基質血管片段促進脂肪移植后再血管化的機制研究進展

汪正財 顧子春 李奕潤 李華

基質血管片段促進脂肪移植后再血管化的機制研究進展

汪正財 顧子春 李奕潤 李華

基質血管片段（Stromal vascular fraction，SVF）是移植的脂肪組織中去除成熟脂肪細胞后所剩余的細胞成分，除含有一定數量的脂肪來源干細胞（Adipose Derived Stem Cells，ADSC）外，還有許多其他細胞，均具有促進血管生成的作用。本文通過對近年來相關研究文獻進行綜述，以闡明SVF促進脂肪移植后再血管化的機制。綜合文獻結果，血管的再生與形成受多種因素調控，SVF細胞不僅可分泌多種因子，協同促進血管再生，還具有周細胞形態可穩定內皮網絡。而SVF包含的ADSC具有多向分化潛能，包含的脂肪巨噬細胞在缺氧環境下可促進局部血管生成，有望為臨床上提高自體脂肪移植的存活率提供方向。

基質血管片段 再血管化 脂肪移植 脂肪來源干細胞 巨噬細胞

自體脂肪移植來源廣泛、取材容易、微創、充填效果好，且不存在免疫排斥反應，已廣泛應用于臨床。但是，存在術后移植脂肪存活率不確定，影響了臨床應用的效果[1]。

研究表明ADSCs輔助下的自體脂肪移植，能夠增加脂肪存活率，術后4個月時脂肪體積可超過原始體積的80%[2]，因為ADSCs能夠在早期促進移植區的血管化[3-4]。實驗證明，血供良好的供區脂肪更容易存活[5]。因此，研究脂肪移植后的血運重建分子機制，可為提高自體脂肪移植存活率提供思路。

SVF輔助自體脂肪移植的臨床前期動物模型實驗表明，與傳統的脂肪移植相比，SVF輔助移植能明顯增加移植受區毛細血管密度、提高移植脂肪的存活率[6]。有研究顯示，脂肪移植術后，SVF細胞與脂肪來源間葉干細胞相比，其表皮生長因子（EGF）、趨化因子（SDF-1 或 CXCL12，NAP-2 或 CXCL7）、趨化因子受體（CXCR1，CCR2 和 CCR3）相關基因表達均明顯上調[7]。另外，SVF能通過下調炎癥相關基因IL-6和趨化因子配體2（CXCL2）的表達，來調節炎癥反應，減少中性粒細胞的浸潤，促進血管再生[8-9]。上述結果表明，SVF可能通過分泌相關活化因子調節血管再生。

但是，SVF通過何種機制促進再血管化目前仍不明確，我們將對SVF的組成細胞成分，及其包含細胞促進再血管化機制的研究進展進行綜述。

1 SVF組成

SVF是脂肪組織經膠原酶消化后提取的細胞成分總和，是一組混雜的細胞群，包含ADSCs、血管內皮祖細胞、單核細胞、周細胞、成纖維細胞、紅細胞、造血干細胞、淋巴細胞、巨噬細胞，以及細胞外基質等[10-13]。

2 SVF在脂肪移植中促進再血管化的機制

2.1 SVF直接參與血管重建

研究表明，在脂肪移植的早期，SVF中已分解細胞成分的再循環利用和血管內皮細胞之間的動態重組，能夠促使SVF快速形成血管網[14]。

2.1.1 ADSC通過分化直接參與血管再生

ADSC是多能干細胞，可以直接分化為血管內皮細胞、平滑肌細胞和周細胞[15-16]。而內皮細胞和血管壁細胞（平滑肌細胞和周細胞）可通過 TGF-β、血管生成素-2、PDGF-B/PDGFR-β、Notch、S1P/Edg信號通路的激活來調節血管生長、穩定、成熟[17-18]。同時，周細胞還可促使血管內皮祖細胞的出現，維持血管完整性，并協同形成血管網[19-20]。

2.1.2 基質細胞穩定內皮網絡并參與形成血管網絡系統

Traktuev等[21]的研究表明，脂肪基質細胞可協同內皮細胞共同參與形成新的微血管，構成穩定的血管網絡系統。該研究將含有脂肪基質細胞和內皮細胞混合物的膠原基質移植到小鼠皮下，2周后發現基質細胞和內皮細胞混合移植區的血管網的密度和成熟程度，要明顯高于單純基質細胞或內皮細胞移植區。

