去分化脂肪細胞多向分化潛能與應用

張洋，肖麗玲

(暨南大學附屬第一醫院整形外科，廣東 廣州 510632)

去分化脂肪細胞多向分化潛能與應用

張洋，肖麗玲

(暨南大學附屬第一醫院整形外科，廣東 廣州 510632)

去分化脂肪細胞(DFAT cells)來源于成熟脂肪細胞，且具有多向分化潛能，其特征類似于干細胞的一種細胞。在體外可通過天花板培養法提取出DFAT細胞，經過誘導后，DFAT細胞可向脂肪細胞、骨細胞、軟骨細胞、內皮細胞、肌細胞、神經細胞等分化。因此，DFAT細胞是一種在組織工程和干細胞治療中很好的潛在資源，從而廣泛應用于多種疾病及組織損傷修復的研究當中。

去分化脂肪細胞；分化；脂肪干細胞；臨床應用

作為干細胞移植治療的代表，骨髓間充質干細胞(bone marrow mesenchymal stem cells，BMSCs)與脂肪來源干細胞(adipose-derived stem cells，ADSCs)的多向分化潛能在轉化醫學的應用中已被大量研究及體內外實驗所證明[1-5]。然而，某些客觀因素卻限制了其在臨床中的廣泛使用，比如BMSCs來源的局限性、取材的有創性、對供體年齡的限制、提取細胞的均一性差，以及傳代后的老化現象；ADSCs雖然來源廣泛，取材創傷性小，但同樣對供體的年齡有所限制，且細胞的均一性較差。

相較于BMSCs與ADSCs，來源于皮下脂肪組織的去分化脂肪細胞(dedifferentiated fat cells，DFAT cells)，除了具有類似ADSCs來源廣、取材易、低免疫性等特征之外，還具有對供體年齡限制低、具有較高的細胞均一性等特點。此外，DFAT細胞同樣擁有與BMSCs和ADSCs相類似的多向分化潛能[6-7]。因此，DFAT細胞在組織工程和干細胞治療中是一個很好的潛在資源。

1 DFAT細胞的分離與鑒定

1.1 DFAT細胞的提取與去分化機制 成熟脂肪細胞經天花板培養法可自發去分化為不含脂滴的類成纖維細胞，即DFAT細胞。相對于傳統的(培養瓶)天花板培養法，宋子儀等[8]首次采用培養皿加細胞載玻片組合的培養法，既保證了去分化的效果，又極大地節省了實驗材料；Wei等[9]也采用了培養皿細胞培養法，并對提取方法進行了改良，使其更有利于脂肪細胞內脂滴的去除。然而，對于成熟脂肪細胞去分化的機制，國內外學者雖然對此做了大量研究，但至今尚未定論。宋子儀等[8]發現在成熟脂肪細胞去分化過程的中后期，脂肪分解的關鍵基因激素敏感脂酶(HSL)和脂肪組織甘油三酯脂肪酶(ATGL)的mRNA水平分別上調了40倍和10倍，而成脂關鍵基因過氧化物酶體增殖物激活受體γ(PPARγ)、脂肪細胞型脂肪酸結合蛋白(aP2)和脂蛋白酯酶(LPL)的mRNA水平分別上調了8倍、3倍和7.5倍，證明了脂肪去分化是一個以脂解為主并伴有一定水平成脂的脂代謝過程。Peng等[10]和Lessard等[11]在最近的研究中也指出，在成熟脂肪細胞去分化的過程中，其脂肪細胞標志物PPARγ、aP2、LPL和脂聯素均有顯著下降。Lessard等[11]還發現，在脂肪細胞去分化的過程中FAP、DPP4、MMP1和TGFβ1均明顯升高，且發現FAP和DPP4對脂肪組織的重塑和細胞可塑性有所關聯。此外，Ono等[12]則首次對DFAT細胞進行了基因表達譜的研究，發現在脂肪細胞去分化的過程中，其功能表型相關基因表達減少，而細胞增殖、細胞形態學的改變和相關基因的分化調控則相對增加。

1.2 DFAT細胞的鑒定 至今DFAT細胞的表型和細胞性質仍不清楚，但是近年來對DFAT細胞表面標志的各項研究表明，其CD29、CD44、CD73、CD90、CD105顯示為陽性，CD14、CD34、CD45、CD117、CD133、CD271、CD309、HLA-DR顯示為陰性，與BMSCs、ADSCs的表面標志基本相同[13-17]。

