋白異常表達(dá)，老化細(xì)胞外基質(zhì)誘導(dǎo)肌肉干細(xì)胞轉(zhuǎn)化為成纖維細(xì)胞，都損傷了肌肉干細(xì)胞的成肌能力[5]。

但是，運(yùn)動(dòng)能夠改善衰老帶來(lái)的肌肉萎縮，增加肌肉細(xì)胞增殖和活化，其機(jī)制包括AKT, MAPK等信號(hào)通路和代謝重編程。這些分子調(diào)節(jié)因子在年老和年輕小鼠體內(nèi)發(fā)揮著不同作用。

例如，長(zhǎng)期運(yùn)動(dòng)能夠通過(guò)激活A(yù)KT通路、恢復(fù)細(xì)胞周期蛋白D1表達(dá)來(lái)促進(jìn)老年小鼠肌肉干細(xì)胞增殖再生。而在年輕小鼠體內(nèi)，運(yùn)動(dòng)則通過(guò)MAPK通路促進(jìn)肌肉干細(xì)胞周期，還通過(guò)抑制AKT-mTOR活性和線粒體代謝、呼吸來(lái)保護(hù)肌肉干細(xì)胞增殖，增加干細(xì)胞更新能力[6-9]。

除了作用于肌肉干細(xì)胞外，運(yùn)動(dòng)還可以通過(guò)AMPK信號(hào)促進(jìn)纖維成脂祖細(xì)胞(FAP)衰老，從而分泌促進(jìn)肌肉干細(xì)胞增殖和分化的因子，引發(fā)“再生炎癥”，激活肌肉再生[10]。

另外，抗阻訓(xùn)練也可提高蛋白質(zhì)合成速率，增加肌肉質(zhì)量和老年人肌纖維間干細(xì)胞數(shù)量[11,12]。

圖注：運(yùn)動(dòng)介導(dǎo)肌肉再生的信號(hào)通路

神經(jīng)

成年人大腦中，海馬齒狀回(DG)區(qū)域可以持續(xù)產(chǎn)生新神經(jīng)元，調(diào)節(jié)學(xué)習(xí)、記憶和情緒[13]。研究表明，運(yùn)動(dòng)能夠促進(jìn)成人海馬神經(jīng)前體細(xì)胞（NPC）增殖和神經(jīng)元分化[14,15]，修復(fù)阿爾茨海默導(dǎo)致的認(rèn)知障礙[16]。

此外，運(yùn)動(dòng)還會(huì)讓老年小鼠神經(jīng)干細(xì)胞恢復(fù)到年輕時(shí)的水平[17]，改善小鼠癡呆[18]，同時(shí)促進(jìn)腦部形成新的突觸，起到提高小鼠記憶力，改善帕金森動(dòng)物運(yùn)動(dòng)能力等作用[19-21]。

以往研究發(fā)現(xiàn)，運(yùn)動(dòng)會(huì)產(chǎn)生很多促進(jìn)神經(jīng)再生的因子，如BDNF[13]、VEGF[22]、IGF1[23，24]、GH[25]、神經(jīng)遞質(zhì)5 -羥色胺[26]和RGS6[29]。

其中BDNF能夠穿過(guò)血腦屏障[27]，即使產(chǎn)生于其它器官(如骨骼肌[28])也能誘導(dǎo)神經(jīng)再生，并且可減輕阿爾茨海默病相關(guān)的腦內(nèi)炎癥[13]。

除了再生因子，運(yùn)動(dòng)還可以通過(guò)胞間作用來(lái)調(diào)節(jié)神經(jīng)干細(xì)胞的增殖，例如通過(guò)血小板因子4 (PF4)激活血小板[11]，從而促進(jìn)神經(jīng)再生。

但是，運(yùn)動(dòng)會(huì)誘導(dǎo)鼻咽癌相關(guān)通路Notch1的活性[12]，目前機(jī)制尚不明確。

圖注：運(yùn)動(dòng)介導(dǎo)神經(jīng)再生的信號(hào)通路

心臟

到目前為止，研究者們還沒(méi)有發(fā)現(xiàn)成年人心臟干細(xì)胞[30]，而胚胎干細(xì)胞誘導(dǎo)形成心臟細(xì)胞的技術(shù)尚不成熟，因此，心臟細(xì)胞的再生是亟待突破的難點(diǎn)。

研究表明，小鼠長(zhǎng)期進(jìn)行跑輪、游泳等運(yùn)動(dòng)可促進(jìn)現(xiàn)有心肌細(xì)胞增殖，進(jìn)而促進(jìn)內(nèi)源性心肌再生[31,32]。

運(yùn)動(dòng)還可以促進(jìn)心肌梗死、心肌炎等心臟損傷后的修復(fù)[33,34]。目前，運(yùn)動(dòng)被認(rèn)為是保護(hù)心血管健康和改善心血管疾病(CVD)的有效方式[35,36]。