2.2 SVF通過旁分泌促進顆粒脂肪移植術后血管再生

在SVF移植組織中，其血管密度、血流量，以及分泌的肝細胞生長因子（Hepatocyte growth factor，HGF）、血管內皮生長因子（Vascular endothelial growth factor，VEGF）和堿性成纖維細胞生長因子（Basic fibroblast growth factor，bFGF）等，均比對照組明顯增多[22-23]。若抑制HGF的合成，可觀察到SVF細胞促缺血組織血管化的能力明顯減弱[24]；且經VEGF抗體處理過的干細胞在缺血組織中喪失了促血管再生能力[25]。

SVF在脂肪移植后可分泌抗炎癥因子，如IL-6、8、11、17，細胞趨化因子，單核細胞趨化蛋白1和2，巨噬細胞集落刺激因子等；也可分泌免疫調節因子如IL-1Ra；還可抑制促炎癥因子干擾素γ和IL-12的分泌[26-27]，促進組織炎癥的修復，對血管生成起著輔助協同作用[28]。SVF同時也可分泌角質形成細胞生長因子、VEGF、成纖維細胞生長因子2和內皮細胞生長因子，促進傷口上皮化；還可分泌血管生成素、瘦素，調節血管的形成[29]。

2.2.1 ADSC分泌眾多生物活性因子以促進血管生成

Procházka等[30]通過分離ADSC分泌的因子，制成濃縮治療因子，注射到兔缺血肢體中，發現實驗組缺血組織血流灌注是對照組的2倍；免疫組化顯示實驗組毛細血管密度明顯多于對照組。這表明ADSC分泌的細胞因子可促進血管再生。

事實上，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可活化內皮祖細胞；誘導內皮細胞表達整合素1、αv、β3、β5及其配體，分泌多種組織蛋白酶，降解細胞外基質；共同促進內皮細胞的增殖、遷移和新生血管的融合，抑制內皮細胞凋亡[33-35]。HGF則與其受體結合后，通過激活Grb2/Sos-Ras-Raf-MAPK信號途徑，以促進血管內皮細胞的增殖[36-37]。bFGF可通過FGFR1（成纖維細胞生長因子受體1）/c-Src/p38/NF-κB （核因子-κB）信號途徑，誘導VEGF的表達[38]；同時核因子-κB的活化可促進內皮細胞DNA合成、細胞分裂增生[39]，促進血管的再生。TGF-β有助于細胞外基質的產生，并能促進內皮細胞和壁細胞之間的相互作用[40]，有利于血管的生成。

血小板源性生長因子 （Platelet Derived Growth Factor，PDGF）促進再血管化的可能機制包括：①PDGF-C促進內皮細胞、周細胞和平滑肌細胞的遷移、增殖；②PDGF-C招募成纖維細胞，促進其增殖遷移，這對于細胞骨架的形成繼而促進新生血管的生成具有重要作用；③PDGF-C通過調節巨噬細胞的遷移增殖和基因表達來促進血管化[41]；④PDGF促使ADSC的VEGF基因表達上調，分泌VEGF增多，促進血管的再生[21]；⑤PDGF刺激 ADSC分泌細胞外囊泡（EV），EV包含一系列促血管再生因子，如MFG-E8、ANGPTL1、血小板生成素和基質金屬蛋白酶（MMP），促進內皮細胞遷移并激活血管再生因子和其他信號分子，從而加快血管的重建[42]。PDGF刺激ADSC產生的EV還合成表達C-Kit和SCF蛋白；C-Kit是一種酪氨酸激酶受體，在祖細胞分化為血管內皮細胞時表達，是內皮祖細胞增殖、動員的關鍵因素[43]，因而EV在脂肪移植后可聚集更多的內皮祖細胞，有利于血管再生。SCF是C-Kit配體，具有促進內皮細胞類血管形成、遷移和存活的作用[44]；若阻斷C-Kit與SCF蛋白可觀察到EV促血管生成效應明顯減弱[45]。

由于脂肪移植后組織處于缺氧狀態，刺激ADSC激活缺氧誘導因子 HIF-1α的表達，而 HIF-1α可使VEGF、血小板生長因子、血管生成素、HGF、bFGF等促血管生成因子基因的表達上調[46-48]。這些細胞因子與血管內皮細胞或相應細胞上的受體結合后，可發揮促血管生成效應[48]。

近期研究發現，ADSC可通過分泌微泡促進血管再生，其潛在機制可能是微小RNA-31通過微泡從ADSC遷移到血管內皮細胞內，標記并抑制缺氧誘導因子抑制因子（一種抗血管生成基因），從而促進新生血管的形成[49]。