此外，Gao等[18]發現DFAT細胞表達若干胚胎干細胞的表面標志，如Oct4、Sox2、c-Myc、Nanog等。在最近的相關研究中，Song等[19]發現DFAT細胞還表達與血管周圍細胞高度相關的標志物，如CD140b、NG2和肌間線蛋白等，且顯示了良好的血管網形成能力；但是常見的血管內皮細胞標記物，如CD31、CD34和cd309則為陰性。

2 DFAT細胞多向分化潛能的研究與應用

2.1 向脂肪細胞分化 成熟的脂肪細胞在去分化的過程后形成DFAT細胞，而DFAT細胞經體外誘導培養后，鏡下可見顯著性脂滴聚集。Kou等[16]研究發現DFAT細胞的成脂能力要優于ADSCs。此外，陳曉煒等[20]將DFAT細胞與纖維蛋白膠混合后注射于裸鼠皮下，并構建出了脂肪組織；而Nobusue等[21]則將DFAT細胞移植到小鼠皮下，14 d后即可發現有高度血管化的脂肪墊生成。目前的各項體內外實驗均證實了DFAT細胞具有強大的成脂分化能力。此外，Guo等[22]發現DFAT細胞在分化的過程中，受胰島素受體底物1(insulin receptorsubstrate 1，IRS1)介導，上調了miR-145，使脂肪的生成受到抑制。最近，Hu等[23]發現在DFAT細胞成脂過程中視網膜母細胞瘤-1(Rb1)基因同樣起到了負調節作用。

2.2 向骨細胞、軟骨細胞分化 相對于傳統的使用地塞米松成骨誘導方法，Nakamura等[24]發現將骨形態發生蛋白-9(bone morphogenetic protein，BMP-9)與FK506聯合使用可有效的誘導DFAT細胞成骨分化。Oki等[25]使用全反式維甲酸即可在體內外完成對DFAT細胞成骨分化的誘導。對于其成骨分化能力研究，Kishimoto等[26]將從頰脂墊中分離出的DFAT細胞與ADSCs誘導成骨后比較，發現DFAT細胞在堿性磷酸酶(BAP)、骨鈣素(OCN)、鈣沉積和茜素紅染法的評估均優于ADSCs。相似的，Sakamoto等[27]發現，DFAT細胞在成骨誘導后，Runx2基因表達、堿性磷酸酶(ALP)活性以及骨鈣素(OCN)和鈣含量的測定均優于hMSCs。此外，Tansriratanawong等[28]將DFAT細胞與牙周韌帶干細胞體外共培養后，增強了RUNX2基因的表達。在新型生物復合材料的研究中，Sakamoto等[27]將DFAT細胞種植到α磷酸三鈣/膠原海綿(α-TCP/CS)上，14 d后電鏡下可見眾多球形細胞幾乎完全將α-TCP/CS覆蓋，形成培養骨的礦化細胞外基質沉積；Kishimoto等[29]則將DFAT細胞與剛性支架組成的鈦纖維網(TFM)結合制成新型生物材料；Shirakata等[30]則將DFAT細胞與聚乳酸-羥基乙酸/羥基磷灰石(PLGA/HA)復合材料使用在了大鼠顱骨缺損的模型上，并取得了明顯效果。這些生物復合材料的誕生對于骨組織工程來說是一種不錯的選擇。此外，將DFAT細胞運用到骨疾病的治療中也逐漸被重視起來[31]，Kikuta等[32]在卵巢摘除后誘導的骨質疏松模型上，將DFAT細胞進行骨髓內注射，可使其骨密度明顯增加。然而在誘導DFAT細胞向軟骨分化的過程中至今并沒有有效的誘導方法。Okita等[33]發現，將適量鍶離子(Sr)添加到誘導軟骨生成的培養基中，明顯促進DFAT細胞早期向軟骨細胞的分化。這對提高DFAT細胞向軟骨分化及用于軟骨再生治療或許是一種可行的方法。

