Abstract
在再生医学中,干细胞疗法是一种有效的组织再生策略,对缺损的组织再生修复具有积极的治疗作用。近年来,一系列研究表明,干细胞治疗的积极效果是由间充质干细胞的旁分泌起主导作用,是由干细胞释放的外泌体所介导,研究者们从而提出将干细胞来源的外泌体单独用于组织再生修复的可能性,并通过研究证实了其可达到与干细胞疗法相似的效果。因此,作为一种极具潜力的治疗策略,基于外泌体的组织再生治疗方法正在被广泛地研究。在这篇综述中,我们讨论了间充质干细胞来源的外泌体的相关理论及其在结缔组织再生修复方面的研究进展,包括骨、软骨、皮肤、脊髓、以及肌腱等组织的再生,并简要探讨了相应的作用机制。同时讨论了基于间充质干细胞外泌体进行组织再生修复的挑战和展望。
Keywords: 间充质干细胞, 外泌体, 组织再生修复
Abstract
In regenerative medicine, stem cell therapy is an effective strategy for tissue regeneration and has a positive therapeutic effect on the regeneration and repair of defective tissues. In recent years, a series of studies have shown that the positive effects of stem cell therapy are mediated by exosomes released by the paracrine action of mesenchymal stem cells. Researchers have thus proposed a novel treatment strategy to use stem-cell-derived exosomes alone for tissue regeneration and repair, and affirmed through studies that the effects achieved were comparable to those of stem-cell-based therapies. Therefore, as a promising treatment strategy, exosome-based tissue regeneration treatment measures have been extensively studied. In this review, we discussed the latest knowledge of exosomes and the research progress in the regeneration and repair of related connective tissues, including the regeneration of bones, cartilage, skin, spinal cord and tendons, and briefly discussed the corresponding mechanisms. In addition, the challenges and prospects of tissue regeneration and repair based on mesenchymal stem cell exosomes were discussed.
Keywords: Mesenchymal stem cells, Exosomes, Tissue regeneration and repair
间充质干细胞(mesenchymal stem cells,MSCs)是一类具有多谱系分化潜能的间质细胞。其来源广泛、免疫原性低、可为组织再生创造良好的微环境,是一种适合免疫调节和再生修复的细胞类型[1]。在干细胞疗法发展早期,基于MSCs的治疗方案在多项人体临床试验中取得了积极的效果[2–5],但后续的一些研究发现干细胞疗法对于多发性硬化、急性心肌梗死、急性肾损伤和中风等疾病具有明显的负面效果[6–7]。首先,MSCs的培养扩增和低温保存条件可能诱发免疫原性,从而降低治疗效果;其次,通过静脉注射的MSCs通常主要聚集在肺部,导致无法直接归巢至发病部位而引发一些负面影响;第三,对干细胞疗法的作用机理认识有限,难以制定特异性治疗方案[8]。因此,干细胞疗法的进一步发展遇到了较大的瓶颈。
近年来,越来越多的研究表明干细胞疗法的正面疗效很大程度上归因于干细胞旁分泌作用释放的外泌体[9]。外泌体是一类具有脂质双分子层的球状细胞外囊泡,直径为40~160 nm。外泌体最初被认为是细胞处理胞内垃圾的一种外泌囊泡,其特殊的生理功能并未发现。直到20世纪90年代后期,研究者发现外泌体的膜表面含有跨膜四蛋白,包括CD63、CD81和CD9,以及核内体膜蛋白flotillin和ALIX(也称为与PDCD6相互作用蛋白),其内部携带有蛋白质、脂质和核酸物质,其中核酸包括mRNA、microRNA(miRNA)和长非编码RNA,其相关的生理功能才进一步被发现。在生理条件下,外泌体通常将这些有功能的生物分子从一个细胞转移到另一个细胞,以促进细胞间的通讯[10–11]。因此,外泌体在细胞间通信中起到关键作用,并且与免疫反应、病毒致病性、妊娠、心血管疾病、中枢神经系统相关疾病以及癌症的进展有关。研究发现,通过体外离心分离技术获得的干细胞外泌体能产生和干细胞类似的积极治疗效果。同时,体外制备的外泌体能长时间保持生物活性、易保存、无免疫原性,并可以通过靶向修饰或局部注射的方式直接递送到发病部位,从而提高治疗效果。因此,使用干细胞来源的外泌体可以较好的规避现有干细胞疗法所存在的诸多不足,特别是间充质干细胞来源的外泌体(MSC-derived exosome, MSC-EXO),由于其包含大量与组织再生相关的活性分子,使之成为具有类似MSCs作用的无细胞治疗策略的有效手段。
