基质血管片段促进脂肪移植后再血管化的机制研究进展

汪正财 顾子春 李奕润 李华

基质血管片段促进脂肪移植后再血管化的机制研究进展

汪正财 顾子春 李奕润 李华

基质血管片段（Stromal vascular fraction，SVF）是移植的脂肪组织中去除成熟脂肪细胞后所剩余的细胞成分，除含有一定数量的脂肪来源干细胞（Adipose Derived Stem Cells，ADSC）外，还有许多其他细胞，均具有促进血管生成的作用。本文通过对近年来相关研究文献进行综述，以阐明SVF促进脂肪移植后再血管化的机制。综合文献结果，血管的再生与形成受多种因素调控，SVF细胞不仅可分泌多种因子，协同促进血管再生，还具有周细胞形态可稳定内皮网络。而SVF包含的ADSC具有多向分化潜能，包含的脂肪巨噬细胞在缺氧环境下可促进局部血管生成，有望为临床上提高自体脂肪移植的存活率提供方向。

基质血管片段 再血管化 脂肪移植 脂肪来源干细胞 巨噬细胞

自体脂肪移植来源广泛、取材容易、微创、充填效果好，且不存在免疫排斥反应，已广泛应用于临床。但是，存在术后移植脂肪存活率不确定，影响了临床应用的效果[1]。

研究表明ADSCs辅助下的自体脂肪移植，能够增加脂肪存活率，术后4个月时脂肪体积可超过原始体积的80%[2]，因为ADSCs能够在早期促进移植区的血管化[3-4]。实验证明，血供良好的供区脂肪更容易存活[5]。因此，研究脂肪移植后的血运重建分子机制，可为提高自体脂肪移植存活率提供思路。

SVF辅助自体脂肪移植的临床前期动物模型实验表明，与传统的脂肪移植相比，SVF辅助移植能明显增加移植受区毛细血管密度、提高移植脂肪的存活率[6]。有研究显示，脂肪移植术后，SVF细胞与脂肪来源间叶干细胞相比，其表皮生长因子（EGF）、趋化因子（SDF-1 或 CXCL12，NAP-2 或 CXCL7）、趋化因子受体（CXCR1，CCR2 和 CCR3）相关基因表达均明显上调[7]。另外，SVF能通过下调炎症相关基因IL-6和趋化因子配体2（CXCL2）的表达，来调节炎症反应，减少中性粒细胞的浸润，促进血管再生[8-9]。上述结果表明，SVF可能通过分泌相关活化因子调节血管再生。

但是，SVF通过何种机制促进再血管化目前仍不明确，我们将对SVF的组成细胞成分，及其包含细胞促进再血管化机制的研究进展进行综述。

1 SVF组成

SVF是脂肪组织经胶原酶消化后提取的细胞成分总和，是一组混杂的细胞群，包含ADSCs、血管内皮祖细胞、单核细胞、周细胞、成纤维细胞、红细胞、造血干细胞、淋巴细胞、巨噬细胞，以及细胞外基质等[10-13]。

2 SVF在脂肪移植中促进再血管化的机制

2.1 SVF直接参与血管重建

研究表明，在脂肪移植的早期，SVF中已分解细胞成分的再循环利用和血管内皮细胞之间的动态重组，能够促使SVF快速形成血管网[14]。

2.1.1 ADSC通过分化直接参与血管再生

ADSC是多能干细胞，可以直接分化为血管内皮细胞、平滑肌细胞和周细胞[15-16]。而内皮细胞和血管壁细胞（平滑肌细胞和周细胞）可通过 TGF-β、血管生成素-2、PDGF-B/PDGFR-β、Notch、S1P/Edg信号通路的激活来调节血管生长、稳定、成熟[17-18]。同时，周细胞还可促使血管内皮祖细胞的出现，维持血管完整性，并协同形成血管网[19-20]。

2.1.2 基质细胞稳定内皮网络并参与形成血管网络系统

Traktuev等[21]的研究表明，脂肪基质细胞可协同内皮细胞共同参与形成新的微血管，构成稳定的血管网络系统。该研究将含有脂肪基质细胞和内皮细胞混合物的胶原基质移植到小鼠皮下，2周后发现基质细胞和内皮细胞混合移植区的血管网的密度和成熟程度，要明显高于单纯基质细胞或内皮细胞移植区。

2.2 SVF通过旁分泌促进颗粒脂肪移植术后血管再生

在SVF移植组织中，其血管密度、血流量，以及分泌的肝细胞生长因子（Hepatocyte growth factor，HGF）、血管内皮生长因子（Vascular endothelial growth factor，VEGF）和碱性成纤维细胞生长因子（Basic fibroblast growth factor，bFGF）等，均比对照组明显增多[22-23]。若抑制HGF的合成，可观察到SVF细胞促缺血组织血管化的能力明显减弱[24]；且经VEGF抗体处理过的干细胞在缺血组织中丧失了促血管再生能力[25]。