2.3 向內皮細胞分化 Jumabay等[34]的研究發現DFAT細胞可以在體外自發進行內皮細胞分化，且使用BMP4和BMP9可促進分化的進行。Kou等[16]卻提出在DFAT細胞經過常見的血管生成因子誘導的前后，均無表達內皮細胞關鍵標志物CD31、CD34、CD309和vWF等。這與Matsumoto等[35]和Poloni等[15]的報道是一致的。而Shimizu等[36]將DFAT細胞培養于微血管內皮細胞生長基-2(microvascularendothelial cell growth medium-2，EGM-2MV)即可檢測到DFAT細胞表達內皮細胞的表面標記；而將DFAT細胞與人齒齦內皮細胞(human gingival endothelial cells，HGECs)共培養后，則可在12 h內形成豐富的毛細血管樣結構，并可保持管狀結構24 h以上不被分解；另外，共培養的DFAT細胞明顯增強周細胞表面標記的表達，促進了微血管的成熟與穩定。此外，Soejim等[37]和Asami等[38]均通過實驗發現，將DFAT細胞與堿性成纖維細胞生長因子(bFGF)混合使用于人工真皮移植后，明顯縮短皮膚再生和血管形成所需要的時間，甚至在移植后第2天即可觀察到真皮內已有毛細血管的滲透。Kashimura等[39]也通過實驗證實局部注射DFAT細胞后，可顯著增加皮瓣移植區新生血管的生成，促進皮瓣的存活。對于牙周組織的再生，Sugawara等[40]將DFAT細胞與膠原支架結合構成的生物支架運用于牙周組織缺損模型，證明了DFAT細胞用于細胞移植治療的可行性。

2.4 向肌肉細胞分化 在向心肌分化的研究中，楊華等[41]通過使用催產素對DFAT細胞進行誘導分化，3周后DFAT細胞在基因及蛋白水平上即可檢測到心臟特異性標記GATA4、Nkx2.5及cTnT的表達，但未發現自主搏動現象。而Jumabay等[42]則通過抑制骨形態發生蛋白(bone morphogenetic proteins，BMP)和Wnt信號通路，可增強DFAT細胞向心肌樣細胞的分化，且檢測到此細胞具有自主收縮性。此外，Jumabay等[43]則將DFAT細胞移植于大鼠急性心肌梗死模型，并檢測到DFAT細胞可有效的聚集于心肌梗死區，表達心臟橫紋肌肌動蛋白，且梗死區的毛細血管密度也得以顯著增加。近期，李福海等[44]首次證明了維生素C可誘導DFAT細胞向心肌分化，并且在心臟細胞裂解液體外模擬心肌微環境的條件下，可進一步提高細胞的心肌分化效率。在向平滑肌分化的研究中，Sakuma等[45]在小鼠膀胱壁冷凍傷模型中注射DFAT細胞后，在受傷的膀胱組織中監測到平滑肌肌動蛋白-α陽性區顯著大于對照組，證明了DFAT細胞可有助于膀胱平滑肌組織的再生。Obinata等[46]則將DFAT細胞注射入小鼠尿道擴張模型中，即可在受損平滑肌層觀察到移植的DFAT細胞，且平滑肌肌動蛋白-α呈陽性染色，其肌肉層厚度增加明顯。Hsiao等[47]利用細胞纖維技術制作出一種螺旋彈簧狀三維細胞結構模型，其中含有的DFAT細胞經誘導后生成平滑肌細胞，這種新型結構可精確控制平滑肌細胞的排列與方向，可作為組織工程的構建模塊，使用于器官或細胞移植等臨床治療。在向骨骼肌分化的研究中，Kazama等[48]通過肌源性誘導后，可導致DFAT細胞MyoD和肌細胞生成素的表達，這些結果表明，DFAT細胞可以在體外培養中誘導分化為骨骼肌細胞。

2.5 向神經細胞分化 Ohta等[49]發現，DFAT細胞可表達如巢蛋白、β微管蛋白和膠質纖維酸性蛋白等神經標志物，并可明顯改善脊髓損傷大鼠模型的后肢運動功能。Yamada等[50]也通過相似實驗證實，并指出DFAT細胞在改善脊髓損傷后肢體運動能力的同時，可促進髓鞘再生和減少膠質瘢痕生成。此外，Matsumine等[51]將DFAT細胞移植入大鼠面神經缺損模型，證明了DFAT細胞可以促進再生神經的成熟。