目前,MSC-EXO作为一种极具潜力的治疗策略,在组织再生方面的应用受到广泛的关注。本文对MSC-EXO应用于骨、软骨、皮肤、脊髓以及肌腱等结缔组织再生修复的研究进展进行系统性的回顾,并简要探讨了相应的作用机制,同时讨论了基于MSC-EXO用于组织再生修复的优势、挑战和展望。
1. MSC-EXO在软骨再生中的作用
关节软骨损伤诱发的骨关节炎(osteoarthritis,OA)是一种慢性关节疾病,全球患者超过2.5亿人。截止到2020年,其发病率进一步增加,已成为致残的第四大原因。然而,关节软骨损伤的治疗仍是一个挑战[12]。MSC-EXO作为一种无细胞治疗策略,对关节软骨损伤的再生具有显著的作用[13],并在治疗骨性关节炎方面也具有良好的效果[14–22]。首先,在体外OA模型中,MSC-EXO可减轻白介素-1β(IL-1β)诱导的成骨细胞衰老和炎症反应[23]。其次,近期研究表明,在通过肿瘤坏死因子-α(TNF-α)[24]或IL-1β[25– 26]刺激诱导的OA模型中,MSC-EXO可恢复基质稳态,抑制细胞凋亡,并减弱软骨细胞的炎症作用。一系列研究表明,MSC-EXO具有促进软骨细胞的基质再生、加速软骨形成的作用,通过MSC-EXO处理的软骨细胞,其迁移、增殖、软骨分化和基质合成均有所增强[27]。同时,通过基因编辑可提高MSC-EXO的治疗性能[19]。例如,TAO等[20]研究表明过表达miR-140-5p的MSC-EXO的疗效优于未处理的MSC-EXO。还有研究表明,通过MSC-EXO与组织工程支架复合,进行MSC-EXO的递送,能协同增强软骨组织的再生修复[14]。例如,LIU等[17]报道,将富含外泌体的水凝胶薄片植入受损的关节软骨部位,其治疗效果优于单独注射外泌体。但值得注意的是,来源于不同组织的间充质干细胞外泌体,其功能和效果也通常有所不同。为了确定用于关节软骨损伤治疗的最佳外泌体来源,有研究比较了不同干细胞来源的外泌体效果差异[15, 22]。ZHU等[22]研究发现,在OA治疗中,诱导多能干细胞外泌体(iPS-MSC-EXO)的疗效优于滑膜间充质干细胞外泌体(SM-MSC-EXO)的效果。
研究者通过探究MSC-EXO靶向受体细胞的分子成分和相关信号通路,以探索MSC-EXO介导软骨组织再生的分子机制。近期研究报道,MSC-EXO对软骨的治疗作用是通过激活蛋白激酶B(AKT)、调节细胞激酶(ERK)和腺苷酸5′-单磷酸(AMP)依赖的蛋白激酶(AMPK)信号通路介导的,归因于MSC-EXO携带的CD73介导的酶活性[26, 28]。同时发现MSC-EXO来源的CD73是将AMP水解为腺苷的关键酶,激活腺苷受体,增强腺苷受体介导的软骨细胞中AKT、ERK和AMPK的快速磷酸化[26]。另外,由MSC-EXO引起的级联反应导致了细胞的多种生理功能的激活,如细胞存活、增殖、分化和迁移,这些都有利于组织修复[26, 28]。近期也有研究报道MSC-EXO通过靶向软骨细胞的哺乳动物雷帕霉素靶蛋白(mTOR)信号来介导软骨的自我保护,MSC-EXO下调mTOR信号通路,导致IL-1β处理的软骨细胞自噬增强,抑制细胞凋亡,调节细胞代谢,促进基质再生。这种作用与MSC-EXO携带的核酸miR-100-5p的转移有关,miR-100-5p通过靶向mTOR的mRNA降低其表达,实现组织再生[25]。
MSC-EXO通过与软骨形成细胞(MSC-软骨细胞谱系的细胞)相互作用促进软骨再生,在治疗关节软骨损伤和骨关节炎方面具有良好的前景。但现阶段对MSC-EXO治疗效果的研究仍处于初步阶段,除少量研究是以家兔作为动物模型[14, 17],大部分研究都是在大鼠或小鼠模型上进行的[15-16, 18, 22]。由此可见,目前的研究还很大程度上局限于小动物模型,需通过大动物模型进行进一步验证,并最终向临床研究的方向发展。
2. MSC-EXO在骨再生中的作用
MSC-EXO通过与不同类型的细胞相互作用,调控组织再生的过程。本节列举了MSC-EXO在骨折[29–30]、骨缺损[31–34]、骨疾病(特别是成骨不全[27])等方面的临床前研究结果。越来越多的研究表明,在不同的动物疾病模型中,注射负载功能性物质或基因修饰的MSC-EXO,可促进新生血管生成和骨组织再生。在这些研究中,最常用的治疗策略是通过局部注射天然的MSC-EXO悬液[25, 34-35],或者是通过静脉注射MSC-EXO[27]。另一种选择是将MSC-EXO固定到工程支架上,如β-TCP、PLA和脱钙牛骨基质支架[36],或将MSC-EXO负载到水凝胶[17, 29]或胶原海绵[28]中,并植入损伤部位。这类复合了MSC-EXO的组织工程支架,可以增强生物学功能。最近一项研究报道,将MSC-EXO固定在钛支架的表面后,间充质干细胞在支架表面的黏附作用增强,这对于进一步的组织再生修复具有积极的作用[37]。此外,研究表明,通过预修饰或后修饰的方法对MSC-EXO进行设计,能够增强其生物学功能。通过转染双亲间充质干细胞过表达分子,如缺氧诱导因子-1α(HIF-1α)[38]或miR-375[33],可以实现MSC-EXO的预修饰;或通过诱导成骨分化[33]、或用细胞因子干扰素-γ(IFN-γ)和TNF-α、或缺氧处理[30]预刺激间充质干细胞等方式来增强MSC-EXO的骨再生效果。
对于MSC-EXO促进骨再生的分子机制也得到深入研究。WANG等[37]报道了来自不同成骨分化阶段的MSC-EXO携带不同类型和含量的microRNA。成骨分化晚期[37]的MSC-EXO中富集了一些特定的成骨相关microRNA,其中促成骨相关的microRNAs(miR-10b和miR-21)表达升高,而抗成骨的microRNAs(miR-31、miR-144和miR-221)表达降低,这与MSC-EXO诱导成骨分化和矿化有关[39]。这一结果表明,MSC-EXO在介导成骨分化的过程中,其携带的成骨相关microRNAs发挥了积极作用。此外,MSC-EXO可上调受体细胞中促成骨和促血管生成的相关miRNAs(miR-2861和miR-210)的表达,从而诱导成血管因子VEGF和成骨因子RUNX2的表达上调,促进成骨分化[31]。另一项研究将MSC-EXO的促成骨作用归因于外泌体中Wnt3a的富集和Wnt信号通路的靶向,Wnt信号通路是受体人原代成骨细胞(OBs)中调控成骨分化的信号通路之一[40]。此外,前期有研究证实了PI3K/Akt信号通路调控成骨细胞分化和骨形成的关键作用[41],而ZHANG等[42]研究发现,MSC-EXO增强MSCs成骨分化作用的积极效果是通过激活PI3K/Akt信号通路实现的。