SVF在脂肪移植后可分泌抗炎症因子，如IL-6、8、11、17，细胞趋化因子，单核细胞趋化蛋白1和2，巨噬细胞集落刺激因子等；也可分泌免疫调节因子如IL-1Ra；还可抑制促炎症因子干扰素γ和IL-12的分泌[26-27]，促进组织炎症的修复，对血管生成起着辅助协同作用[28]。SVF同时也可分泌角质形成细胞生长因子、VEGF、成纤维细胞生长因子2和内皮细胞生长因子，促进伤口上皮化；还可分泌血管生成素、瘦素，调节血管的形成[29]。

2.2.1 ADSC分泌众多生物活性因子以促进血管生成

Procházka等[30]通过分离ADSC分泌的因子，制成浓缩治疗因子，注射到兔缺血肢体中，发现实验组缺血组织血流灌注是对照组的2倍；免疫组化显示实验组毛细血管密度明显多于对照组。这表明ADSC分泌的细胞因子可促进血管再生。

事实上，ADSC在脂肪移植后，可有效地分泌大量促血管生成因子和抗凋亡因子，如HGF、bFGF、VEGF、PDGF-B和TGF-β等[31-32]。其中，VEGF可活化内皮祖细胞；诱导内皮细胞表达整合素1、αv、β3、β5及其配体，分泌多种组织蛋白酶，降解细胞外基质；共同促进内皮细胞的增殖、迁移和新生血管的融合，抑制内皮细胞凋亡[33-35]。HGF则与其受体结合后，通过激活Grb2/Sos-Ras-Raf-MAPK信号途径，以促进血管内皮细胞的增殖[36-37]。bFGF可通过FGFR1（成纤维细胞生长因子受体1）/c-Src/p38/NF-κB （核因子-κB）信号途径，诱导VEGF的表达[38]；同时核因子-κB的活化可促进内皮细胞DNA合成、细胞分裂增生[39]，促进血管的再生。TGF-β有助于细胞外基质的产生，并能促进内皮细胞和壁细胞之间的相互作用[40]，有利于血管的生成。

血小板源性生长因子 （Platelet Derived Growth Factor，PDGF）促进再血管化的可能机制包括：①PDGF-C促进内皮细胞、周细胞和平滑肌细胞的迁移、增殖；②PDGF-C招募成纤维细胞，促进其增殖迁移，这对于细胞骨架的形成继而促进新生血管的生成具有重要作用；③PDGF-C通过调节巨噬细胞的迁移增殖和基因表达来促进血管化[41]；④PDGF促使ADSC的VEGF基因表达上调，分泌VEGF增多，促进血管的再生[21]；⑤PDGF刺激 ADSC分泌细胞外囊泡（EV），EV包含一系列促血管再生因子，如MFG-E8、ANGPTL1、血小板生成素和基质金属蛋白酶（MMP），促进内皮细胞迁移并激活血管再生因子和其他信号分子，从而加快血管的重建[42]。PDGF刺激ADSC产生的EV还合成表达C-Kit和SCF蛋白；C-Kit是一种酪氨酸激酶受体，在祖细胞分化为血管内皮细胞时表达，是内皮祖细胞增殖、动员的关键因素[43]，因而EV在脂肪移植后可聚集更多的内皮祖细胞，有利于血管再生。SCF是C-Kit配体，具有促进内皮细胞类血管形成、迁移和存活的作用[44]；若阻断C-Kit与SCF蛋白可观察到EV促血管生成效应明显减弱[45]。

由于脂肪移植后组织处于缺氧状态，刺激ADSC激活缺氧诱导因子 HIF-1α的表达，而 HIF-1α可使VEGF、血小板生长因子、血管生成素、HGF、bFGF等促血管生成因子基因的表达上调[46-48]。这些细胞因子与血管内皮细胞或相应细胞上的受体结合后，可发挥促血管生成效应[48]。

近期研究发现，ADSC可通过分泌微泡促进血管再生，其潜在机制可能是微小RNA-31通过微泡从ADSC迁移到血管内皮细胞内，标记并抑制缺氧诱导因子抑制因子（一种抗血管生成基因），从而促进新生血管的形成[49]。

2.2.2 脂肪巨噬细胞的旁分泌作用

Koh等[14]在动物实验中，将去除了巨噬细胞的SVF移植到去除了巨噬细胞的小鼠中，发现其在中央和周围的移植区血管数量比对照组明显减少，且周边形成的血管末端是钝性而不连续的。这表明巨噬细胞对于移植后血管网的形成具有重要作用；而去巨噬细胞的SVF移植到正常的小鼠中形成的血管在移植中央区域较多，周边区域较少，加入VEGF-A后血管网的密度可部分恢复正常，表明脂肪巨噬细胞可能通过分泌VEGF-A和其他血管生成因子促进新血管网形成。研究表明，缺氧可诱导巨噬细胞分泌VEGF、bFGF等血管再生因子，促进新生血管的形成[50]。