3 DFAT細胞的臨床應用潛力

相關實驗證明DFAT細胞即使體外傳代22代后仍保有增殖和分化的能力[21]，且Poloni等[52]證實了DFAT細胞經過去分化過程后并無基因學改變和致瘤傾向。因此DFAT細胞在臨床應用領域將擁有廣闊的前景。上文中已綜合敘述了DFAT細胞移植療法用于牙周組織再生[28，36，40]、皮膚移植[37-38]、脊髓損傷[49-50]、骨質疏松[32]、尿道、膀胱平滑肌損傷[45-46]等方面的治療，并取得了顯著的效果。此外，在慢性腎功能不全、腎小球腎炎的治療中，DFAT細胞移植療法也取得了不錯的效果[53-54]。

DFAT細胞移植治療在慢性創面修復中也備受關注，近些年來諸如糖尿病足、壓瘡、血管源性疾病等多因素、多系統病變所致慢性潰瘍的發病率逐年升高。而糖尿病已經成為第三大威脅人類健康的慢性疾病，糖尿病微循環改變損傷組織內血管重建過程[55]是導致潰瘍難愈的原因之一。BMSCs與ADSCs是干細胞移植治療的代表，雖然可以從糖尿病患者脂肪中成功分離到ADSCs，且已證明了其多向分化的潛能[56]，但是相關研究發現糖尿病可使ADSCs的血管生成能力減弱，從而影響了新生血管形成及傷口愈合[57]，而且對干細胞的自我修復能力與自體干細胞治療的效果也會產生影響[58]。而Jumabay等[59]實驗發現，與ADSCs相比，糖尿病可增強DFAT細胞的增殖能力，且其向脂肪細胞和內皮細胞分化的能力也相應的增強。此外，Watson等[17]通過比較了來源自同一糖尿病患者體內脂肪的DFAT細胞與ADSCs，發現DFAT細胞的端粒酶水平是ADSCs的2.5倍，其細胞衰老過程也因此較之緩慢，而且DFAT細胞上清液與ADSCs上清液對人皮膚成纖維細胞(human dermalfibroblasts，HDFs)的遷移具有相似的作用，各種相關研究都表明DFAT細胞對于慢性創面治療具有巨大潛力。

4 展 望

DFAT細胞較之ADSCs，其均一性高、增殖能力強、成脂分化能力強及對供者的年齡要求低，并且具有與ADSCs相似的體內及體外成脂、成骨、成軟骨、成肌肉、成神經等多向分化潛能，這些特點使DFAT細胞具有更為廣泛的臨床應用價值。如何建立一種DFAT細胞高效的提取、擴增方法對其在轉化醫學應用方面是很有必要的。對于DFAT細胞的研究，目前仍未有用于臨床治療的報道。

隨著社會老齡化的進程，難愈性創面患者數量的逐漸增多，結合DFAT細胞的各種臨床潛在應用優勢，推測DFAT細胞在轉化醫學領域將發揮其巨大潛力。因此對DFAT細胞在細胞治療與醫學轉化應用中應予以足夠的重視。相信隨著進一步的深入研究，DFAT細胞的臨床應用前景將會更加廣闊。

[1]Park JS,Suryaprakash S,Lao YH,et al.Engineering mesenchymal stem cells for regenerative medicine and drug delivery[J].Methods, 2015,84:3-16.

[2]Teng M,Huang Y,Zhang H.Application of stems cells in wound healing—an update[J].Wound Repair Regen,2014,22(2):151-160.

[3]Rammal H,Harmouch C,Lataillade JJ,et al.Stem cells:a promising source for vascular regenerative medicine[J].Stem Cells Dev,2014, 23(24):2931-2949.

[4]嚴龍宗,陳斌.慢性創面愈合的細胞治療[J].中國組織工程研究, 2013,17(46):8096-8101.

[5]王賢,張培華.脂肪干細胞的研究及應用進展[J].海南醫學,2016, 27(6):965-967.

[6]Shen JF,Sugawara A,Yamashita J,et al.Dedifferentiated fat cells: an alternative source of adult multipotent cells from the adipose tissues[J].Int JOral Sci,2011,3(3):117-124.

[7]史琳麗,楊向群.脂肪組織來源干細胞的分化潛能和應用[J].中國修復重建外科雜志,2012,26(8):1007-1011.

[8]宋子儀,史新娥,楊浩,等.基于一種新的天花板培養方法分析豬成熟脂肪細胞去分化過程中關鍵基因表達模式[J].農業生物技術學報,2013,21(4):379-387.