骨损伤部位的血管化和血液供应的恢复是组织修复过程中的关键,对组织再生和功能恢复均有重要意义。MSC-EXO有促进血管形成细胞〔如人源静脉内皮细胞(HUVECs)〕再生的作用,有助于血管再生,进而促进骨组织再生。首先,MSC-EXO可促进HUVECs的增殖和迁移,并上调VEGF和HIF-1α等血管生成相关基因,增加血管形成能力[29, 36, 38, 42–45]。其次,MSC-EXO通过转染外泌体携带的microRNAs(miR-30b和miR-210),分别靶向受体HUVECs中的Delta样配体4(DLL4)和Ephrin A3(EFNA3),可促进血管生成[43–44]。除了MSC-EXO携带的microRNA介导作用外,将外泌体携带的Wnt4转移到HUVECs,可以激活β-Catenin蛋白功能,从而促进血管生成[45]。最近的一项研究表明,缺氧预处理可激活MSCs中的HIF-1α表达,以促进外泌体的释放,然后通过诱导MSC-EXO携带的miR-126富集,并将miR-126转移到HUVECs中,抑制Ras/ERK通路抑制因子(SPRED1)的表达,从而激活Ras/ERK通路,促进HUVEC的增殖、迁移和血管生成[46]。
因此,通过不同的MSC-EXO的应用形式,进行功能化修饰或基因调控以增强其携带的生物因子活性,或通过与支架复合等手段递送生物活性物质至受体细胞等,均可以有效调控细胞的生物学功能,促进成骨相关细胞和成血管相关细胞的增殖迁移以及基质合成,对骨再生过程发挥积极的作用。
3. MSC-EXO在皮肤再生中的作用
皮肤可保护机体免受环境挑战,但皮肤大面积受损后,无法正常愈合,特别是在患有糖尿病(慢性伤口或溃疡)等疾病的情况下。因此加速皮肤组织再生、更快地恢复受损皮肤功能,是皮肤组织再生修复的重点[47]。皮肤创面愈合包括4个阶段:稳态阶段、炎症阶段、增殖阶段和重塑阶段[48]。这些阶段的生物过程紧密协调,以确保至关重要的皮肤屏障功能。相关研究表明,MSC-EXO在皮肤再生过程各个阶段中均发挥了重要作用。
在稳态阶段,血小板可形成血栓以保护受伤部位。虽然到目前为止还没有直接证据表明MSC-EXO参与了伤口愈合过程中的血液凝固,但最近的一项研究结果表明了MSC-EXO在伤口愈合过程中对伤口止血的潜在益处,即人类脐带来源的MSC-EXO(UC-MSC-EXO)在体外可以诱导凝血[49]。然而,需要进一步的研究来分析MSC-EXO在健康和疾病条件下的凝血作用。
在炎症阶段,良好的炎症调节可加速伤口愈合过程。炎症是机体对有害刺激的自我防御机制,目的是恢复生物体的体内平衡。因此,急性和良好的炎症调节有利于伤口愈合,而慢性和不适当的炎症反应可能导致伤口愈合延迟,包括纤维化、过度的疤痕形成或上皮形成抑制[50]。巨噬细胞是皮肤再生过程中的主要炎症细胞,分为促炎性M1型和抗炎性M2型两种不同的表型极化。MSC-EXO可促进巨噬细胞向抗炎性M2表型的极化[51]。此外,伤口组织中存在的B淋巴细胞和T淋巴细胞在伤口愈合中也具有一定的作用:B淋巴细胞不仅分泌抗体,还通过产生各种细胞因子和生长因子来影响免疫反应;活化的调节性T细胞可通过减少IFN-γ的产生和降低促炎性M1巨噬细胞的积累来促进伤口愈合[52]。近期研究表明,MSC-EXO可以调节B淋巴细胞的分化和增殖,也可以抑制T淋巴细胞的增殖,还能将活化的T淋巴细胞转化为调节性T细胞表型,从而发挥免疫抑制作用[53]。
在增殖阶段,成纤维细胞可从周围正常组织迁移到损伤部位,并产生各种基质蛋白,包括Ⅰ型胶原蛋白和Ⅲ型胶原蛋白,以促进疤痕组织的形成。不同组织来源的MSC-EXO都能与成纤维细胞等相互作用,调节细胞的迁移和增殖以及基质的生成,从而促进皮肤再生:人源脂肪间充质干细胞外泌体(ASC-MSC-EXO)可体外诱导真皮组织的成纤维细胞或角质形成细胞的迁移和增殖,并增强Ⅰ/Ⅲ胶原和弹性蛋白的产生,从而促进小鼠皮肤伤口愈合[54];人胚胎真皮间充质干细胞外泌体(FD-MSC-EXO)通过传递Jagged 1蛋白,激活Notch通路,诱导Ⅰ/Ⅲ型胶原、弹性蛋白和纤维连接蛋白mRNA的表达[55];人源骨髓间充质干细胞外泌体(BMSC-EXO)可体外诱导成纤维细胞(取自糖尿病患者伤口)增殖和迁移[56]。MSC-EXO对角质形成细胞也有一定的作用;人源UC-MSC-EXO通过激活AKT通路保护人永生化角质形成细胞(HaCaT)免受热诱导的凋亡[57];人源Wharton’s Jelly-MSC-EXO和诱导多功能干细胞外泌体(iPSC-MSC-EXO)均可增强HaCaT中胶原的分泌[58]。
在重塑阶段,MSC-EXO有助于减少疤痕的形成。疤痕形成主要是肌成纤维细胞在伤口部位不受控制的积累所导致。因此,减少肌成纤维细胞的过度聚集,有利于减少疤痕的形成。人源UC-MSC-EXO可通过抑制小鼠肌成纤维细胞的积累来减少疤痕的形成[59]。此外,成纤维细胞、巨噬细胞、表皮细胞和内皮细胞控制释放的基质金属蛋白酶(MMPs)有助于降解大部分Ⅲ型胶原纤维,减少疤痕生成。WANG等[54]研究证实了ASC-MSC-EXO对细胞外基质重塑的调控,即通过调节TGF-β3与TGF-β1,MMP3与MMP1的表达比例调控Ⅰ型胶原与Ⅲ型胶原的形成比例,从而促进皮肤创伤无疤痕修复。
综上,MSC-EXO可参与皮肤创伤愈合的稳态、炎症、增殖和重塑4个阶段,通过介导炎症反应和免疫调节,以及对细胞增殖、迁移和基质形成等方面的促进,对皮肤损伤再生发挥积极作用。
