喚醒幹細胞,誘導多個組織再生!長期運動可讓身體脫胎換骨
再生醫學,指通過生物學或生物工程技術,使人體組織自我修復、更新的醫療手段。減緩、制止甚至逆轉衰老過程則便是再生醫學的目的之一。
近20年來,隨着老齡化的加重,再生醫學受到了政府的高度重視與支持,成爲我國醫學研究的熱點,幹細胞、人造組織、基因治療等新技術層出不窮[1,2]。
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但是,有研究者告訴我們,除了這些高大上的技術,跑步、游泳等日常運動也可以促進人體組織再生,讓我們越活越年輕。
今年5月,上海大學肖俊傑教授團隊聯合海外機構發表了綜述[3],闡述了長期運動對小鼠多個組織和系統再生的影響,並且通過對信號通路的研究,揭示了運動介導幹細胞活化的機制。
肌肉
成人骨骼肌由肌細胞和少量肌肉乾細胞組成,其中肌肉乾細胞在成年後便處於靜止狀態,只有肌肉損傷或受到運動刺激時纔會被激活[4]。
然而,在衰老等條件下,肌肉乾細胞的調節因子被破壞,活化和再生能力被限制。例如鈣結合蛋白異常表達,老化細胞外基質誘導肌肉乾細胞轉化爲成纖維細胞,都損傷了肌肉乾細胞的成肌能力[5]。
善待警察新血
但是,運動能夠改善衰老帶來的肌肉萎縮,增加肌肉細胞增殖和活化,其機制包括AKT, MAPK等信號通路和代謝重編程。這些分子調節因子在年老和年輕小鼠體內發揮着不同作用。
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例如,長期運動能夠通過激活AKT通路、恢復細胞週期蛋白D1表達來促進老年小鼠肌肉乾細胞增殖再生。而在年輕小鼠體內,運動則通過MAPK通路促進肌肉乾細胞週期,還通過抑制AKT-mTOR活性和線粒體代謝、呼吸來保護肌肉乾細胞增殖,增加幹細胞更新能力[6-9]。
除了作用於肌肉乾細胞外,運動還可以通過AMPK信號促進纖維成脂祖細胞(FAP)衰老,從而分泌促進肌肉乾細胞增殖和分化的因子,引發“再生炎症”,激活肌肉再生[10]。
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另外,抗阻訓練也可提高蛋白質合成速率,增加肌肉質量和老年人肌纖維間幹細胞數量[11,12]。
圖注:運動介導肌肉再生的信號通路
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神經
成年人大腦中,海馬齒狀回(DG)區域可以持續產生新神經元,調節學習、記憶和情緒[13]。研究表明,運動能夠促進成人海馬神經前體細胞(NPC)增殖和神經元分化[14,15],修復阿爾茨海默導致的認知障礙[16]。
此外,運動還會讓老年小鼠神經幹細胞恢復到年輕時的水平[17],改善小鼠癡呆[18],同時促進腦部形成新的突觸,起到提高小鼠記憶力,改善帕金森動物運動能力等作用[19-21]。
以往研究發現,運動會產生很多促進神經再生的因子,如BDNF[13]、VEGF[22]、IGF1[23,24]、GH[25]、神經遞質5 -羥色胺[26]和RGS6[29]。
其中BDNF能夠穿過血腦屏障[27],即使產生於其它器官(如骨骼肌[28])也能誘導神經再生,並且可減輕阿爾茨海默病相關的腦內炎症[13]。
除了再生因子,運動還可以通過胞間作用來調節神經幹細胞的增殖,例如通過血小板因子4 (PF4)激活血小板[11],從而促進神經再生。
但是,運動會誘導鼻咽癌相關通路Notch1的活性[12],目前機制尚不明確。
圖注:運動介導神經再生的信號通路
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心臟
到目前爲止,研究者們還沒有發現成年人心臟幹細胞[30],而胚胎幹細胞誘導形成心臟細胞的技術尚不成熟,因此,心臟細胞的再生是亟待突破的難點。
研究表明,小鼠長期進行跑輪、游泳等運動可促進現有心肌細胞增殖,進而促進內源性心肌再生[31,32]。
運動還可以促進心肌梗死、心肌炎等心臟損傷後的修復[33,34]。目前,運動被認爲是保護心血管健康和改善心血管疾病(CVD)的有效方式[35,36]。
目前發現運動介導心臟再生的途徑有IGF-PI3K-Akt軸[37-39]、ADAR2 – mir -34a – cyclin D1軸[22]、非編碼RNA[40,41]、小RNA [21,24,42]、長鏈非編碼RNA LncCPhar和lncExACT1等[43,44]。
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圖注:運動介導心臟再生的信號通路
血管和淋巴管
內皮祖細胞(EPC)是血管生成的關鍵細胞。研究發現,游泳可以增加老年小鼠EPC數量,改善後肢缺血,同時,已經有研究證明適度的低氧運動可促進人類血管生成[45]。
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最近的一項研究還表明,游泳等運動能夠誘導小鼠的心臟淋巴管生成,促進心肌細胞增殖[46]。
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雖然運動可以有效刺激組織再生,但是某些羣體由於身體原因,不適合進行運動,運動的健康作用就被大大限制了。
爲了解決這個問題,研究者們把目光放在了運動誘導再生的機制上,通過直接干預作用靶點,達到和運動一樣的效果。目前,這類治療方案已初見成效。
IGF1
在多個器官中,IGF1的表達隨着運動而升高,對提高肌肉力量[47]、減少衰老導致的腦細胞凋亡[48],以及心肌細胞生長[49]都起到重要作用。
研究發現,IGF1基因治療能顯著恢復脊髓損傷的成年大鼠神經功能[50],還促進脊髓損傷小鼠的脊髓再生[51]。
由於IGF1治療可能引發腫瘤,一些研究者開發了間接干預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
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在肌肉,大腦和心臟中,PI3K信號的激活都會促進組織再生,而且目前發現多種可以作用於PI3K的小分子藥物。
例如,PTEN是PI3K信號通路的負調控因子[53]。Bisperoxovanadium可以通過抑制PTEN激活PI3K,進行肌肉修復[54]。
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在神經系統中,芒柄花素可以通過激活PI3K通路來預防腦缺血;外源性FGF10則通過該信號,促進外周神經損傷後的軸突再生[55,56]。
磷脂酰肌醇3-激酶(caPI3K-p110α)是作用於心臟的靶向藥物,目前發現可以通過刺激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牀潛力。
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miRNA
小鼠的運動實驗證明,miRNA介導多個器官的細胞增殖。例如,miR-23a/miR-27a可減輕慢性腎炎小鼠的肌肉損失[60];miR-135a下調可增加神經前體細胞的增殖,促進軸突再生[61,62];miR-17-3p有助於誘導的心肌細胞增殖。
這些觀察結果表明,干預miRNA表達在組織再生方面有很大研究前景。
不用親自運動,直接用藥物就能達到同等效果,可能聽起來很誘人,但是作者對這一研究提出了新的思考,那就是運動的調節分子對不同類型的細胞具有特異性作用,如果靶向精確性不夠,則可能產生相反的效果。
另外,作者認爲單純的運動是不夠的,需要結合其它因素一起治療。我們期待研究能夠近一步突破,早日發展新的再生醫學。
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