[9]Wei S,Du M,Jiang Z,et al.Bovine dedifferentiated adipose tissue (DFAT)cells:DFAT cell isolation[J].Adipocyte,2013,2(3): 148-159.

[10]Peng X,Song T,Hu X,et al.Phenotypic and functional properties of porcine dedifferentiated fat cells during the long-term culture in vitro [J].Biomed Res Int,2015,2015:673651.

[11]Lessard J,Pelletier M,Biertho L,etal.Characterization of dedifferentiating human mature adipocytes from the visceral and subcutaneous fat compartments:fibroblast-activation protein alpha and dipeptidyl peptidase 4 as major components of matrix remodeling[J].PLoS One,2015,10(3):e0122065.

[12]Ono H,Oki Y,Bono H,et al.Gene expression profiling in multipotent DFAT cells derived from mature adipocytes[J].Biochem Biophys Res Commun,2011,407(3):562-567.

[13]Wei S,Zan L,Hausman GJ,et al.Dedifferentiated adipocyte-derived progeny cells(DFAT cells):potential stem cells of adipose tissue[J]. Adipocyte,2013,2(3):122-127.

[14]Kono S,Kazama T,Kano K,etal.Phenotypic and functionalproperties of feline dedifferentiated fat cells and adipose-derived stem cells [J].Vet J,2014,199(1):88-96.

[15]Poloni A,Maurizi G,Leoni P,et al.Human dedifferentiated adipocytes show similar properties to bone marrow-derived mesenchymal stem cells[J].Stem Cells,2012,30(5):965-974.

[16]Kou L,Lu XW,Wu MK,et al.The phenotype and tissue-specific nature of multipotent cells derived from human mature adipocytes[J]. Biochem Biophys Res Commun,2014,444(4):543-548.

[17]Watson JE,Patel NA,Carter G,et al.Comparison of markers and functional attributes of human adipose-derived stem cells and dedifferentiated adipocyte cells from subcutaneous fat of an obese diabetic donor[J].Adv Wound Care(New Rochelle),2014,3(3): 219-228.

[18]Gao Q,Zhao L,Song Z,et al.Expression pattern of embryonic stem cell markers in DFAT cells and ADSCs[J].Mol Biol Rep,2012,39 (5):5791-5804.

[19]Song N,Kou L,Lu XW,etal.The perivascular phenotype and behaviors of dedifferentiated cells derived from human mature adipocytes [J].Biochem Biophys Res Commun,2015,457(3):479-484.

[20]陳曉煒,姜平,高建華,等.脂肪細胞去分化及構建組織工程化脂肪的實驗研究[J].南方醫科大學學報,2009,29(4):606-610.

[21]Nobusue H,Endo T,Kano K.Establishment of a preadipocyte cell line derived from mature adipocytes of GFP transgenic mice and formation of adipose tissue[J].Cell Tissue Res,2008,332(3): 435-446.

[22]Guo Y,Chen Y,Zhang Y,etal.Up-regulated miR-145 expression inhibits porcine preadipocytes differentiation by targeting IRS1[J].Int JBiol Sci,2012,8(10):1408-1417.

[23]Hu X,Luo P,Peng X,et al.Molecular cloning,expression pattern analysis of porcine Rb1 gene and its regulatory roles during primary dedifferentiated fat cells adipogenic differentiation[J].General and Comparative Endocrinology,2015,214:77-86.

[24]Nakamura T,Shinohara Y,Momozaki S,et al.Co-stimulation with bone morphogenetic protein-9 and FK506 induces remarkable osteoblastic differentiation in rat dedifferentiated fat cells[J].Biochem Biophys Res Commun,2013,440(2):289-294.

[25]Oki Y,Watanabe S,Endo T,etal.Mature adipocyte-derived dedifferentiated fatcells can trans-differentiate into osteoblasts in vitro and in vivo only by all-trans retinoic acid[J].Cell Struct Funct,2008,33(2): 211-222.

[26]Kishimoto N,Momota Y,Hashimoto Y,et al.The osteoblastic differentiation ability of human dedifferentiated fat cells is higher than that of adipose stem cells from the buccal fat pad[J].Clin Oral Investig, 2014,18(8):1893-1901.

[27]Sakamoto F,Hashimoto Y,Kishimoto N,et al.The utility of human dedifferentiated fat cells in bone tissue engineering in vitro[J].Cytotechnology,2015,67(1):75-84.