4. MSC-EXO在脊髓损伤修复中的作用
脊髓损伤(spinal cord injury,SCI)常导致肢体的运动和感觉功能的障碍,不仅会对患者的身体和心理造成伤害,还会给患者的家庭和社会造成巨大的经济负担。由于目前尚无有效的治疗方法,脊髓损伤患者的预防、治疗和康复已成为亟待解决的问题。近年来,MSC-EXO在SCI中的治疗潜力受到研究者们密切的关注,并有望成为一种良好的SCI治疗方法。许多研究证明,SCI的功能恢复主要与炎症调节有关,因此抑制剧烈炎症环境的形成是治疗脊髓损伤的主要策略[60]。炎症反应的调节主要与促炎因子(如IL-1β、IL-6、TNF-α等)和抗炎因子(如IL-4和IL-10等)的相对表达水平有关。许多研究表明,MSC-EXO在脊椎损伤中通过抑制促炎因子的表达,可以改善SCI的功能恢复。ROMANELLI等[61]报道了人源UC-MSC-EXO在体外直接与活化的小胶质细胞相互作用,并在SCI二次损伤中抑制促炎因子的表达。在脊髓损伤大鼠模型中,静脉注射人UC-MSC-EXO可抑制IL-1β和IL-6的表达,从而促进运动功能的恢复。最近的另外一些研究表明,在创伤性脑损伤模型和脊髓损伤模型中,NLRP3炎症小体被激活,其活性增强[62–63]。NLRP3炎症小体位于细胞质中,由NLRP3(一种凋亡相关的斑点样蛋白,包含Caspase招募域)和Caspase-1组装而成,对免疫反应的调节具有重要作用[64–65]。因此,抑制NLRP3炎症的激活可以促进脊髓损伤后的功能恢复。HUANG等[66]发现来自硬膜外ASC-MSC-EXO可促进神经功能的恢复,减少损伤面积的扩大。其主要的作用机制是,注射到SCI动物模型中的外泌体显著抑制了NLRP3炎症小体的激活,并降低炎症细胞因子的表达。SUN等[67]的研究也得到了类似的结果,发现人源UC-MSC-EXO可降低促炎细胞因子TNF-α、IL-6、IFN-γ和粒细胞集落刺激因子的水平,同时增加抗炎细胞因子IL-4和IL-10的水平。MSC-EXO的治疗作用也被发现与促进巨噬细胞极化有关,如LANKFORD等[68]发现静脉注射MSC-EXO可迅速到达损伤脊髓处,并与M2型巨噬细胞特异性结合,可缓解脊髓损伤。
目前,关于MSC-EXO促进巨噬细胞极化来治疗脊髓损伤的研究仍处于初期阶段。当前研究主要集中在MSC-EXO介导炎症反应和免疫调节,从而改善脊髓损伤导致的生理功能障碍。且大多数都基于啮齿动物模型,因此研究范围需要扩大。此外,虽然外泌体对脊髓损伤有一定的治疗作用,但具体的治疗机制和靶点尚不明确,需要进一步的研究。
5. MSC-EXO在肌腱损伤修复中的作用
肌腱损伤在体育活动和竞技运动中很常见。肌腱受伤后愈合缓慢,保守治疗和手术治疗效果均不理想,再伤率高,且容易形成瘢痕组织。一些研究报道了MSC-EXO对肌腱或韧带修复的有利作用。在一项大鼠肌腱损伤模型修复研究中,BMSC-EXO治疗以剂量依赖的方式促进大鼠跟腱的愈合,改善纤维结构和肌腱结构,促进Ⅰ型胶原的表达,且Ⅲ型胶原表达降低[69]。YU等[70]研究表明,在大鼠髌骨肌腱缺损区注射MSC-EXO,在组织学和生物力学方面均能明显改善肌腱修复。最近的一项研究表明,在兔肩袖撕裂和修复模型中,在肌腱-骨交界处局部注射ASC-MSC-EXO可减少脂肪浸润,促进肌腱-骨愈合,增加新生成的纤维软骨,并改善肌腱-骨交界处的生物力学性能[71]。在另一项研究中,负载BMSC-EXO的水凝胶促进了小鼠模型的肌腱-骨愈合和纤维软骨生成,并改善了组织的生物力学性能[72]。但目前关于MSC-EXO在增强肌腱-骨连接修复中作用的研究还相对有限,MSC-EXO对肌腱损伤修复的积极作用需要进一步在临床上验证,其相关的治疗机制和作用靶点也需要在进一步的研究探索。
6. 挑战和展望
尽管大量的研究报道了MSC-EXO在结缔组织再生治疗中的积极作用,但这些结果还需要在临床研究中进一步验证。同时,MSC-EXO治疗相关的临床转化仍然存在较大的挑战。具体的问题表现在以下几个方面:第一,由于技术限制,目前获取高纯度和高产量的MSC-EXO尚有较大的难度,因此需要进一步发展技术,提高分离效率和产能,以满足临床应用。第二,目前尚不清楚MSC-EXO中具体的内载物质(脂质、蛋白质和核酸)与其产生积极治疗效果之间的直接关系。在将MSC-EXO作为治疗剂使用时,各种内载物质的治疗效果、安全性和有效剂量都还需要进行深入研究。第三,MSC-EXO的非特异性靶向治疗可能导致不可预见的副作用。由于MSC-EXO已被证明可靶向多种细胞类型,但目前还不清楚MSC-EXO是如何选择优先受体,特别是在复杂的体内环境中。因此提高MSC-EXO的靶向性将更好地提高其安全性和作用效率。第四,将MSC-EXO作为一种药物传递载体的相关研究也是当前热点之一,而载药效率是另一个需要克服的挑战。未来的研究需要开发高效的既能将足够剂量的药物装载到MSC-EXO中,又能保持MSC-EXO物理完整性和生物活性的技术方法。
目前,MSC-EXO的研究是一个活跃的热点领域,正在发展的技术和相关研究的进展可能会为外泌体的异质性和生物学功能的揭示提供更多有价值的信息,并推动MSC-EXO在医学治疗和诊断方面的发展。未来的研究成果可望为外泌体对组织再生、器官退化以及衰老等生理过程的作用提供新的见解。通过外泌体的分离纯化、特异性鉴定以及相关分析检测技术的进步,将极大地推动对外泌体的基础生物学的理解和在医学治疗技术中的应用。
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利益冲突 所有作者均声明不存在利益冲突
Funding Statement
国家重点研发计划重点专项(No. 2018YFC1105900)、国家自然科学基金(No. 32071352)和四川省重点研发计划重点专项(No. 2019YFS0007)资助
Contributor Information
曼雨 陈 (Man-yu CHEN), Email: 15261816763@163.com.