脂肪巨噬细胞根据其活化状态不同可分为M1型巨噬细胞和M2型巨噬细胞。在SVF中，90%以上的脂肪巨噬细胞都是M2型[51]。M1型巨噬细胞是一种促炎症型巨噬细胞，可被促炎症介质（如 IFNγ）激活，而大量分泌 TNF-α、IL-6、IL-12等促炎症因子；M2型巨噬细胞则是一种抗炎症型巨噬细胞，ADSC分泌的PGE2通过PGE2-EP2/4途径促进M2巨噬细胞分化，分化成熟的M2巨噬细胞能够分泌IL-4、IL-10、TGF-β等抗炎因子，以及bFGF、VEGF等促血管生成因子，抑制炎症反应、促血管网生成[33，52]，增加SVF辅助自体脂肪移植术后的脂肪细胞长期生存率[53]。而IL-10不仅能够在缺氧条件下促进M2巨噬细胞分泌VEGF，抑制M1巨噬细胞增殖[54]，还可修复内皮细胞衰老性功能损伤，维持动脉正常结构[55-56]，改善移植区域缺血状态。

巨噬细胞可分泌基质金属蛋白酶1（MMP-1），降解血管基底膜及其周围的细胞外基质[57]，还可分泌MMP-9、MMP-12、MMP-7，促进相邻血管内皮顶端细胞之间的融合，迁移延伸而形成新生管腔，生成血管[58-59]。有实验表明，巨噬细胞通过调节TIE-2的表达，来参与缺血组织的血管形成[60]。

2.2.3 内皮细胞的分泌作用

内皮细胞可分泌外泌体，相邻的内皮细胞可作为靶细胞与外泌体结合，其中含有的mi-RNA（miR-214）可抑制相邻内皮细胞的毛细血管共济失调突变基因的表达和凋亡，促进内皮生长、迁移以及新生血管的形成[61-62]。

内皮细胞也可通过表达CXCL-1激活ERK1/2信号通路，诱导表皮细胞生长因子（Epidermal Growth Factor，EGF）的分泌，促进血管生成[63]。

脂肪移植后的组织损伤，可诱导受损的内皮细胞、细胞外基质、血小板等渗出液的其他成分，共同释放大量的促血管化因子，如 bFGF、PDGF、TGF-β 和 EGF，以促进移植区域的血管再生，改善缺血、缺氧情况[64]。

2.2.4 其他细胞成分的促血管作用

SVF含有的细胞外基质能通过促进血管的出芽延伸、内腔的形成和形态的成熟，从而促进新生血管网的生长[37，65]。基质细胞、成纤维细胞和平滑肌细胞均能分泌HGF，调节血管再生[37]。

3 结论与展望

血管生成的基本过程包括：血管基底膜的降解；内皮细胞的增殖、迁移；血管的融合、重塑；周细胞的稳定。而SVF是一组混杂的细胞群，包含有各类细胞成分，可直接参与或间接分泌生物活性因子诱导基底膜的降解，影响内皮细胞的增殖、迁移，促进新生血管的融合与重塑，增加周细胞对血管网的稳定，从而调节脂肪移植术后的血管再生。因此，SVF是一个整体，各成分之间相互影响，协同作用于血管生成的整个过程，但是各成分之间协同促血管再生和各细胞促再血管化的具体机制仍需要进一步探索。

SVF促脂肪移植术后再血管化，在临床有着广阔的应用前景，不仅可提高颗粒脂肪移植术后脂肪细胞的存活率、促进烧伤创面愈合、改善糖尿病足溃疡与糖尿病视网膜病变的血运，还可改善心肌缺血、提高心功能、促放射性溃疡创面愈合[12]。但有关SVF的细胞辅助治疗尚处于临床前期研究或人体实验研究阶段，其有效性和安全性仍需进一步探讨。

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Mechanism of Promoted Neovascularization by SVF after Fat Grafting

WANG Zhengcai,GU Zichun,LI Yirun,LI Hua．Department of Plastic and Reconstructive Surgery,Sir Run Run Shaw Hospital,Medical College,Zhejiang University,Hangzhou 310016,China.Corresponding author:LI Hua(E-mail:hualihz@sina.com).

【Summary】Stromal vascular fraction(SVF)are the remaining cells of the ingredients after removing mature fat cells in the adipose tissue of transplantation.In addition to containing a certain amount of adipose derived stem cells(ADSC),SVF also includes many other cells,which may all have the potential of promoting angiogenesis.In this paper,the role of SVF in angiogenesis after fat transplantation was summarized by reviewing relative literature in recent years.According to the literature,angiogenesis and fat graft revascularization are regulated by various factors:SVF promotes secretion of a diverse array of cytokines and growth;SVF differentiated to pericytes has the function of stabilizing endothelium vascular network;As components of SVF,adipose derived stem cells (ADSC)have the potential of multi-directional differentiation,and macrophages can promote local angiogenesis in hypoxia environment.These results may provide directions of improving the survival rate of fat cells in clinical autologous fat transplantation.

Stromal vascular fraction;Revascularization;Fat graft;Adipose-derived stem cells;Adipose macrophages

R622+.9

B

1673－0364（2017）06－0349－05

10.3969/j.issn.1673-0364.2017.06.014

浙江省自然科学基金项目（LY14H150001）。

310003 浙江省杭州市 浙江大学医学院附属邵逸夫医院整形外科。

李华（E-mail：hualihz@sina.com）。

2017年9月29日；

2017年10月23日）