[28]Tansriratanawong K,Tamaki Y,Ishikawa H,et al.Co-culture with periodontal ligament stem cells enhances osteogenic gene expression in de-differentiated fatcells[J].Hum Cell,2014,27(4):151-161.

[29]Kishimoto N,Momota Y,Hashimoto Y,et al.Dedifferentiated fat cells differentiate into osteoblasts in titanium fiber mesh[J].Cytotechnology,2013,65(1):15-22.

[30]Shirakata Y,Nakamura T,Shinohara Y,etal.An exploratory study on the efficacy of rat dedifferentiated fat cells(rDFATs)with a poly lactic-co-glycolic acid/hydroxylapatite(PLGA/HA)composite for bone formation in a ratcalvarial defect model[J].J Mater Sci Mater Med, 2014,25(3):899-908.

[31]Mikami Y,Matsumoto T,Kano K,et al.Current status of drug therapies for osteoporosis and the search for stem cells adapted for bone regenerative medicine[J].AnatSci Int,2014,89(1):1-10.

[32]Kikuta S,Tanaka N,Kazama T,et al.Osteogenic effects of dedifferentiated fat cell transplantation in rabbit models of bone defect and ovariectomy-induced osteoporosis[J].Tissue Eng Part A,2013,19 (15-16):1792-1802.

[33]Okita N,Honda Y,Kishimoto N,et al.Supplementation of strontium to a chondrogenic medium promotes chondrogenic differentiation of human dedifferentiated fat cells[J].Tissue Eng Part A,2015,21 (9-10):1695-1704.

[34]Jumabay M,Abdmaulen R,Urs S,etal.Endothelial differentiation in multipotentcells derived from mouse and human white mature adipocytes[J].J Mol Cell Cardiol,2012,53(6):790-800.

[35]Matsumoto T,Kano K,Kondo D,etal.Mature adipocyte-derived dedifferentiated fatcells exhibit multilineage potential[J].J Cell Physiol,2008,215(1):210-222.

[36]Shimizu Y,Sato S.In vitro study on regeneration of periodontal tissue microvasculature using human dedifferentiated fat cells[J].J Periodontol,2015,86(1):129-136.

[37]Soejima K,Kashimura T,Asami T,et al.Effects of mature adipocyte-derived dedifferentiated fat(DFAT)cells on generation and vascularisation of dermis-like tissue after artificial dermis grafting[J].J Plast Surg Hand Surg,2015,49(1):25-31.

[38]AsamiT,Soejima K,Kashimura T,etal.Effects ofcombination therapy using basic fibroblast growth factor and mature adipocyte-deriveddedifferentiated fat(DFAT)cells on skin graft revascularisation[J].J Plast Surg Hand Surg,2015,49(4):229-233.

[39]Kashimura T,Soejima K,Asami T,et al.The effect of mature adipocyte-derived dedifferentiated fat(DFAT)cells on a dorsal skin flap model[J].J Invest Surg,2016,29(1):6-12.

[40]Sugawara A,Sato S.Application of dedifferentiated fat cells for periodontaltissue regeneration[J].Hum Cell,2014,27(1):12-21.

[41]楊華,陳連鳳,沈珠軍.催產素誘導去分化脂肪細胞向心肌細胞方向分化(英文)[J].心臟雜志,2011,23(6):705-710,726.

[42]Jumabay M,Zhang R,Yao Y,etal.Spontaneously beating cardiomyocytes derived from white mature adipocytes[J].Cardiovasc Res, 2010,85(1):17-27.

[43]Jumabay M,Matsumoto T,Yokoyama S,et al.Dedifferentiated fat cells convert to cardiomyocyte phenotype and repair infarcted cardiac tissue in rats[J].J Mol Cell Cardiol,2009,47(5):565-575.

[44]李福海,王志,張陳勻.DFAT細胞體外分化誘導實驗及體內生物學特性綜述[J].北京生物醫學工程,2015,34(3):310-315.

[45]Sakuma T,Matsumoto T,Kano K,et al.Mature,adipocyte derived, dedifferentiated fat cells can differentiate into smooth muscle-like cells and contribute to bladder tissue regeneration[J].J Urol,2009, 182(1):355-365.

[46]Obinata D,Matsumoto T,Ikado Y,etal.Transplantation of mature adipocyte-derived dedifferentiated fat(DFAT)cells improves urethral sphincter contractility in a rat model[J].Int J Urol,2011,18(12): 827-834.