渝江 樊 (Yu-jiang FAN), Email: fan_yujiang@scu.edu.cn.
References
- 1.WANG Y, CHEN X, CAO W, et al Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications. Nat Immunol. 2014;15(11):1009–1016. doi: 10.1038/ni.3002. [DOI] [PubMed] [Google Scholar]
- 2.PENG X, XU H, ZHOU Y, et al Human umbilical cord mesenchymal stem cells attenuate cisplatin-induced acute and chronic renal injury. Exp Biol Med. 2013;238(8):960–970. doi: 10.1177/1535370213497176. [DOI] [PubMed] [Google Scholar]
- 3.MURATA D, AKIEDA S, MISUMI K, et al Osteochondral regeneration with a scaffold-free three-dimensional construct of adipose tissue-derived mesenchymal stromal cells in pigs. Tissue Eng Regen Med. 2017;15(1):101–113. doi: 10.1007/s13770-017-0091-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.SROUJI S, BEN-DAVID D, FROMIGUE O, et al Lentiviral-mediated integrin alpha 5 expression in human adult mesenchymal stromal cells promotes bone repair in mouse cranial and long-bone defects. Hum Gene Ther. 2012;23(2):167–172. doi: 10.1089/hum.2011.059. [DOI] [PubMed] [Google Scholar]
- 5.INGAVLE G C, GIONET-GONZALES M, VORWALD C E, et al Injectable mineralized microsphere-loaded composite hydrogels for bone repair in a sheep bone defect model. Biomaterials. 2019;197:119–128. doi: 10.1016/j.biomaterials.2019.01.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.GYOENGYOESI M, WOJAKOWSKI W, LEMARCHAND P, et al Meta-analysis of cell-based CaRdiac stUdiEs (ACCRUE) in patients with acute myocardial infarction based on individual patient data. Circ Res. 2015;116(8):1346–1360. doi: 10.1161/CIRCRESAHA.116.304346. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.SWAMINATHAN M, STAFFORD-SMITH M, CHERTOW G M, et al Allogeneic mesenchymal stem cells for treatment of AKI after cardiac surgery. J Am Soc Nephrol. 2018;29(1):260–267. doi: 10.1681/ASN.2016101150. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.KIM N, CHO S G New strategies for overcoming limitations of mesenchymal stem cell-based immune modulation. Int J Stem Cells. 2015;8(1):54–68. doi: 10.15283/ijsc.2015.8.1.54. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.GNECCHI M, HE H M, LIANG O D, et al Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nat Med. 2005;11(4):367–368. doi: 10.1038/nm0405-367. [DOI] [PubMed] [Google Scholar]
- 10.LENER T, GIMONA M, AIGNER L, et al Applying extracellular vesicles based therapeutics in clinical trials—An ISEV position paper. J Extracell Vesicles. 2015;4:30087[2021-04-18]. https://doi.org/10.3402/jev.v4.30087. doi: 10.3402/jev.v4.30087. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.MATEESCU B, KOWAL E J K, VAN BALKOM B W M, et al Obstacles and opportunities in the functional analysis of extracellular vesicle RNA—An ISEV position paper. J Extracell Vesicles. 2017;6:1286095[2021-04-18]. https://doi.org/10.1080/20013078.2017.1286095. doi: 10.1080/20013078.2017.1286095. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.HUNTER D J, BIERMA-ZEINSTRA S Osteoarthritis. The Lancet. 2019;393(9991):1745–1759. doi: 10.1016/S0140-6736(19)30417-9. [DOI] [PubMed] [Google Scholar]
- 13.WITWER K W, VAN BALKOM B W M, BRUNO S, et al Defining mesenchymal stromal cell (MSC)-derived small extracellular vesicles for therapeutic applications. J Extracell Vesicles. 2019;8:1609206[2021-04-18]. https://doi.org/10.1080/20013078.2019.1609206. doi: 10.1080/20013078.2019.1609206. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.CHEN P, ZHENG L, WANG Y, et al Desktop-stereolithography 3D printing of a radially oriented extracellular matrix/mesenchymal stem cell exosome bioink for osteochondral defect regeneration. Theranostics. 2019;9(9):2439–2459. doi: 10.7150/thno.31017. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.CHEN Y, XUE K, ZHANG X, et al Exosomes derived from mature chondrocytes facilitate subcutaneous stable ectopic chondrogenesis of cartilage progenitor cells. Stem Cell Res Ther. 2018;9:318[2021-04-18]. https://doi.org/10.1186/s13287-018-1047-2. doi: 10.1186/s13287-018-1047-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.COSENZA S, RUIZ M, TOUPET K, et al Mesenchymal stem cells derived exosomes and microparticles protect cartilage and bone from degradation in osteoarthritis. Sci Rep. 2017;7:16214[2021-04-18]. https://doi.org/10.1038/s41598-017-15376-8. doi: 10.1038/s41598-017-15376-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.LIU X, YANG Y, LI Y, et al Integration of stem cell-derived exosomes within situ hydrogel glue as a promising tissue patch for articular cartilage regeneration . Nanoscale. 2017;9(13):4430–4438. doi: 10.1039/c7nr00352h. [DOI] [PubMed] [Google Scholar]
- 18.LIU Y, ZOU R, WANG Z, et al Exosomal KLF3-AS1 from hMSCs promoted cartilage repair and chondrocyte proliferation in osteoarthritis. Biochem J. 2018;475(22):3629–3638. doi: 10.1042/BCJ20180675. [DOI] [PubMed] [Google Scholar]