目前發(fā)現(xiàn)運(yùn)動(dòng)介導(dǎo)心臟再生的途徑有IGF-PI3K-Akt軸[37-39]、ADAR2 - mir -34a - cyclin D1軸[22]、非編碼RNA[40,41]、小RNA [21,24,42]、長(zhǎng)鏈非編碼RNA LncCPhar和lncExACT1等[43,44]。

圖注：運(yùn)動(dòng)介導(dǎo)心臟再生的信號(hào)通路

血管和淋巴管

內(nèi)皮祖細(xì)胞(EPC)是血管生成的關(guān)鍵細(xì)胞。研究發(fā)現(xiàn)，游泳可以增加老年小鼠EPC數(shù)量，改善后肢缺血，同時(shí)，已經(jīng)有研究證明適度的低氧運(yùn)動(dòng)可促進(jìn)人類血管生成[45]。

最近的一項(xiàng)研究還表明，游泳等運(yùn)動(dòng)能夠誘導(dǎo)小鼠的心臟淋巴管生成，促進(jìn)心肌細(xì)胞增殖[46]。

雖然運(yùn)動(dòng)可以有效刺激組織再生，但是某些群體由于身體原因，不適合進(jìn)行運(yùn)動(dòng)，運(yùn)動(dòng)的健康作用就被大大限制了。

為了解決這個(gè)問(wèn)題，研究者們把目光放在了運(yùn)動(dòng)誘導(dǎo)再生的機(jī)制上，通過(guò)直接干預(yù)作用靶點(diǎn)，達(dá)到和運(yùn)動(dòng)一樣的效果。目前，這類治療方案已初見(jiàn)成效。

IGF1

在多個(gè)器官中，IGF1的表達(dá)隨著運(yùn)動(dòng)而升高，對(duì)提高肌肉力量[47]、減少衰老導(dǎo)致的腦細(xì)胞凋亡[48]，以及心肌細(xì)胞生長(zhǎng)[49]都起到重要作用。

研究發(fā)現(xiàn)，IGF1基因治療能顯著恢復(fù)脊髓損傷的成年大鼠神經(jīng)功能[50]，還促進(jìn)脊髓損傷小鼠的脊髓再生[51]。

由于IGF1治療可能引發(fā)腫瘤，一些研究者開(kāi)發(fā)了間接干預(yù)IGF1的小分子藥物。例如，BGP-15可以提高IGF1磷酸化，改善心力衰竭小鼠的心臟功能[52]。

PI3K-Akt通路

在肌肉，大腦和心臟中，PI3K信號(hào)的激活都會(huì)促進(jìn)組織再生，而且目前發(fā)現(xiàn)多種可以作用于PI3K的小分子藥物。

例如，PTEN是PI3K信號(hào)通路的負(fù)調(diào)控因子[53]。Bisperoxovanadium可以通過(guò)抑制PTEN激活PI3K，進(jìn)行肌肉修復(fù)[54]。

在神經(jīng)系統(tǒng)中，芒柄花素可以通過(guò)激活PI3K通路來(lái)預(yù)防腦缺血；外源性FGF10則通過(guò)該信號(hào)，促進(jìn)外周神經(jīng)損傷后的軸突再生[55,56]。

磷脂酰肌醇3-激酶(caPI3K-p110α)是作用于心臟的靶向藥物，目前發(fā)現(xiàn)可以通過(guò)刺激PI3K通路，改善小鼠心臟功能[57,58,59]，提示PI3K基因治療在治療心血管疾病方面具有臨床潛力。

miRNA

小鼠的運(yùn)動(dòng)實(shí)驗(yàn)證明，miRNA介導(dǎo)多個(gè)器官的細(xì)胞增殖。例如，miR-23a/miR-27a可減輕慢性腎炎小鼠的肌肉損失[60]；miR-135a下調(diào)可增加神經(jīng)前體細(xì)胞的增殖，促進(jìn)軸突再生[61,62]；miR-17-3p有助于誘導(dǎo)的心肌細(xì)胞增殖。

這些觀察結(jié)果表明，干預(yù)miRNA表達(dá)在組織再生方面有很大研究前景。

不用親自運(yùn)動(dòng)，直接用藥物就能達(dá)到同等效果，可能聽(tīng)起來(lái)很誘人，但是作者對(duì)這一研究提出了新的思考，那就是運(yùn)動(dòng)的調(diào)節(jié)分子對(duì)不同類型的細(xì)胞具有特異性作用，如果靶向精確性不夠，則可能產(chǎn)生相反的效果。

另外，作者認(rèn)為單純的運(yùn)動(dòng)是不夠的，需要結(jié)合其它因素一起治療。我們期待研究能夠近一步突破，早日發(fā)展新的再生醫(yī)學(xué)。

—— TIMEPIE ——

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