[47]Hsiao AY,Okitsu T,Onoe H,et al.Smooth muscle-like tissue constructs with circumferentially oriented cells formed by the cell fiber technology[J].PLoS One,2015,10(3):e0119010.

[48]Kazama T,Fujie M,Endo T,et al.Mature adipocyte-derived dedifferentiated fat cells can transdifferentiate into skeletal myocytes in vitro [J].Biochem Biophys Res Commun,2008,377(3):780-785.

[49]Ohta Y,Takenaga M,Tokura Y,et al.Mature adipocyte-derived cells, dedifferentiated fat cells(DFAT),promoted functional recovery from spinal cord injury-induced motor dysfunction in rats[J].Cell Transplant,2008,17(8):877-886.

[50]Yamada H,Ito D,Oki Y,et al.Transplantation of mature adipocyte-derived dedifferentiated fat cells promotes locomotor functional recovery by remyelination and glial scar reduction after spinal cord injury in mice[J].Biochem Biophys Res Commun,2014,454(2): 341-346.

[51]Matsumine H,Takeuchi Y,Sasaki R,et al.Adipocyte-derived and dedifferentiated fat cells promoting facial nerve regeneration in a rat model[J].PlastReconstr Surg,2014,134(4):686-697.

[52]Poloni A,Maurizi G,Mattiucci D,et al.Biosafety evidence for human dedifferentiated adipocytes[J].J Cell Physiol,2015,230(7): 1525-1533.

[53]Nur R,Fukuda N,Matsumoto T,etal.Implantation of dedifferentiated fat cells ameliorates habu snake venom-induced chronic renaldysfunction in tenascin-C-deficient mice[J].Nephron Exp Nephrol, 2008,110(3):e91-98.

[54]Maruyama T,Fukuda N,Matsumoto T,etal.Systematic implantation of dedifferentiated fat cells ameliorated monoclonal antibody 1-22-3-induced glomerulonephritis by immunosuppression with increases in TNF-stimulated gene 6[J].Stem Cell Res Ther,2015,6 (1):80.

[55]Guo WY,Wang GJ,Wang P,et al.Acceleration of diabetic wound healing by low-dose radiation is associated with peripheral mobilization of bone marrow stem cells[J].Radiat Res,2010,174(4): 467-479.

[56]拾莉,張德明,任思坡,等.糖尿病患者脂肪間充質干細胞的分離培養與鑒定[J].山東醫藥,2014,54(42):17-19.

[57]Rennert RC,Sorkin M,Januszyk M,etal.Diabetes impairs the angiogenic potential of adipose-derived stem cells by selectively depleting cellularsubpopulations[J].Stem Cell Res Ther,2014,5(3):79.

[58]Ferrer-Lorente R,Bejar MT,Tous M,etal.Systems biology approach to identify alterations in the stem cell reservoir of subcutaneous adipose tissue in a rat model of diabetes:effects on differentiation potentialand function[J].Diabetologia,2014,57(1):246-256.

[59]Jumabay M,Moon JH,Yeerna H,et al.Effectof diabetes mellitus on adipocyte-derived stem cells in rat[J].J Cell Physiol,2015,230(11): 2821-2828.

Multilineage differentiation potential and application of dedifferentiated fat cells.

ZHANG Yang,XIAO Li-ling. Departmentof Plastic Surgery,the FirstAffiliated Hospitalof Jinan University,Guangzhou 510632,Guangdong,CHINA

Dedifferentiated fatcells(DFAT cells)derived from matured adipocytes,similar to stem cells,have multilineage differentiation potential.DFAT cells can be collected by ceiling culture in vitro.Under appropriate culture conditions for inducing differentiation,DFAT cells can transdifferentiate into adipocytes,osteoblasts,chondrocytes,endothelial cells,muscle cells,nerve cells and so on.Therefore,DFAT cells are considered as a potential resource for tissue engineering and stem celltherapy,which are widely used in various diseases and tissue damage repair studies.

Dedifferentiated fatcells(DFAT);Differentiation;Adipose-derived stem cells;Clinicalapplication

R329.2+8

A

1003—6350（2017）09—1458—05

10.3969/j.issn.1003-6350.2017.09.029

2016-07-27)

廣東省自然科學基金（編號：S2013010015264）

肖麗玲。E-mail：xlilin@live.cn