- 19.MAO G, ZHANG Z, HU S, et al Exosomes derived from miR-92a-3p-overexpressing human mesenchymal stem cells enhance chondrogenesis and suppress cartilage degradation via targeting WNT5A. Stem Cell Res Ther. 2018;9:247[2021-04-18]. https://doi.org/10.1186/s13287-018-1004-0. doi: 10.1186/s13287-018-1004-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.TAO S C, YUAN T, ZHANG Y L, et al Exosomes derived from miR-140-5p-overexpressing human synovial mesenchymal stem cells enhance cartilage tissue regeneration and prevent osteoarthritis of the knee in a rat model. Theranostics. 2017;7(1):180–195. doi: 10.7150/thno.17133. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.ZHANG S, CHUAH S J, LAI R C, et al MSC exosomes mediate cartilage repair by enhancing proliferation, attenuating apoptosis and modulating immune reactivity. Biomaterials. 2018;156:16–27. doi: 10.1016/j.biomaterials.2017.11.028. [DOI] [PubMed] [Google Scholar]
- 22.ZHU Y, WANG Y, ZHAO B, et al Comparison of exosomes secreted by induced pluripotent stem cell-derived mesenchymal stem cells and synovial membrane-derived mesenchymal stem cells for the treatment of osteoarthritis. Stem Cell Res Ther. 2017;8(1):64[2021-04-18]. https://doi.org/10.1186/s13287-017-0510-9. doi: 10.1186/s13287-017-0510-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.TOFINO-VIAN M, ISABEL GUILLEN M, PEREZ DEL CAZ M D, et al Extracellular vesicles from adipose-derived mesenchymal stem cells downregulate senescence features in osteoarthritic osteoblasts. Oxid Med Cell Longev. 2017;2017:7197598[2021-04-18]. https://doi.org/10.1155/2017/7197598. doi: 10.1155/2017/7197598. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.VONK L A, VAN DOOREMALEN S F J, LIV N, et al Mesenchymal stromal/stem cell-derived extracellular vesicles promote human cartilage regeneration in vitro . Theranostics. 2018;8(4):906–920. doi: 10.7150/thno.20746. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.WU J, KUANG L, CHEN C, et al miR-100-5p-abundant exosomes derived from infrapatellar fat pad MSCs protect articular cartilage and ameliorate gait abnormalities via inhibition of mTOR in osteoarthritis. Biomaterials. 2019;206:87–100. doi: 10.1016/j.biomaterials.2019.03.022. [DOI] [PubMed] [Google Scholar]
- 26.ZHANG S P, TEO K Y W, CHUAH S J, et al MSC exosomes alleviate temporomandibular joint osteoarthritis by attenuating inflammation and restoring matrix homeostasis. Biomaterials. 2019;200:35–47. doi: 10.1016/j.biomaterials.2019.02.006. [DOI] [PubMed] [Google Scholar]
- 27.OTSURU S, DESBOURDES L, GUESS A J, et al Extracellular vesicles released from mesenchymal stromal cells stimulate bone growth in osteogenesis imperfecta. Cytotherapy. 2018;20(1):62–73. doi: 10.1016/j.jcyt.2017.09.012. [DOI] [PubMed] [Google Scholar]
- 28.CHEW J R J, CHUAH S J, TEO K Y W, et al Mesenchymal stem cell exosomes enhance periodontal ligament cell functions and promote periodontal regeneration. Acta Biomater. 2019;89:252–264. doi: 10.1016/j.actbio.2019.03.021. [DOI] [PubMed] [Google Scholar]
- 29.ZHANG Y, HAO Z, WANG P, et al Exosomes from human umbilical cord mesenchymal stem cells enhance fracture healing through HIF-1 alpha-mediated promotion of angiogenesis in a rat model of stabilized fracture. Cell Prolif. 2019;52(2):e12570[2021-04-18]. https://doi.org/10.1111/cpr.12570. doi: 10.1111/cpr.12570. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.LIU W, LI L, RONG Y, et al Hypoxic mesenchymal stem cell-derived exosomes promote bone fracture healing by the transfer of miR-126. Acta Biomater. 2020;103:196–212. doi: 10.1016/j.actbio.2019.12.020. [DOI] [PubMed] [Google Scholar]
- 31.PIZZICANNELLA J, DIOMEDE F, GUGLIANDOLO A, et al 3D printing PLA/gingival stem cells/ EVs upregulate miR-2861 and -210 during osteoangiogenesis commitment. Int J Mol Sci. 2019;20(13):3256[2021-04-18]. https://doi.org/10.3390/ijms20133256. doi: 10.3390/ijms20133256. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.CHEN S, TANG Y, LIU Y, et al Exosomes derived from miR-375-overexpressing human adipose mesenchymal stem cells promote bone regeneration. Cell Prolif. 2019;52(5):e12669[2021-04-18]. https://doi.org/10.1111/cpr.12669. doi: 10.1111/cpr.12669. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.LI W, LIU Y, ZHANG P, et al Tissue-engineered bone immobilized with human adipose stem cells-derived exosomes promotes bone regeneration. Acs Appl Mater Interfaces. 2018;10(6):5240–5254. doi: 10.1021/acsami.7b17620. [DOI] [PubMed] [Google Scholar]
- 34.PIZZICANNELLA J, GUGLIANDOLO A, ORSINI T, et al Engineered extracellular vesicles from human periodontal-ligament stem cells increase VEGF/VEGFR2 expression during bone regeneration. Front Physiol. 2019;10:512[2021-04-18]. https://doi.org/10.3389/fphys.2019.00512. doi: 10.3389/fphys.2019.00512. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.MOHAMMED E, KHALIL E, SABRY D Effect of adipose-derived stem cells and their Exo as adjunctive therapy to nonsurgical periodontal treatment: a histologic and histomorphometric study in rats. Biomolecules. 2018;8(4):167[2021-04-18]. https://doi.org/10.3390/biom8040167. doi: 10.3390/biom8040167. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.XIE H, WANG Z, ZHANG L, et al Extracellular vesicle-functionalized decalcified bone matrix scaffolds with enhanced pro-angiogenic and pro-bone regeneration activities. Sci Rep. 2017;7:45622[2021-04-18]. https://doi.org/10.1038/srep45622. doi: 10.1038/srep45622. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.WANG X, SHAH F A, VAZIRISANI F, et al Exosomes influence the behavior of human mesenchymal stem cells on titanium surfaces. Biomaterials. 2020;230:119571[2021-04-18]. https://doi.org/10.1016/j.biomaterials.2019.119571. doi: 10.1016/j.biomaterials.2019.119571. [DOI] [PubMed] [Google Scholar]