2.2.2 脂肪巨噬細胞的旁分泌作用

Koh等[14]在動物實驗中，將去除了巨噬細胞的SVF移植到去除了巨噬細胞的小鼠中，發現其在中央和周圍的移植區血管數量比對照組明顯減少，且周邊形成的血管末端是鈍性而不連續的。這表明巨噬細胞對于移植后血管網的形成具有重要作用；而去巨噬細胞的SVF移植到正常的小鼠中形成的血管在移植中央區域較多，周邊區域較少，加入VEGF-A后血管網的密度可部分恢復正常，表明脂肪巨噬細胞可能通過分泌VEGF-A和其他血管生成因子促進新血管網形成。研究表明，缺氧可誘導巨噬細胞分泌VEGF、bFGF等血管再生因子，促進新生血管的形成[50]。

脂肪巨噬細胞根據其活化狀態不同可分為M1型巨噬細胞和M2型巨噬細胞。在SVF中，90%以上的脂肪巨噬細胞都是M2型[51]。M1型巨噬細胞是一種促炎癥型巨噬細胞，可被促炎癥介質（如 IFNγ）激活，而大量分泌 TNF-α、IL-6、IL-12等促炎癥因子；M2型巨噬細胞則是一種抗炎癥型巨噬細胞，ADSC分泌的PGE2通過PGE2-EP2/4途徑促進M2巨噬細胞分化，分化成熟的M2巨噬細胞能夠分泌IL-4、IL-10、TGF-β等抗炎因子，以及bFGF、VEGF等促血管生成因子，抑制炎癥反應、促血管網生成[33，52]，增加SVF輔助自體脂肪移植術后的脂肪細胞長期生存率[53]。而IL-10不僅能夠在缺氧條件下促進M2巨噬細胞分泌VEGF，抑制M1巨噬細胞增殖[54]，還可修復內皮細胞衰老性功能損傷，維持動脈正常結構[55-56]，改善移植區域缺血狀態。

巨噬細胞可分泌基質金屬蛋白酶1（MMP-1），降解血管基底膜及其周圍的細胞外基質[57]，還可分泌MMP-9、MMP-12、MMP-7，促進相鄰血管內皮頂端細胞之間的融合，遷移延伸而形成新生管腔，生成血管[58-59]。有實驗表明，巨噬細胞通過調節TIE-2的表達，來參與缺血組織的血管形成[60]。

2.2.3 內皮細胞的分泌作用

內皮細胞可分泌外泌體，相鄰的內皮細胞可作為靶細胞與外泌體結合，其中含有的mi-RNA（miR-214）可抑制相鄰內皮細胞的毛細血管共濟失調突變基因的表達和凋亡，促進內皮生長、遷移以及新生血管的形成[61-62]。

內皮細胞也可通過表達CXCL-1激活ERK1/2信號通路，誘導表皮細胞生長因子（Epidermal Growth Factor，EGF）的分泌，促進血管生成[63]。

脂肪移植后的組織損傷，可誘導受損的內皮細胞、細胞外基質、血小板等滲出液的其他成分，共同釋放大量的促血管化因子，如 bFGF、PDGF、TGF-β 和 EGF，以促進移植區域的血管再生，改善缺血、缺氧情況[64]。

2.2.4 其他細胞成分的促血管作用

SVF含有的細胞外基質能通過促進血管的出芽延伸、內腔的形成和形態的成熟，從而促進新生血管網的生長[37，65]。基質細胞、成纖維細胞和平滑肌細胞均能分泌HGF，調節血管再生[37]。

3 結論與展望

血管生成的基本過程包括：血管基底膜的降解；內皮細胞的增殖、遷移；血管的融合、重塑；周細胞的穩定。而SVF是一組混雜的細胞群，包含有各類細胞成分，可直接參與或間接分泌生物活性因子誘導基底膜的降解，影響內皮細胞的增殖、遷移，促進新生血管的融合與重塑，增加周細胞對血管網的穩定，從而調節脂肪移植術后的血管再生。因此，SVF是一個整體，各成分之間相互影響，協同作用于血管生成的整個過程，但是各成分之間協同促血管再生和各細胞促再血管化的具體機制仍需要進一步探索。

SVF促脂肪移植術后再血管化，在臨床有著廣闊的應用前景，不僅可提高顆粒脂肪移植術后脂肪細胞的存活率、促進燒傷創面愈合、改善糖尿病足潰瘍與糖尿病視網膜病變的血運，還可改善心肌缺血、提高心功能、促放射性潰瘍創面愈合[12]。但有關SVF的細胞輔助治療尚處于臨床前期研究或人體實驗研究階段，其有效性和安全性仍需進一步探討。

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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

浙江省自然科學基金項目（LY14H150001）。

310003 浙江省杭州市 浙江大學醫學院附屬邵逸夫醫院整形外科。

李華（E-mail：hualihz@sina.com）。

2017年9月29日；

2017年10月23日）