- 38.LI H, LIU D, LI C, et al Exosomes secreted from mutant-HIF-1-modified bone-marrow-derived mesenchymal stem cells attenuate early steroid-induced avascular necrosis of femoral head in rabbit. Cell Biol Int. 2017;41(12):1379–1390. doi: 10.1002/cbin.10869. [DOI] [PubMed] [Google Scholar]
- 39.WANG X, OMAR O, VAZIRISANI F, et al Mesenchymal stem cell-derived exosomes have altered microRNA profiles and induce osteogenic differentiation depending on the stage of differentiation. PLoS One. 2018;13(2):e0193059[2021-04-18]. https://doi.org/10.1371/journal.pone.0193059. doi: 10.1371/journal.pone.0193059. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.LU Z, CHEN Y, DUNSTAN C, et al Priming adipose stem cells with tumor necrosis factor-alpha preconditioning potentiates their exosome efficacy for bone regeneration. Tissue Eng Part A. 2017;23(21-22):1212–1220. doi: 10.1089/ten.tea.2016.0548. [DOI] [PubMed] [Google Scholar]
- 41.FUJITA T, AZUMA Y, FUKUYAMA R, et al Runx2 induces osteoblast and chondrocyte differentiation and enhances their migration by coupling with PI3K-Akt signaling. J Cell Biol. 2004;166(1):85–95. doi: 10.1083/jcb.200401138. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.ZHANG J, LIU X, LI H, et al Exosomes/tricalcium phosphate combination scaffolds can enhance bone regeneration by activating the PI3K/Akt signaling pathway. Stem Cell Res Ther. 2016;7(1):136[2021-04-18]. https://doi.org/10.1186/s13287-016-0391-3. doi: 10.1186/s13287-016-0391-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.ZHU Y, JIA Y, WANG Y, et al Impaired bone regenerative effect of exosomes derived from bone marrow mesenchymal stem cells in type 1 diabetes. Stem Cells Transl Med. 2019;8(6):593–605. doi: 10.1002/sctm.18-0199. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.GONG M, YU B, WANG J, et al Mesenchymal stem cells release exosomes that transfer miRNAs to endothelial cells and promote angiogenesis. Oncotarget. 2017;8(28):45200–45212. doi: 10.18632/oncotarget.16778. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45.WANG N, CHEN C, YANG D, et al Mesenchymal stem cells-derived extracellular vesicles, via miR-210, improve infarcted cardiac function by promotion of angiogenesis. Biochim Biophys Acta-Mol Basis Dis. 2017;1863(8):2085–2092. doi: 10.1016/j.bbadis.2017.02.023. [DOI] [PubMed] [Google Scholar]
- 46.ZHANG B, WU X, ZHANG X, et al Human umbilical cord mesenchymal stem cell exosomes enhance angiogenesis through the Wnt4/beta-Catenin pathway. Stem Cells Transl Med. 2015;4(5):513–522. doi: 10.5966/sctm.2014-0267. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47.SEN C K Human wounds and its burden: an updated compendium of estimates. Adv Wound Care. 2019;8(2):39–48. doi: 10.1089/wound.2019.0946. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 48.FERREIRA A D F, GOMES D A Stem cell extracellular vesicles in skin repair. Bioengineering. 2018;6(1):4[2021-04-18]. https://doi.org/10.3390/bioengineering6010004. doi: 10.3390/bioengineering6010004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49.SILACHEV D N, GORYUNOV K V, SHPILYUK M A, et al Effect of MSCs and MSC-derived extracellular vesicles on human blood coagulation. Cells. 2019;8(3):258[2021-04-18]. https://doi.org/10.3390/cells8030258. doi: 10.3390/cells8030258. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 50.KRZYSZCZYK P, SCHLOSS R, PALMER A, et al The role of macrophages in acute and chronic wound healing and interventions to promote pro-wound healing phenotypes. Front Physiol. 2018;9:419[2021-04-18]. https://doi.org/10.3389/fphys.2018.00419. doi: 10.3389/fphys.2018.00419. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 51.LO SICCO C, REVERBERI D, BALBI C, et al Mesenchymal stem cell-derived extracellular vesicles as mediators of anti-inflammatory effects: endorsement of macrophage polarization. Stem Cells Transl Med. 2017;6(3):1018–1028. doi: 10.1002/sctm.16-0363. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 52.LIPSKY P E Systemic lupus erythematosus: an autoimmune disease of B cell hyperactivity. Nat Immunol. 2001;2(9):764–766. doi: 10.1038/ni0901-764. [DOI] [PubMed] [Google Scholar]
- 53.NOSBAUM A, PREVEL N, TRUONG H A, et al Cutting edge: regulatory T cells facilitate cutaneous wound healing. J Immunol. 2016;196(5):2010–2014. doi: 10.4049/jimmunol.1502139. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 54.WANG L, HU L, ZHOU X, et al Exosomes secreted by human adipose mesenchymal stem cells promote scarless cutaneous repair by regulating extracellular matrix remodelling. Sci Rep. 2017;7(1):13321[2021-04-18]. https://doi.org/10.1038/s41598-017-12919-x. doi: 10.1038/s41598-017-12919-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 55.WANG X, JIAO Y, PAN Y, et al Fetal dermal mesenchymal stem cell-derived exosomes accelerate cutaneous wound healing by activating notch signaling. Stem Cells Int. 2019;2019:2402916[2021-04-18]. https://doi.org/10.1155/2019/2402916. doi: 10.1155/2019/2402916. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 56.SHABBIR A, COX A, RODRIGUEZ-MENOCAL L, et al Mesenchymal stem cell exosomes induce proliferation and migration of normal and chronic wound fibroblasts, and enhance angiogenesisin vitro . Stem Cells Dev. 2015;24(14):1635–1647. doi: 10.1089/scd.2014.0316. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 57.ZHANG B, WANG M, GONG A, et al HucMSC-exosome mediated-Wnt4 signaling is required for cutaneous wound healing. Stem Cells. 2015;33(7):2158–2168. doi: 10.1002/stem.1771. [DOI] [PubMed] [Google Scholar]
- 58.KIM S, LEE SK, KIM H, et al Exosomes secreted from induced pluripotent stem cell-derived mesenchymal stem cells accelerate skin cell proliferation. Int J Mol Sci. 2018;19(10):3119[2021-04-18]. https://doi.org/10.3390/ijms19103119. doi: 10.3390/ijms19103119. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 59.SHI Q, QIAN Z, LIU D, et al GMSC-derived exosomes combined with a chitosan/silk hydrogel sponge accelerates wound healing in a diabetic rat skin defect model. Front Physiol. 2017;8:904[2021-04-18]. https://doi.org/10.3389/fphys.2017.00904. doi: 10.3389/fphys.2017.00904. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 60.KWON B K, STREIJGER F, FALLAH N, et al Cerebrospinal fluid biomarkers to stratify injury severity and predict outcome in human traumatic spinal cord injury. J Neurotrauma. 2017;34(3):567–580. doi: 10.1089/neu.2016.4435. [DOI] [PubMed] [Google Scholar]
- 61.ROMANELLI P, BIELER L, SCHARLER C, et al Extracellular vesicles can deliver anti-inflammatory and anti-scarring activities of mesenchymal stromal cells after spinal cord Injury. Front Neurol. 2019;10:1225[2021-04-18]. https://doi.org/10.3389/fneur.2019.01225. doi: 10.3389/fneur.2019.01225. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 62.ZENDEDEL A, MOENNINK F, HASSANZADEH G, et al Estrogen attenuates local inflammasome expression and activation after spinal cord injury. Mol Neurobiol. 2018;55(2):1364–1375. doi: 10.1007/s12035-017-0400-2. [DOI] [PubMed] [Google Scholar]
- 63.JIANG W, HUANG Y, HAN N, et al Quercetin suppresses NLRP3 inflammasome activation and attenuates histopathology in a rat model of spinal cord injury. Spinal Cord. 2016;54(8):592–596. doi: 10.1038/sc.2015.227. [DOI] [PubMed] [Google Scholar]
- 64.ZHOU K, SHI L, WANG Y, et al Recent advances of the NLRP3 inflammasome in central nervous system disorders. J Immunol Res. 2016;2016:9238290[2021-04-18]. https://doi.org/10.1155/2016/9238290. doi: 10.1155/2016/9238290. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 65.JIANG W, HUANG Y, HE F, et al Dopamine D1 receptor agonist A-68930 inhibits NLRP3 inflammasome activation, controls inflammation, and alleviates histopathology in a rat model of spinal cord injury. Spine. 2016;41(6):E330–E334. doi: 10.1097/BRS.0000000000001287. [DOI] [PubMed] [Google Scholar]
- 66.HUANG J H, FU C H, XU Y, et al Extracellular vesicles derived from epidural fat-mesenchymal stem cells attenuate NLRP3 inflammasome activation and improve functional recovery after spinal cord injury. Neurochem Res. 2020;45(4):760–771. doi: 10.1007/s11064-019-02950-x. [DOI] [PubMed] [Google Scholar]
- 67.SUN G, LI G, LI D, et al hucMSC derived exosomes promote functional recovery in spinal cord injury mice via attenuating inflammation. Mater Sci Eng C Mater Biol Appl. 2018;89:194–204. doi: 10.1016/j.msec.2018.04.006. [DOI] [PubMed] [Google Scholar]
- 68.LANKFORD K L, ARROYO E J, NAZIMEK K, et al Intravenously delivered mesenchymal stem cell-derived exosomes target M2-type macrophages in the injured spinal cord. PLoS One. 2018;13(1):e0190358[2021-04-18]. https://doi.org/10.1371/journal.pone.0190358. doi: 10.1371/journal.pone.0190358. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 69.FILARDO G, DI MATTEO B, KON E, et al Platelet-rich plasma in tendon-related disorders: results and indications. Knee Surg Sports Traumatol Arthrosc. 2018;26(7):1984–1999. doi: 10.1007/s00167-016-4261-4. [DOI] [PubMed] [Google Scholar]
- 70.YU H, CHENG J, SHI W, et al Bone marrow mesenchymal stem cell-derived exosomes promote tendon regeneration by facilitating the proliferation and migration of endogenous tendon stem/progenitor cells. Acta Biomater. 2020;106:328–341. doi: 10.1016/j.actbio.2020.01.051. [DOI] [PubMed] [Google Scholar]
- 71.WANG C, HU Q, SONG W, et al Adipose stem cell-derived exosomes decrease fatty infiltration and enhance rotator cuff healing in a rabbit model of chronic tears. Am J Sports Med. 2020;48(6):1456–1464. doi: 10.1177/0363546520908847. [DOI] [PubMed] [Google Scholar]
- 72.SHI Z, WANG Q, JIANG D Extracellular vesicles from bone marrow-derived multipotent mesenchymal stromal cells regulate inflammation and enhance tendon healing. J Transl Med. 2019;17(1):211[2021-04-18]. https://doi.org/10.1186/s12967-019-1960-x. doi: 10.1186/s12967-019-1960-x. [DOI] [PMC free article] [PubMed] [Google Scholar]